2	32827765	Amplification or overexpression of BET proteins has been identified in breast tumors highlighting their clinical significance.	('breast tumors', 'Phenotype', 'HP:0100013', (71, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('Amplification', 'Var', (0, 13))	('breast tumors', 'Disease', 'MESH:D001943', (71, 84))	('BET proteins', 'Protein', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('breast tumors', 'Disease', (71, 84))	('overexpression', 'PosReg', (17, 31))
13	32827765	During carcinogenesis, extensive epigenetic modifications occur, including aberrant acetylation and methylation patterns.	('aberrant', 'Var', (75, 83))	('acetylation', 'MPA', (84, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (7, 21))	('carcinogenesis', 'Disease', (7, 21))	('methylation patterns', 'MPA', (100, 120))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))
50	32827765	Depletion of BRD4 disrupted the E2-dependent transcription, mimicking JQ1 activity.	('BRD4', 'Gene', (13, 17))	('Depletion', 'Var', (0, 9))	('E2-dependent transcription', 'MPA', (32, 58))	('transcription', 'biological_process', 'GO:0006351', ('45', '58'))	('disrupted', 'NegReg', (18, 27))	('E2', 'Chemical', 'MESH:D004958', (32, 34))
53	32827765	Subsequently, WHSC1 methylates K36 on histone H3 so as to activate the transcription of ESR1, while estrogen binding to ERa stimulates the expression of WHSC1, creating a vicious cycle.	('WHSC1', 'Gene', (14, 19))	('transcription', 'biological_process', 'GO:0006351', ('71', '84'))	('stimulates', 'PosReg', (124, 134))	('activate', 'PosReg', (58, 66))	('methylates', 'Var', (20, 30))	('WHSC1', 'Gene', '7468', (14, 19))	('ESR1', 'Gene', '2099', (88, 92))	('ER', 'Gene', '2069', (120, 122))	('WHSC1', 'Gene', '7468', (153, 158))	('K36', 'Gene', '8689', (31, 34))	('estrogen binding', 'molecular_function', 'GO:0099130', ('100', '116'))	('expression', 'MPA', (139, 149))	('WHSC1', 'Gene', (153, 158))	('ESR1', 'Gene', (88, 92))	('K36', 'Gene', (31, 34))	('transcription', 'MPA', (71, 84))
55	32827765	As a result, JQ1 efficiently inhibited proliferation of tamoxifen-resistant ER + cell lines as well as that of four long-term estrogen deprived lines (mimicking aromatase inhibitor resistance), mainly by inducing prolonged G1 cell cycle arrest.	('inhibited', 'NegReg', (29, 38))	('arrest', 'Disease', (237, 243))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('226', '243'))	('JQ1', 'Var', (13, 16))	('proliferation', 'CPA', (39, 52))	('tamoxifen', 'Chemical', 'MESH:D013629', (56, 65))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (226, 243))	('inducing', 'Reg', (204, 212))	('ER', 'Gene', '2069', (76, 78))	('arrest', 'Disease', 'MESH:D006323', (237, 243))
57	32827765	Moreover, abundant BRD4 occupancy to MYC results in upregulation of MYC-related genes and drives resistance to mTOR inhibition BET inhibition reverses this BRD4-mediated resistance, sensitizing breast cells to mTOR inhibitors Furthermore, BRD3 is enriched at active ESR1 enhancers leading to significantly higher levels of transcription and E2 responsiveness.	('mTOR', 'Gene', (210, 214))	('ESR1', 'Gene', '2099', (266, 270))	('BRD4', 'Gene', (19, 23))	('occupancy', 'Var', (24, 33))	('BRD3', 'Gene', '8019', (239, 243))	('ESR1', 'Gene', (266, 270))	('mTOR', 'Gene', '2475', (210, 214))	('E2', 'Chemical', 'MESH:D004958', (341, 343))	('MYC', 'Gene', '4609', (37, 40))	('MYC', 'Gene', '4609', (68, 71))	('levels of transcription', 'MPA', (313, 336))	('higher', 'PosReg', (306, 312))	('transcription', 'biological_process', 'GO:0006351', ('323', '336'))	('mTOR', 'Gene', (111, 115))	('E2 responsiveness', 'MPA', (341, 358))	('upregulation', 'PosReg', (52, 64))	('mTOR', 'Gene', '2475', (111, 115))	('BRD3', 'Gene', (239, 243))	('MYC', 'Gene', (37, 40))	('MYC', 'Gene', (68, 71))
58	32827765	Overall, high expression of BRDs seems to correlate with poor overall survival in ER + breast cancer.	('overall', 'MPA', (62, 69))	('poor', 'NegReg', (57, 61))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('ER', 'Gene', '2069', (82, 84))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('BRDs', 'Protein', (28, 32))	('high', 'Var', (9, 13))
60	32827765	Providing in vivo evidence, JQ1-injected mice exhibited substantial decrease in uterine growth as a sign of reduced estrogen signaling.	('estrogen signaling', 'MPA', (116, 134))	('JQ1-injected', 'Var', (28, 40))	('reduced', 'NegReg', (108, 115))	('decrease', 'NegReg', (68, 76))	('mice', 'Species', '10090', (41, 45))	('uterine growth', 'CPA', (80, 94))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))
63	32827765	JQ1 inhibited growth of TNBC lines either of the basal-like (HCC1143, MDA-MB-468, HCC70) or of the claudin-low (MDA-MB-231, BT549, HCC38) population in several studies.	('HCC1143', 'CellLine', 'CVCL:1245', (61, 68))	('BT549', 'CellLine', 'CVCL:1092', (124, 129))	('growth', 'CPA', (14, 20))	('inhibited', 'NegReg', (4, 13))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (70, 80))	('JQ1', 'Var', (0, 3))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))
65	32827765	JQ1 induces cell cycle arrest at G1 phase, as indicated by the elevated p21, p27 and cyclin D1, D3 levels.	('cyclin D1, D3', 'Gene', '595;896', (85, 98))	('arrest', 'Disease', (23, 29))	('G1 phase', 'biological_process', 'GO:0051318', ('33', '41'))	('cyclin', 'molecular_function', 'GO:0016538', ('85', '91'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (12, 29))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('12', '29'))	('p21', 'Gene', (72, 75))	('arrest', 'Disease', 'MESH:D006323', (23, 29))	('p21', 'Gene', '644914', (72, 75))	('JQ1', 'Var', (0, 3))	('p27', 'Gene', '3429', (77, 80))	('elevated', 'PosReg', (63, 71))	('p27', 'Gene', (77, 80))
70	32827765	In consistence with these findings, either BCL-xL knockdown or combination of JQ1 and Obatoclax, an inhibitor of Bcl-2 family of proteins, reduced cell viability and increased the number of apoptotic cells.	('cell viability', 'CPA', (147, 161))	('increased', 'PosReg', (166, 175))	('knockdown', 'Var', (50, 59))	('BCL-xL', 'Gene', '598', (43, 49))	('Bcl-2', 'molecular_function', 'GO:0015283', ('113', '118'))	('reduced', 'NegReg', (139, 146))	('Bcl-2', 'Gene', (113, 118))	('Bcl-2', 'Gene', '596', (113, 118))	('BCL-xL', 'Gene', (43, 49))	('JQ1', 'Gene', (78, 81))
73	32827765	However, JQ1 attenuated the expression of many transcription factors, as Forkhead box M1 (FOXM1), Lim domain only 4 (LM04) and DEP domain containing 1 (DEPDC).	('attenuated', 'NegReg', (13, 23))	('FOXM1', 'Gene', '2305', (90, 95))	('Forkhead box M1', 'Gene', '2305', (73, 88))	('FOXM1', 'Gene', (90, 95))	('DEP domain containing 1', 'Gene', '55635', (127, 150))	('JQ1', 'Var', (9, 12))	('expression', 'MPA', (28, 38))	('Forkhead box M1', 'Gene', (73, 88))	('DEP domain containing 1', 'Gene', (127, 150))	('transcription', 'biological_process', 'GO:0006351', ('47', '60'))	('Lim domain only 4', 'Gene', (98, 115))	('Lim domain only 4', 'Gene', '8543', (98, 115))
78	32827765	However, LIN9 appears to be the most profound since knockdown of either FOXM1 or MYBL2 did not produce the same effect.	('FOXM1', 'Gene', (72, 77))	('LIN9', 'Gene', (9, 13))	('MYBL2', 'Gene', '4605', (81, 86))	('MYBL2', 'Gene', (81, 86))	('knockdown', 'Var', (52, 61))	('LIN9', 'Gene', '286826', (9, 13))	('FOXM1', 'Gene', '2305', (72, 77))
84	32827765	An AURKA inhibitor, MLN8237 (Alisertib) also exhibited the same antiproliferative activity with JQ1 in TNBC cells.	('antiproliferative', 'MPA', (64, 81))	('AURKA', 'Gene', (3, 8))	('MLN8237', 'Chemical', 'MESH:C550258', (20, 27))	('MLN8237', 'Var', (20, 27))	('Alisertib', 'Chemical', 'MESH:C550258', (29, 38))	('AURKA', 'Gene', '6790', (3, 8))
86	32827765	Moreover, JQ1 disrupts Twist and BRD4 interaction and Twist/BRD4/P-TEFb/RNA-PolII complex formation at the WNT5 promoter.	('Twist', 'Gene', (54, 59))	('BRD4', 'Protein', (33, 37))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('disrupts', 'NegReg', (14, 22))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('Twist', 'Gene', '7291', (23, 28))	('JQ1', 'Var', (10, 13))	('Twist', 'Gene', '7291', (54, 59))	('Twist', 'Gene', (23, 28))
90	32827765	In the same context, BRD4 is essential for basal epithelial phenotype by promoting the expression of epithelial-specific genes, such as TP63 gene and GRHL3, a transcription factor of the Grainyhead-like family.	('transcription factor', 'molecular_function', 'GO:0000981', ('159', '179'))	('promoting', 'PosReg', (73, 82))	('transcription', 'biological_process', 'GO:0006351', ('159', '172'))	('TP63', 'Gene', '8626', (136, 140))	('TP63', 'Gene', (136, 140))	('expression', 'MPA', (87, 97))	('BRD4', 'Var', (21, 25))	('GRHL3', 'Gene', (150, 155))	('GRHL3', 'Gene', '57822', (150, 155))
94	32827765	Homologous recombination (HR) efficiency and formation of single-stranded DNA by BRCA1 upon DNA damage are both impaired by BETi treatment Considering that BRCA1/2 mutated breast cancer patients demonstrated a better overall response rate to carboplatin in clinical trials, BETi treatment could synergize with platinum therapy.	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('platinum', 'Chemical', 'MESH:D010984', (310, 318))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('BETi', 'Chemical', '-', (124, 128))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('better', 'PosReg', (210, 216))	('BRCA1/2', 'Gene', (156, 163))	('breast cancer', 'Disease', (172, 185))	('carboplatin', 'Chemical', 'MESH:D016190', (242, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('mutated', 'Var', (164, 171))	('BETi', 'Chemical', '-', (274, 278))	('BRCA1/2', 'Gene', '672;675', (156, 163))	('Homologous recombination', 'biological_process', 'GO:0035825', ('0', '24'))	('patients', 'Species', '9606', (186, 194))
95	32827765	Not only BET inhibition leads to a BRCA-mutant like phenotype, but also BRCA1 mutation sensitizes TNBC tumors to BET inhibitors.	('sensitizes', 'Reg', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutation', 'Var', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA', 'Gene', '672', (72, 76))	('TNBC tumors', 'Disease', 'MESH:D009369', (98, 109))	('BRCA', 'Gene', (35, 39))	('BRCA', 'Gene', '672', (35, 39))	('BRCA', 'Gene', (72, 76))	('TNBC tumors', 'Disease', (98, 109))
99	32827765	As already established in prostate cancer, JQ1 disrupted interaction of BRD4 and androgen receptor (AR), providing an effect that could be exploited in AR + TNBC breast cancer treatment.	('BRD4', 'Gene', (72, 76))	('TNBC breast cancer', 'Disease', 'MESH:D001943', (157, 175))	('androgen receptor', 'Gene', '367', (81, 98))	('AR', 'Gene', '367', (100, 102))	('AR', 'Gene', '367', (152, 154))	('prostate cancer', 'Disease', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('disrupted', 'NegReg', (47, 56))	('TNBC breast cancer', 'Disease', (157, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('androgen receptor', 'Gene', (81, 98))	('JQ1', 'Var', (43, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('interaction', 'Interaction', (57, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))
100	32827765	Indeed, JQ1 demonstrated a dose-dependent antitumor efficacy in AR + TNBC cell lines and xenograft model, which was further enhanced by addition of enzalutamide in vitro but not in vivo.	('JQ1', 'Var', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('enzalutamide', 'Chemical', 'MESH:C540278', (148, 160))	('tumor', 'Disease', (46, 51))	('AR', 'Gene', '367', (64, 66))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
101	32827765	JQ1 did not directly downregulate AR expression, but rather inhibited interactions between ATAD2, a co-activator of AR, with BRD4 and AR complex, suppressing the transcription of AR-induced genes.	('ATAD2', 'Gene', '29028', (91, 96))	('AR', 'Gene', '367', (116, 118))	('transcription', 'biological_process', 'GO:0006351', ('162', '175'))	('inhibited', 'NegReg', (60, 69))	('AR', 'Gene', '367', (134, 136))	('transcription', 'MPA', (162, 175))	('interactions', 'Interaction', (70, 82))	('JQ1', 'Var', (0, 3))	('AR', 'Gene', '367', (34, 36))	('suppressing', 'NegReg', (146, 157))	('ATAD2', 'Gene', (91, 96))	('AR', 'Gene', '367', (179, 181))
102	32827765	Finally, BET inhibition disrupted hypoxia response and angiogenesis in triple negative breast cancer via downregulation of hypoxia-induced genes.	('hypoxia', 'Disease', 'MESH:D000860', (123, 130))	('downregulation', 'NegReg', (105, 119))	('inhibition', 'Var', (13, 23))	('angiogenesis', 'biological_process', 'GO:0001525', ('55', '67'))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('hypoxia', 'Disease', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('hypoxia', 'Disease', (34, 41))	('disrupted', 'NegReg', (24, 33))	('hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('angiogenesis', 'CPA', (55, 67))
103	32827765	JQ1 altered the expression of multiple hypoxia-induced genes, including hypoxia-inducible factor (HIF) genes, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A).	('vascular endothelial growth factor A', 'Gene', '7422', (141, 177))	('HIF', 'Disease', 'None', (98, 101))	('altered', 'Reg', (4, 11))	('hypoxia', 'Disease', (39, 46))	('hypoxia', 'Disease', 'MESH:D000860', (39, 46))	('vascular endothelial growth factor A', 'Gene', (141, 177))	('VEGF-A', 'Gene', '7422', (179, 185))	('VEGF-A', 'Gene', (179, 185))	('carbonic anhydrase 9', 'Gene', '768', (110, 130))	('CA9', 'Gene', (132, 135))	('hypoxia', 'Disease', (72, 79))	('hypoxia', 'Disease', 'MESH:D000860', (72, 79))	('JQ1', 'Var', (0, 3))	('HIF', 'Disease', (98, 101))	('CA9', 'Gene', '768', (132, 135))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('141', '175'))	('expression', 'MPA', (16, 26))	('carbonic anhydrase 9', 'Gene', (110, 130))
105	32827765	As far as metastatic ability is concerned, JQ1 reduced migration of two TNBC cell lines via impairing Jagged/Notch1 signaling pathway.	('migration', 'CPA', (55, 64))	('impairing', 'NegReg', (92, 101))	('signaling pathway', 'biological_process', 'GO:0007165', ('116', '133'))	('JQ1', 'Var', (43, 46))	('reduced', 'NegReg', (47, 54))	('Notch1', 'Gene', '4851', (109, 115))	('Notch1', 'Gene', (109, 115))
111	32827765	Clinical trials demonstrated an increased response to carboplatin in BRCA1/2 mutated TNBC population (41).	('BRCA1/2', 'Gene', (69, 76))	('TNBC', 'Gene', (85, 89))	('mutated', 'Var', (77, 84))	('BRCA1/2', 'Gene', '672;675', (69, 76))	('response to carboplatin', 'biological_process', 'GO:0097328', ('42', '65'))	('increased', 'PosReg', (32, 41))	('response', 'MPA', (42, 50))	('carboplatin', 'Chemical', 'MESH:D016190', (54, 65))
114	32827765	BET inhibition increased sensitivity of BRCA wild-type TNBC cells to treatment with Olaparib both in vitro and in vivo via inducing a BRCA mutant-like phenotype.	('Olaparib', 'Chemical', 'MESH:C531550', (84, 92))	('BRCA', 'Gene', '672', (134, 138))	('BRCA', 'Gene', (134, 138))	('sensitivity', 'MPA', (25, 36))	('mutant-like', 'Var', (139, 150))	('increased', 'PosReg', (15, 24))	('BRCA', 'Gene', '672', (40, 44))	('BRCA', 'Gene', (40, 44))	('inhibition', 'NegReg', (4, 14))	('inducing', 'Reg', (123, 131))
115	32827765	JQ1 attenuated proliferation of tamoxifen-resistant ER + cells at a greater extent comparing to parental cells, by reducing BRD3/4 recruitment to ERa promoter.	('tamoxifen', 'Chemical', 'MESH:D013629', (32, 41))	('ER', 'Gene', '2069', (146, 148))	('attenuated', 'NegReg', (4, 14))	('BRD3/4', 'Gene', '8019;23476', (124, 130))	('proliferation', 'CPA', (15, 28))	('BRD3/4', 'Gene', (124, 130))	('recruitment', 'MPA', (131, 142))	('JQ1', 'Var', (0, 3))	('reducing', 'NegReg', (115, 123))	('ER', 'Gene', '2069', (52, 54))
116	32827765	In addition to this, ENST00000456526 is a long noncoding RNA, namely LOL (lncRNA of luminal), which is overexpressed in luminal breast cancer.	('ENST00000456526', 'Var', (21, 36))	('luminal breast cancer', 'Disease', 'MESH:D001943', (120, 141))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('luminal', 'Chemical', 'MESH:D010634', (84, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('luminal breast cancer', 'Disease', (120, 141))	('luminal', 'Chemical', 'MESH:D010634', (120, 127))
125	32827765	Resistance to PI3K inhibition is often mediated by feedback activation of alternative tyrosine kinase receptors (RTKs), like AKT and mTOR pathways, despite the initial response.	('PI3K', 'Var', (14, 18))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))	('mTOR', 'Gene', '2475', (133, 137))	('activation', 'PosReg', (60, 70))	('mTOR', 'Gene', (133, 137))	('AKT', 'Pathway', (125, 128))
134	32827765	BET inhibition increased sensitivity to lapatinib in HER2+ cell lines and HER2+ xenograft models by decreasing lapatinib-induced MYC upregulation without affecting FOXO levels.	('sensitivity', 'MPA', (25, 36))	('HER2', 'Gene', (74, 78))	('lapatinib', 'Chemical', 'MESH:D000077341', (111, 120))	('MYC', 'Gene', '4609', (129, 132))	('HER2', 'Gene', (53, 57))	('increased', 'PosReg', (15, 24))	('inhibition', 'Var', (4, 14))	('HER2', 'Gene', '2064', (74, 78))	('HER2', 'Gene', '2064', (53, 57))	('lapatinib', 'Chemical', 'MESH:D000077341', (40, 49))	('MYC', 'Gene', (129, 132))	('decreasing', 'NegReg', (100, 110))
137	32827765	This resistance mechanism was blocked by BET inhibition through dissociation of BRD4 and thus RNA PolII from lapatinib-induced kinase genes.	('lapatinib', 'Chemical', 'MESH:D000077341', (109, 118))	('RNA', 'cellular_component', 'GO:0005562', ('94', '97'))	('dissociation', 'Var', (64, 76))	('BRD4', 'Gene', (80, 84))
139	32827765	On the other hand, inhibition of AKT suppresses FOXO3a phosphorylation, allowing its nuclear translocation and its interaction with BD2 domain of BRD4.	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('inhibition', 'Var', (19, 29))	('suppresses', 'NegReg', (37, 47))	('BD2', 'Gene', (132, 135))	('AKT', 'Pathway', (33, 36))	('FOXO3a', 'Gene', '2309', (48, 54))	('BD2', 'Gene', '1673', (132, 135))	('FOXO3a', 'Gene', (48, 54))	('phosphorylation', 'MPA', (55, 70))	('interaction', 'Interaction', (115, 126))	('nuclear translocation', 'MPA', (85, 106))	('BRD4', 'Gene', (146, 150))
151	32827765	Combination treatment with GSK2801 and JQ1 exhibited increased efficacy in a series of TNBC cell lines, by causing BRD2 dissociation from promoter and enhancer regions additionally to JQ-1-induced BRD4 loss.	('BRD4 loss', 'Disease', 'MESH:D014786', (197, 206))	('BRD4 loss', 'Disease', (197, 206))	('GSK2801', 'Var', (27, 34))	('GSK', 'molecular_function', 'GO:0050321', ('27', '30'))	('dissociation', 'MPA', (120, 132))	('BRD2', 'Gene', '6046', (115, 119))	('BRD2', 'Gene', (115, 119))	('GSK2801', 'Chemical', 'MESH:C000609271', (27, 34))
154	32827765	PIK3CA mutation is associated with resistance to BET inhibition.	('associated', 'Reg', (19, 29))	('resistance to BET inhibition', 'MPA', (35, 63))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))
155	32827765	A66, a PIK3CA inhibitor increased susceptibility to JQ1 treatment.	('PIK3CA', 'Gene', (7, 13))	('PIK3CA', 'Gene', '5290', (7, 13))	('increased', 'PosReg', (24, 33))	('susceptibility', 'MPA', (34, 48))	('A66', 'Var', (0, 3))
157	32827765	ABT737, an anti-BCL-xL molecule sensitized cells to JQ1 and enhanced its activity.	('ABT737', 'Var', (0, 6))	('ABT737', 'Chemical', 'MESH:C501332', (0, 6))	('activity', 'MPA', (73, 81))	('sensitized', 'Reg', (32, 42))	('enhanced', 'PosReg', (60, 68))	('BCL-xL', 'Gene', (16, 22))	('BCL-xL', 'Gene', '598', (16, 22))
159	32827765	Another mechanism of BETi resistance is the inactivation of the PP2A phosphatase tumor suppressor gene, which results in hyperphosphorylation of BRD4 and increased binding of BRD4 to MED1.	('binding', 'molecular_function', 'GO:0005488', ('164', '171'))	('inactivation', 'Var', (44, 56))	('MED1', 'Gene', '5469', (183, 187))	('PP2A', 'Gene', '5524', (64, 68))	('BRD4', 'Gene', (145, 149))	('phosphatase', 'molecular_function', 'GO:0016791', ('69', '80'))	('hyperphosphorylation', 'MPA', (121, 141))	('increased', 'PosReg', (154, 163))	('BETi', 'Chemical', '-', (21, 25))	('tumor', 'Disease', (81, 86))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('121', '141'))	('PP2A', 'Gene', (64, 68))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('BRD4', 'Protein', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('MED1', 'Gene', (183, 187))	('binding', 'Interaction', (164, 171))
164	32827765	Indeed, treatment with FGFR1 inhibitor PD173074 and JQ1 enhanced cytotoxic effect in ILC and IDC resistant cell lines.	('FGFR1', 'Gene', (23, 28))	('PD173074', 'Var', (39, 47))	('IDC', 'Disease', (93, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('PD173074', 'Chemical', 'MESH:C115711', (39, 47))	('FGFR1', 'Gene', '2260', (23, 28))	('JQ1', 'Gene', (52, 55))	('cytotoxic effect', 'CPA', (65, 81))	('ILC', 'Disease', (85, 88))	('enhanced', 'PosReg', (56, 64))
167	32827765	Silence of VDAC1 in breast cancer cell lines increased sensitivity to JQ1 treatment.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('increased', 'PosReg', (45, 54))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('VDAC1', 'Gene', (11, 16))	('VDAC1', 'Gene', '7416', (11, 16))	('sensitivity to JQ1 treatment', 'MPA', (55, 83))	('Silence', 'Var', (0, 7))
172	32827765	OTX015/MK-8628 (Birabresib) is a triazolothienodiazepine selective inhibitor of BRD2, BRD3, BRD4 which has exhibited efficacy in hematological malignancies and solid tumors Moreover, OTX015 exhibited antitumor activity in different triple negative breast cancer cell lines as a single agent or in combination with everolimus.	('hematological malignancies', 'Disease', (129, 155))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('solid tumors', 'Disease', 'MESH:D009369', (160, 172))	('triazolothienodiazepine', 'Chemical', '-', (33, 56))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('everolimus', 'Chemical', 'MESH:D000068338', (314, 324))	('MK-8628', 'Chemical', 'MESH:C000605331', (7, 14))	('BRD2', 'Gene', '6046', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('BRD3', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Birabresib', 'Chemical', 'MESH:C000605331', (16, 26))	('BRD2', 'Gene', (80, 84))	('BRD3', 'Gene', '8019', (86, 90))	('hematological malignancies', 'Disease', 'MESH:D019337', (129, 155))	('tumor', 'Disease', (166, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('hematological malignancies', 'Phenotype', 'HP:0004377', (129, 155))	('solid tumors', 'Disease', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('OTX015', 'Var', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (248, 261))	('tumor', 'Disease', (204, 209))	('breast cancer', 'Disease', (248, 261))
173	32827765	Concomitant treatment with OTX015 and everolimus was effective in TNBC xenograft models and also more potent than either monotherapy or paclitaxel.	('potent', 'MPA', (102, 108))	('TNBC', 'Disease', (66, 70))	('paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('OTX015', 'Var', (27, 33))	('everolimus', 'Chemical', 'MESH:D000068338', (38, 48))
190	32827765	INCB057643 is a BET inhibitor effective in AML, MM, DLBCL and CRPC xenograft models.	('INCB057643', 'Var', (0, 10))	('INCB057643', 'Chemical', '-', (0, 10))	('AML', 'Disease', 'MESH:D015470', (43, 46))	('AML', 'Disease', (43, 46))	('DLBCL', 'Disease', (52, 57))
196	32827765	Of 134 patients receiving INCB057643, 6 patients achieved objective response, with two patients exhibiting complete response (follicular lymphoma and relapsed AML), 4 patients exhibiting partial response (three patients with follicular lymphoma and one breast cancer patient in combination treatment with paclitaxel) and 27 patients achieved stable disease, 6 of whom remained on SD for more than six months.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('paclitaxel', 'Chemical', 'MESH:D017239', (305, 315))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('AML', 'Disease', 'MESH:D015470', (159, 162))	('breast cancer', 'Disease', (253, 266))	('lymphoma', 'Disease', (236, 244))	('patients', 'Species', '9606', (7, 15))	('patient', 'Species', '9606', (40, 47))	('patients', 'Species', '9606', (324, 332))	('AML', 'Disease', (159, 162))	('patients', 'Species', '9606', (211, 219))	('lymphoma', 'Disease', 'MESH:D008223', (236, 244))	('patient', 'Species', '9606', (7, 14))	('patient', 'Species', '9606', (167, 174))	('patient', 'Species', '9606', (87, 94))	('patient', 'Species', '9606', (324, 331))	('lymphoma', 'Disease', (137, 145))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('INCB057643', 'Var', (26, 36))	('patient', 'Species', '9606', (211, 218))	('one breast', 'Phenotype', 'HP:0012813', (249, 259))	('INCB057643', 'Chemical', '-', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('patient', 'Species', '9606', (267, 274))	('patients', 'Species', '9606', (40, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (236, 244))	('patients', 'Species', '9606', (167, 175))	('patients', 'Species', '9606', (87, 95))
210	32827765	INCB054329 exhibited a faster absorption and clearance rate and a shorter half-life than INCB057643.	('INCB057643', 'Chemical', '-', (89, 99))	('INCB054329', 'Var', (0, 10))	('INCB054329', 'Chemical', 'MESH:C000627927', (0, 10))	('absorption', 'MPA', (30, 40))	('clearance', 'MPA', (45, 54))	('faster', 'PosReg', (23, 29))
211	32827765	However, treatment with INCB054329 was characterized by high interpatient variability in drug clearance of the same drug doses.	('drug clearance', 'MPA', (89, 103))	('INCB054329', 'Chemical', 'MESH:C000627927', (24, 34))	('INCB054329', 'Var', (24, 34))	('patient', 'Species', '9606', (66, 73))
230	32827765	Another Phase I Study was designed to assess the combination of R06870810 BET inhibitor and Atezolizumab anti-PD-L1 antibody in advanced ovarian and triple negative breast cancer (NCT03292172).	('PD-L1', 'Gene', (110, 115))	('ovarian', 'Disease', (137, 144))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('Atezolizumab', 'Chemical', 'MESH:C000594389', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('antibody', 'cellular_component', 'GO:0019815', ('116', '124'))	('PD-L1', 'Gene', '29126', (110, 115))	('antibody', 'cellular_component', 'GO:0019814', ('116', '124'))	('antibody', 'molecular_function', 'GO:0003823', ('116', '124'))	('R06870810', 'Chemical', '-', (64, 73))	('R06870810', 'Var', (64, 73))	('antibody', 'cellular_component', 'GO:0042571', ('116', '124'))	('ovarian', 'Disease', 'MESH:D010049', (137, 144))
231	32827765	The same BET inhibitor R06870810 is explored in the two-part, Phase I trial with a dose escalation cohort in solid tumors and a dose expansion cohort in selected malignancies (NCT01987362).	('solid tumors', 'Disease', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('malignancies', 'Disease', 'MESH:D009369', (162, 174))	('R06870810', 'Var', (23, 32))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('R06870810', 'Chemical', '-', (23, 32))	('malignancies', 'Disease', (162, 174))
248	32827765	BMS-986158 is another potent BET inhibitor which caused >70% tumor inhibition in patient derived xenograft models (triple negative breast cancer, lung and colorectal).	('patient', 'Species', '9606', (81, 88))	('BMS-986158', 'Var', (0, 10))	('lung', 'Disease', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('tumor', 'Disease', (61, 66))
249	32827765	A Phase I/IIa trial is ongoing to assess BMS-986158 as monotherapy or in combination with nivolumab in selected advanced solid tumors (TNBC, SCLC, serous ovarian cancer BRCA1/2 wild type) and hematological malignancies (NCT02419417).	('ovarian cancer', 'Phenotype', 'HP:0100615', (154, 168))	('SCLC', 'Disease', (141, 145))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (147, 168))	('SCLC', 'Disease', 'MESH:D018288', (141, 145))	('BMS-986158', 'Var', (41, 51))	('hematological malignancies', 'Disease', (192, 218))	('BRCA1/2', 'Gene', (169, 176))	('solid tumors', 'Disease', 'MESH:D009369', (121, 133))	('hematological malignancies', 'Phenotype', 'HP:0004377', (192, 218))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('hematological malignancies', 'Disease', 'MESH:D019337', (192, 218))	('BRCA1/2', 'Gene', '672;675', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('solid tumors', 'Disease', (121, 133))	('serous ovarian cancer', 'Disease', (147, 168))	('nivolumab', 'Chemical', 'MESH:D000077594', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))
262	32827765	BI 894999 is a novel potent, selective BET inhibitor with a greater affinity to BRD4-BD2 bromodomain and an established efficacy in AML cell lines.	('BD2', 'Gene', '1673', (85, 88))	('BI 894999', 'Var', (0, 9))	('AML', 'Disease', (132, 135))	('BD2', 'Gene', (85, 88))	('AML', 'Disease', 'MESH:D015470', (132, 135))
279	32827765	Another BET degrader, BETd-246 effectively decreased BRD2, BRD3 and BRD4 protein levels and induced apoptosis in TNBC cell lines.	('BETd', 'Chemical', '-', (22, 26))	('induced', 'Reg', (92, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('BRD4 protein levels', 'MPA', (68, 87))	('BETd-246', 'Var', (22, 30))	('BRD3', 'Gene', (59, 63))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('BRD3', 'Gene', '8019', (59, 63))	('BRD2', 'Gene', (53, 57))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('BRD2', 'Gene', '6046', (53, 57))	('decreased', 'NegReg', (43, 52))
301	31467758	It is also associated with relatively increased likelihood of Her2 positivity and lower estrogen and progesterone receptor expression when compared with the classical ILC.	('Her2', 'Gene', '2064', (62, 66))	('progesterone receptor', 'Gene', '5241', (101, 122))	('progesterone receptor', 'Gene', (101, 122))	('lower estrogen and progesterone receptor expression', 'Phenotype', 'HP:0008233', (82, 133))	('positivity', 'Var', (67, 77))	('Her2', 'Gene', (62, 66))	('lower', 'NegReg', (82, 87))
333	31467758	Weak ER expression in an otherwise pure mucinous carcinoma should prompt one to perform an E-cadherin stain to rule out a pleomorphic lobular carcinoma.	('pure', 'molecular_function', 'GO:0034023', ('35', '39'))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('pleomorphic lobular carcinoma', 'Disease', 'MESH:D018275', (122, 151))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (40, 58))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (134, 151))	('E-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', '999', (91, 101))	('Weak', 'Var', (0, 4))	('mucinous carcinoma', 'Disease', (40, 58))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (40, 58))	('pleomorphic lobular carcinoma', 'Disease', (122, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
335	29600240	NACT induces tumor downstaging, increases rates of breast-conserving surgery (BCS), and also provides an opportunity to monitor the tumor's chemosensitivity in vivo.	('NACT', 'Chemical', '-', (0, 4))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('breast-conserving surgery', 'Disease', (51, 76))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('downstaging', 'NegReg', (19, 30))	('increases', 'PosReg', (32, 41))	('NACT', 'Var', (0, 4))
355	29600240	Because the majority of patients with ILC have low-grade ER-positive tumors, they are unlikely to derive significant benefit from NACT, thus efforts to develop reliable biomarkers that can identify the fraction of patients that truly derive benefit from cytotoxic agents.	('ILC', 'Disease', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('patients', 'Species', '9606', (214, 222))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('patients', 'Species', '9606', (24, 32))	('low-grade', 'Var', (47, 56))	('NACT', 'Chemical', '-', (130, 134))
368	23092107	Serum levels of CA125, CA19-9, LDH and estradiol were 30.1 U/ml, 5.5 U/ml, 182 IU/l, and 131 pg/ml, respectively.	('LDH', 'MPA', (31, 34))	('CA125', 'Gene', '94025', (16, 21))	('CA125', 'Gene', (16, 21))	('CA19-9', 'Var', (23, 29))	('estradiol', 'Chemical', 'MESH:D004958', (39, 48))
371	23092107	Immunohistochemical staining of the tumor was positive for estrogen receptor and cytokeratin 903 (34 beta E12), also suggestive of breast origin.	('breast origin', 'Disease', (131, 144))	('34 beta E12', 'Var', (98, 109))	('estrogen receptor', 'Protein', (59, 76))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('positive', 'Reg', (46, 54))	('tumor', 'Disease', (36, 41))
533	28589366	Conflicting evidence, from both randomized controlled trials (RCTs) and observational studies, regarding whether MRI improves surgical treatment or whether it simply leads to more mastectomies;;, has led to divergent interpretation of its impact and variability in its use as a pre-operative test for BC patients.	('BC', 'Phenotype', 'HP:0003002', (301, 303))	('patients', 'Species', '9606', (304, 312))	('mastectomies', 'Disease', (180, 192))	('pre', 'molecular_function', 'GO:0003904', ('278', '281'))	('improves', 'PosReg', (117, 125))	('MRI', 'Var', (113, 116))	('surgical treatment', 'CPA', (126, 144))
543	28589366	Two studies excluded patients with BRCA gene mutations;, otherwise this information was not explicitly reported.	('mutations', 'Var', (45, 54))	('excluded', 'NegReg', (12, 20))	('BRCA', 'Gene', (35, 39))	('patients', 'Species', '9606', (21, 29))	('BRCA', 'Gene', '672', (35, 39))
557	28589366	Of responding surgeons, 29% incorrectly indicated that MRI decreases the need for re-excision in patients undergoing breast conserving surgery and 41% did not believe that the likelihood of mastectomy was increased by pre-operative MRI.	('pre', 'molecular_function', 'GO:0003904', ('218', '221'))	('decreases', 'NegReg', (59, 68))	('MRI', 'Var', (55, 58))	('mastectomy', 'Disease', (190, 200))	('patients', 'Species', '9606', (97, 105))
568	28589366	The outcome associated with pre-operative MRI is an increased likelihood of receipt of mastectomy for the cancerous breast, and increased likelihood of contralateral prophylactic mastectomy, as surgical treatment in newly diagnosed BC patients.	('cancerous breast', 'Disease', (106, 122))	('cancerous breast', 'Disease', 'MESH:D001943', (106, 122))	('pre', 'molecular_function', 'GO:0003904', ('28', '31'))	('patients', 'Species', '9606', (235, 243))	('MRI', 'Var', (42, 45))	('BC', 'Phenotype', 'HP:0003002', (232, 234))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
579	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))
682	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))
1032	26998111	High TUBB3 positivity was associated with high tumor grade (P<0.0001), negativity for estrogen (P<0.0001) and progesterone receptors (P<0.004), as well as the presence of human epidermal growth factor 2 amplification (P<0.0001) and a triple-negative phenotype (P<0.0001).	('human', 'Species', '9606', (171, 176))	('High', 'Var', (0, 4))	('progesterone receptor', 'Gene', (110, 131))	('estrogen', 'Protein', (86, 94))	('positivity', 'Var', (11, 21))	('progesterone receptor', 'Gene', '5241', (110, 131))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('177', '200'))	('TUBB3', 'Gene', (5, 10))	('TUBB3', 'Gene', '10381', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
1043	26998111	High levels of TUBB3 expression have additionally been linked to poor clinical outcomes in non-small cell lung, gastric, breast and ovarian cancer, and to a reduced response to taxane-based microtubule-targeting anticancer drugs in these cancer types.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (121, 146))	('non-small cell lung', 'Disease', (91, 110))	('High levels', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('TUBB3', 'Gene', '10381', (15, 20))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('gastric', 'Disease', (112, 119))	('cancer', 'Disease', (140, 146))	('microtubule', 'cellular_component', 'GO:0005874', ('190', '201'))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('response to', 'MPA', (165, 176))	('reduced', 'NegReg', (157, 164))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('taxane', 'Chemical', 'MESH:C080625', (177, 183))	('TUBB3', 'Gene', (15, 20))
1046	26998111	For example, certain studies identified an association between high TUBB3 expression levels and high tumor grade, advanced tumor stage, negative hormone receptor state, human epidermal growth factor 2 (HER2) positivity and a triple-negative phenotype, while alternative studies were unable to confirm these results.	('TUBB3', 'Gene', '10381', (68, 73))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('175', '198'))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('HER2', 'Gene', (202, 206))	('human', 'Species', '9606', (169, 174))	('expression levels', 'MPA', (74, 91))	('high', 'Var', (63, 67))	('HER2', 'Gene', '2064', (202, 206))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('TUBB3', 'Gene', (68, 73))
1052	26998111	A custom-made semiautomatic robotic precision instrument was used to punch out one tissue cylinder (diameter, 0.6 mm) for each case, from representative tumor areas of each patient tissue block.	('punch', 'Var', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('semiautomatic robotic', 'Disease', (14, 35))	('semiautomatic robotic', 'Disease', 'None', (14, 35))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('patient', 'Species', '9606', (173, 180))
1072	26998111	If all breast cancer cases were jointly analyzed, a statistically significant association existed between low and high TUBB3 expression and shortened raw survival (P=0.0088; Fig.	('TUBB3', 'Gene', '10381', (119, 124))	('high', 'Var', (114, 118))	('shortened', 'NegReg', (140, 149))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('raw survival', 'MPA', (150, 162))	('breast cancer', 'Disease', (7, 20))	('expression', 'MPA', (125, 135))	('low', 'NegReg', (106, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('TUBB3', 'Gene', (119, 124))
1078	26998111	A high proliferation index (Ki67 labeling index; i.e., the % of Ki67-positive cancer cells per high power field) was associated with high TUBB3 immunostaining if all types of breast cancer were jointly analyzed (P<0.0001); however, subset analysis revealed that this association was primarily driven by BRE grade, as there was no statistically significant increase in cell proliferation rates within the subgroups of breast cancer cases of identical BRE grade (Fig.	('cell proliferation', 'biological_process', 'GO:0008283', ('368', '386'))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Disease', (175, 188))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (424, 430))	('TUBB3', 'Gene', (138, 143))	('high', 'Var', (133, 137))	('cancer', 'Disease', (182, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (417, 430))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('TUBB3', 'Gene', '10381', (138, 143))	('cancer', 'Disease', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (417, 430))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', (417, 430))	('cancer', 'Disease', (424, 430))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (424, 430))
1079	26998111	The results of the present study demonstrated that TUBB3 is frequently expressed in breast cancer cases, and is associated with adverse prognostic features, including a triple-negative hormone receptor status and the presence of HER2 amplification.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('HER2', 'Gene', (229, 233))	('TUBB3', 'Gene', (51, 56))	('presence', 'Reg', (217, 225))	('TUBB3', 'Gene', '10381', (51, 56))	('HER2', 'Gene', '2064', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('amplification', 'Var', (234, 247))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('associated', 'Reg', (112, 122))	('breast cancer', 'Disease', (84, 97))
1083	26998111	Despite variable thresholds for TUBB3 expression levels, these previous studies reported TUBB3 positivity in 34-62% of samples.	('TUBB3', 'Gene', '10381', (89, 94))	('TUBB3', 'Gene', (32, 37))	('TUBB3', 'Gene', '10381', (32, 37))	('reported', 'Reg', (80, 88))	('TUBB3', 'Gene', (89, 94))	('positivity', 'Var', (95, 105))
1088	26998111	The results of the present study are supported by those of previous studies, which reported increased levels of TUBB3 expression in grade 3 tumors, compared with those of grade 1 and 2 tumors, in hormone receptor-negative cancer compared with hormone receptor-positive cancer, in HER2 amplified cancer and in triple-negative cancer.	('tumors', 'Disease', (185, 191))	('cancer', 'Disease', (295, 301))	('increased', 'PosReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('HER2', 'Gene', (280, 284))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (325, 331))	('cancer', 'Disease', (222, 228))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Disease', (269, 275))	('levels', 'MPA', (102, 108))	('tumors', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('TUBB3', 'Gene', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('expression', 'MPA', (118, 128))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('HER2', 'Gene', '2064', (280, 284))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('amplified', 'Var', (285, 294))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('TUBB3', 'Gene', '10381', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
1094	26998111	Loss of E-cadherin induces epithelial mesenchymal transition, a significant event in the development of cancer.	('E-cadherin', 'Gene', (8, 18))	('induces', 'Reg', (19, 26))	('E-cadherin', 'Gene', '999', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('27', '60'))	('Loss', 'Var', (0, 4))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('epithelial mesenchymal transition', 'CPA', (27, 60))
1098	26998111	In the present study, TUBB3 expression was significantly associated with shortened survival when all 1,649 cancer cases were jointly analyzed.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('shortened', 'NegReg', (73, 82))	('expression', 'Var', (28, 38))	('TUBB3', 'Gene', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('TUBB3', 'Gene', '10381', (22, 27))	('cancer', 'Disease', (107, 113))	('survival', 'MPA', (83, 91))
1099	26998111	In a multivariate analysis including established prognosticators, the hazard ratio for overall survival was increased by expression of TUBB3, however, this was not dependent on the expression level in multivariate analysis.	('increased', 'PosReg', (108, 117))	('TUBB3', 'Gene', (135, 140))	('TUBB3', 'Gene', '10381', (135, 140))	('expression', 'Var', (121, 131))	('overall survival', 'MPA', (87, 103))
1105	26998111	Increased levels of TUBB3 have additionally been linked to adverse phenotypes and poor prognosis in various other types of solid cancer, including colon, prostate, lung, ovarian and neurological cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung', 'Disease', (164, 168))	('ovarian and neurological cancer', 'Disease', 'MESH:D010051', (170, 201))	('linked to', 'Reg', (49, 58))	('levels', 'Var', (10, 16))	('solid cancer', 'Disease', (123, 135))	('colon', 'Disease', (147, 152))	('neurological cancer', 'Phenotype', 'HP:0004375', (182, 201))	('prostate', 'Disease', (154, 162))	('Increased', 'PosReg', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('solid cancer', 'Disease', 'MESH:D009369', (123, 135))	('TUBB3', 'Gene', (20, 25))	('TUBB3', 'Gene', '10381', (20, 25))	('colon', 'Disease', 'MESH:D015179', (147, 152))
1124	30483806	Mutations of MUC1 were analyzed by the Catalogue of Somatic Mutations in Cancer and cBioPortal databases.	('MUC1', 'Gene', '4582', (13, 17))	('Mutations', 'Var', (0, 9))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MUC1', 'Gene', (13, 17))
1141	30483806	In addition, aberrant overexpression of MUC1 is associated with angiogenesis and chemoresistance in cancer.	('angiogenesis', 'biological_process', 'GO:0001525', ('64', '76'))	('overexpression', 'PosReg', (22, 36))	('MUC1', 'Gene', (40, 44))	('angiogenesis', 'CPA', (64, 76))	('associated', 'Reg', (48, 58))	('MUC1', 'Gene', '4582', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('chemoresistance', 'CPA', (81, 96))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('aberrant', 'Var', (13, 21))
1151	30483806	The COSMIC database , a high-resolution resource for investigating the influence of somatic mutations in all forms of human tumors, was used to analyze the mutations of MUC1.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mutations', 'Var', (156, 165))	('MUC1', 'Gene', (169, 173))	('MUC1', 'Gene', '4582', (169, 173))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (118, 123))
1152	30483806	An overview of the distribution and substitutions on the coding strand in breast cancer were depicted in a pie chart.	('breast cancer', 'Disease', (74, 87))	('substitutions', 'Var', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
1157	30483806	cBioPortal was also used to analyze the alteration frequency of MUC1 mutations in breast cancer.	('mutations', 'Var', (69, 78))	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('MUC1', 'Gene', (64, 68))	('MUC1', 'Gene', '4582', (64, 68))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
1168	30483806	The pie chart depicts that the mutant types of breast cancer were all missense substitutions (Fig.	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('missense substitutions', 'Var', (70, 92))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
1169	30483806	The breast cancer data contained A>G, C>T, G>T and T>C mutations, each accounting for 25% of the MUC1 coding strand (Fig.	('MUC1', 'Gene', (97, 101))	('MUC1', 'Gene', '4582', (97, 101))	('T>C mutations', 'Var', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('C>T', 'Var', (38, 41))	('breast cancer', 'Disease', (4, 17))	('G>T', 'Var', (43, 46))
1170	30483806	cBioPortal was used to evaluate the alteration frequency of MUC1 mutations in breast cancer, and <1.0% of the mutations were identified in patients with breast cancer (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('breast cancer', 'Disease', (78, 91))	('patients', 'Species', '9606', (139, 147))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('MUC1', 'Gene', (60, 64))	('MUC1', 'Gene', '4582', (60, 64))	('breast cancer', 'Disease', (153, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (65, 74))
1202	30483806	The present results revealed that the only type of mutation of MUC1 in the breast cancer data were missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('missense mutations', 'Var', (99, 117))	('MUC1', 'Gene', (63, 67))	('MUC1', 'Gene', '4582', (63, 67))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
1203	30483806	Furthermore, the alteration frequency of MUC1 in breast cancer is notably low.	('low', 'NegReg', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('alteration', 'Var', (17, 27))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('MUC1', 'Gene', (41, 45))	('MUC1', 'Gene', '4582', (41, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
1205	30483806	The results indicated a negative association between MUC1 expression and methylation status.	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('methylation status', 'Var', (73, 91))	('expression', 'MPA', (58, 68))	('MUC1', 'Gene', (53, 57))	('MUC1', 'Gene', '4582', (53, 57))	('negative', 'NegReg', (24, 32))
1206	30483806	Survival analysis revealed that overexpressed MUC1 associated significantly with reduced OS, RFS, and DSS time, which indicated that the mRNA level of MUC1 may be a valuable biomarker for the prognosis of patients with breast carcinoma.	('breast carcinoma', 'Phenotype', 'HP:0003002', (219, 235))	('DSS', 'Chemical', '-', (102, 105))	('patients', 'Species', '9606', (205, 213))	('DSS time', 'MPA', (102, 110))	('MUC1', 'Gene', (46, 50))	('MUC1', 'Gene', '4582', (46, 50))	('breast carcinoma', 'Disease', (219, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('breast carcinoma', 'Disease', 'MESH:D001943', (219, 235))	('MUC1', 'Gene', (151, 155))	('RFS', 'Disease', (93, 96))	('MUC1', 'Gene', '4582', (151, 155))	('overexpressed', 'Var', (32, 45))	('reduced', 'NegReg', (81, 88))	('RFS', 'Disease', 'MESH:D005198', (93, 96))
1397	33828068	The HER2 positivity rate in ILC cases, according to Almubarak et al, is 9%, and in our review, we found a very similar rate of 8.8%.	('positivity', 'Var', (9, 19))	('HER2', 'Gene', '2064', (4, 8))	('ILC', 'Disease', (28, 31))	('HER2', 'Gene', (4, 8))
1419	31249446	The role of endoscopy in the management of hereditary diffuse gastric cancer syndrome Hereditary diffuse gastric cancer (HDGC) syndrome is an inherited cancer risk syndrome associated with pathogenic germline CDH1 variants.	('CDH1', 'Gene', '999', (209, 213))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('hereditary diffuse gastric cancer syndrome', 'Disease', 'MESH:D013274', (43, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))	('cancer', 'Disease', (113, 119))	('variants', 'Var', (214, 222))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('gastric cancer (HDGC) syndrome', 'Disease', 'MESH:D013274', (105, 135))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('hereditary diffuse gastric cancer syndrome', 'Disease', (43, 85))	('CDH1', 'Gene', (209, 213))
1420	31249446	Given the high risk for developing diffuse gastric cancer, CDH1 carriers are recommended to undergo prophylactic total gastrectomy for cancer risk reduction.	('cancer', 'Disease', (135, 141))	('CDH1', 'Gene', '999', (59, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (43, 57))	('gastric cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('carriers', 'Var', (64, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (43, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('CDH1', 'Gene', (59, 63))
1421	31249446	Current guidelines recommend upper endoscopy in CDH1 carriers prior to surgery and then annually for individuals deferring prophylactic total gastrectomy.	('carriers', 'Var', (53, 61))	('CDH1', 'Gene', '999', (48, 52))	('CDH1', 'Gene', (48, 52))
1422	31249446	Management of individuals from HDGC families without CDH1 pathogenic variants remains less clear, and management of families with CDH1 pathogenic variants in the absence of a family history of gastric cancer is particularly problematic at present.	('CDH1', 'Gene', '999', (130, 134))	('gastric cancer', 'Disease', (193, 207))	('variants', 'Var', (69, 77))	('CDH1', 'Gene', '999', (53, 57))	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	('variants', 'Var', (146, 154))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('CDH1', 'Gene', (53, 57))	('CDH1', 'Gene', (130, 134))
1425	31249446	Herein, we review what is known and what remains unclear about endoscopic surveillance for HDGC, among individuals with and without germline CDH1 pathogenic variants.	('CDH1', 'Gene', (141, 145))	('variants', 'Var', (157, 165))	('CDH1', 'Gene', '999', (141, 145))	('HDGC', 'Disease', (91, 95))
1426	31249446	Core tip: Individuals with hereditary diffuse gastric cancer (HDGC) syndrome are at increased risk of diffuse gastric cancer, and are often recommended to undergo prophylactic total gastrectomy, especially in the presence of a pathogenic germline CDH1 variant.	('gastric cancer', 'Disease', (110, 124))	('CDH1', 'Gene', '999', (247, 251))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('increased risk of diffuse gastric cancer', 'Phenotype', 'HP:0006753', (84, 124))	('gastric cancer', 'Disease', (46, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('hereditary diffuse gastric cancer (HDGC) syndrome', 'Disease', 'MESH:D013274', (27, 76))	('variant', 'Var', (252, 259))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('CDH1', 'Gene', (247, 251))
1430	31249446	Pa-thogenic germline CDH1 variants have been associated with HDGC, although some families fulfilling HDGC clinical criteria do not have detectable germline variants.	('CDH1', 'Gene', '999', (21, 25))	('HDGC', 'Disease', (61, 65))	('associated', 'Reg', (45, 55))	('CDH1', 'Gene', (21, 25))	('variants', 'Var', (26, 34))
1432	31249446	The connection of CDH1 mutations to HDGC syndrome was first described in New Zealand, when Jones et al suspected genetic predisposition as the cause of a high rate of gastric cancer in three Maori families.	('HDGC syndrome', 'Disease', (36, 49))	('CDH1', 'Gene', (18, 22))	('gastric cancer', 'Disease', (167, 181))	('CDH1', 'Gene', '999', (18, 22))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('mutations', 'Var', (23, 32))	('HDGC syndrome', 'Disease', 'MESH:D013274', (36, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
1433	31249446	Since 1998, more than 120 different pathogenic variants of CDH1 have been described, and carrying a germline CDH1 pathogenic variant has been shown to portend a high risk of diffuse gastric cancer, characterized by signet ring cell carcinoma (SRCC) on histopathology, as well as lobular breast cancer in women.	('CDH1', 'Gene', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('gastric cancer', 'Disease', (182, 196))	('ring cell carcinoma', 'Disease', (222, 241))	('CDH1', 'Gene', '999', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))	('CDH1', 'Gene', (59, 63))	('ring cell carcinoma', 'Disease', 'MESH:D018279', (222, 241))	('lobular breast cancer', 'Disease', (279, 300))	('variant', 'Var', (125, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('variants', 'Var', (47, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('women', 'Species', '9606', (304, 309))	('lobular breast cancer', 'Disease', 'MESH:D013274', (279, 300))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (279, 300))	('CDH1', 'Gene', '999', (109, 113))
1434	31249446	Genetic testing for CDH1 variants is recommended for those who meet clinical criteria for HDGC.	('HDGC', 'Disease', (90, 94))	('CDH1', 'Gene', '999', (20, 24))	('variants', 'Var', (25, 33))	('CDH1', 'Gene', (20, 24))
1437	31249446	Testing for CDH1 should include both sequencing and deletion/duplication analysis, and is now commonly performed by numerous commercial laboratories.	('deletion/duplication analysis', 'Var', (52, 81))	('CDH1', 'Gene', (12, 16))	('CDH1', 'Gene', '999', (12, 16))
1438	31249446	Germline CDH1 pathogenic variants are found in approximately 25%-50% of families meeting HDGC criteria, though rates vary by ethnic background and country.	('pathogenic', 'Reg', (14, 24))	('variants', 'Var', (25, 33))	('CDH1', 'Gene', (9, 13))	('CDH1', 'Gene', '999', (9, 13))
1439	31249446	Those who meet testing criteria but do not have an identified CDH1 pathogenic variant pose their own challenges in management and risk stra-tification.	('CDH1', 'Gene', '999', (62, 66))	('CDH1', 'Gene', (62, 66))	('variant', 'Var', (78, 85))
1442	31249446	The lifetime risk of diffuse gastric cancer in individuals with a germline CDH1 pathogenic variant is reported to be up to 80%.	('CDH1', 'Gene', '999', (75, 79))	('variant', 'Var', (91, 98))	('gastric cancer', 'Disease', (29, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (29, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('CDH1', 'Gene', (75, 79))
1443	31249446	However, this high cumulative lifetime risk of diffuse gastric cancer may be an over-estimate, as the advent of multi-gene panel testing has identified a notable number of CDH1 pathogenic variants in families without a history of diffuse gastric cancer, suggesting reduced pe-netrance in some families.	('variants', 'Var', (188, 196))	('gastric cancer', 'Disease', (55, 69))	('CDH1', 'Gene', (172, 176))	('gastric cancer', 'Disease', (238, 252))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pathogenic', 'Reg', (177, 187))	('gastric cancer', 'Disease', 'MESH:D013274', (238, 252))	('CDH1', 'Gene', '999', (172, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (238, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))
1444	31249446	Currently, individuals with a germline CDH1 pathogenic variant are recommended to undergo prophylactic total gastrectomy, typically between the ages of 20-30.	('CDH1', 'Gene', (39, 43))	('variant', 'Var', (55, 62))	('CDH1', 'Gene', '999', (39, 43))
1447	31249446	For patients with a pathogenic germline CDH1 variant who undergo prophylactic total gastrectomy, baseline upper endoscopy is recommended prior to surgery to evaluate for gross tumor or other concomitant pathology that may alter the surgical approach.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('alter', 'Reg', (222, 227))	('tumor', 'Disease', (176, 181))	('CDH1', 'Gene', (40, 44))	('pathogenic', 'Reg', (20, 30))	('variant', 'Var', (45, 52))	('patients', 'Species', '9606', (4, 12))	('CDH1', 'Gene', '999', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
1453	31249446	Endoscopic detection of SRCC foci in CDH1 carriers is poor, and evaluation of surgical pathology demonstrates cancer foci in 45%-60% of those with negative endoscopic evaluations.	('cancer foci', 'Disease', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer foci', 'Disease', 'MESH:D009369', (110, 121))	('CDH1', 'Gene', (37, 41))	('carriers', 'Var', (42, 50))	('CDH1', 'Gene', '999', (37, 41))
1454	31249446	A model developed by Fujita et al eva-luated yield of cancer foci in a topographic pattern on 10 gastrectomy specimens from individuals with pathogenic germline CDH1 variants.	('cancer foci', 'Disease', 'MESH:D009369', (54, 65))	('CDH1', 'Gene', '999', (161, 165))	('variants', 'Var', (166, 174))	('cancer foci', 'Disease', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('CDH1', 'Gene', (161, 165))
1457	31249446	Unfortunately, the specific CDH1 variant itself does not aid in determining the potential location of SRCC or the probability of finding SRCC, especially given the vast number of CDH1 pathogenic variants that have been described.	('CDH1', 'Gene', (179, 183))	('variants', 'Var', (195, 203))	('CDH1', 'Gene', '999', (179, 183))	('CDH1', 'Gene', (28, 32))	('CDH1', 'Gene', '999', (28, 32))
1458	31249446	There is also limited data of the benefit of continued surveillance in CDH1 carriers.	('CDH1', 'Gene', (71, 75))	('carriers', 'Var', (76, 84))	('CDH1', 'Gene', '999', (71, 75))
1461	31249446	Based on a Japanese study, Shaw et al published a series in 2005 describing annual chromoendoscopic surveillance in 33 patients with a pathogenic CDH1 variant over a 5-year period.	('CDH1', 'Gene', '999', (146, 150))	('patients', 'Species', '9606', (119, 127))	('CDH1', 'Gene', (146, 150))	('variant', 'Var', (151, 158))
1467	31249446	Beyond careful white-light examination with targeted and random biopsies, electronic enhanced imaging techniques have not proven to be particularly valuable for diagnosis, screening or surveillance of patients with pathologic CDH1 gene mutations.	('CDH1', 'Gene', (226, 230))	('patients', 'Species', '9606', (201, 209))	('CDH1', 'Gene', '999', (226, 230))	('mutations', 'Var', (236, 245))
1470	31249446	To evaluate the utility of EUS in patients with HDGC due to a CDH1 pathogenic variant, a retrospective analysis of 13 patients who underwent radial scanning endosonography in addition to guideline-recommended upper endoscopy before gastrectomy found no benefit in performing endoscopic ultrasound to improve detection of cancer foci.	('cancer foci', 'Disease', 'MESH:D009369', (321, 332))	('CDH1', 'Gene', (62, 66))	('CDH1', 'Gene', '999', (62, 66))	('variant', 'Var', (78, 85))	('improve', 'PosReg', (300, 307))	('patients', 'Species', '9606', (34, 42))	('cancer foci', 'Disease', (321, 332))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('patients', 'Species', '9606', (118, 126))
1471	31249446	Although the majority of research on HDGC has focused on the role of upper endoscopic examination, there is limited evidence that there may be an association of colorectal SRCC in patients with germline CDH1 pathogenic variants.	('colorectal SRCC', 'Disease', (161, 176))	('CDH1', 'Gene', (203, 207))	('variants', 'Var', (219, 227))	('CDH1', 'Gene', '999', (203, 207))	('colorectal SRCC', 'Disease', 'MESH:D015179', (161, 176))	('association', 'Interaction', (146, 157))	('patients', 'Species', '9606', (180, 188))
1472	31249446	More recent work has also speculated that the CDH1 variant location may be an important predictor of colorectal cancer risk.	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('CDH1', 'Gene', (46, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('variant', 'Var', (51, 58))	('CDH1', 'Gene', '999', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))
1473	31249446	Although based on limited data, enhanced colorectal cancer screening by colonoscopy is recommended for CDH1 carriers with a family history of colon cancer, especially when there is a presence of signet ring cells and/or mucinous features of the cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('carriers', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('CDH1', 'Gene', (103, 107))	('colon cancer', 'Disease', (142, 154))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('colorectal cancer', 'Disease', (41, 58))	('cancer', 'Disease', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CDH1', 'Gene', '999', (103, 107))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
1474	31249446	In all other CDH1 carriers, standard colorectal cancer screening guidelines should be followed based on the individual's personal and/or family history.	('carriers', 'Var', (18, 26))	('colorectal cancer', 'Disease', (37, 54))	('CDH1', 'Gene', '999', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('CDH1', 'Gene', (13, 17))
1475	31249446	Individuals with a pathogenic variant of CDH1, but without family history of gastric cancer, pose a unique challenge.	('CDH1', 'Gene', '999', (41, 45))	('gastric cancer', 'Disease', (77, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('variant', 'Var', (30, 37))	('pathogenic', 'Reg', (19, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('CDH1', 'Gene', (41, 45))
1480	31249446	Recent studies regarding the management of lobular breast cancer, to which a pathogenic variant of CDH1 increased risk, in the absence of gastric cancer family history have been small, though informative.	('gastric cancer', 'Disease', (138, 152))	('lobular breast cancer', 'Disease', (43, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CDH1', 'Gene', '999', (99, 103))	('lobular breast cancer', 'Disease', 'MESH:D013274', (43, 64))	('variant', 'Var', (88, 95))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (43, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('CDH1', 'Gene', (99, 103))
1482	31249446	This has clinical consequences for the screening of breast cancer in those with a pathogenic variant of CDH1, though the need for gastrectomy in these individuals is similarly cloudy.	('CDH1', 'Gene', (104, 108))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('CDH1', 'Gene', '999', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('pathogenic', 'Reg', (82, 92))	('variant', 'Var', (93, 100))
1485	31249446	However, we would expect the sensitivity of endoscopy to be lacking, as it is in those with pathogenic variants of CDH1 and HDGC, and therefore a negative endoscopic examination should not be overly reassuring regarding gastric cancer risk.	('gastric cancer', 'Disease', 'MESH:D013274', (220, 234))	('gastric cancer', 'Phenotype', 'HP:0012126', (220, 234))	('CDH1', 'Gene', (115, 119))	('variants', 'Var', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('CDH1', 'Gene', '999', (115, 119))	('gastric cancer', 'Disease', (220, 234))	('HDGC', 'Gene', (124, 128))
1486	31249446	This is an area with much uncertainty that requires fur-ther research, especially in light of the growing preponderance of multi-gene panel testing with its resulting identification of incidental CDH1 variants in families without a history of CDH1-associated cancers.	('CDH1', 'Gene', '999', (196, 200))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('CDH1', 'Gene', (196, 200))	('cancers', 'Disease', (259, 266))	('variants', 'Var', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('fur-ther', 'Chemical', '-', (52, 60))	('CDH1', 'Gene', (243, 247))	('CDH1', 'Gene', '999', (243, 247))
1487	31249446	Individuals from families meeting HDGC criteria who lack a germline CDH1 pathogenic variant present a significant challenge as prophylactic total gastrectomy is typically not recommended for these individuals.	('variant', 'Var', (84, 91))	('CDH1', 'Gene', (68, 72))	('CDH1', 'Gene', '999', (68, 72))
1488	31249446	However, the yield of endoscopy for identifying malignant lesions is lower in those from families meeting HDGC criteria without a detectable CDH1 pathogenic variant.	('CDH1', 'Gene', (141, 145))	('variant', 'Var', (157, 164))	('CDH1', 'Gene', '999', (141, 145))	('lower', 'NegReg', (69, 74))
1489	31249446	This was demonstrated in a United Kingdom-based prospective cohort study of endoscopic surveillance in families with and without CDH1 pathogenic variants; patients with CDH1 pathogenic variants had significantly higher rates of SRCC on endoscopy than their CDH1 negative counterparts.	('CDH1', 'Gene', (257, 261))	('higher rates', 'PosReg', (212, 224))	('CDH1', 'Gene', '999', (257, 261))	('variants', 'Var', (185, 193))	('SRCC on', 'Disease', (228, 235))	('CDH1', 'Gene', (169, 173))	('CDH1', 'Gene', (129, 133))	('patients', 'Species', '9606', (155, 163))	('CDH1', 'Gene', '999', (169, 173))	('CDH1', 'Gene', '999', (129, 133))
1490	31249446	In this study, 85 individuals underwent endoscopic surveillance, including 54 patients (63.5%) with a CDH1 pathogenic variant opting to delay gastrectomy and 31 patients undergoing surveillance who were CDH1 negative.	('CDH1', 'Gene', '999', (102, 106))	('CDH1', 'Gene', (203, 207))	('variant', 'Var', (118, 125))	('CDH1', 'Gene', '999', (203, 207))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (161, 169))	('CDH1', 'Gene', (102, 106))
1492	31249446	Of those with CDH1 pathogenic variants, 33 (61.1%) had foci of SRCC detected during surveillance, the majority of which occurred at the index endoscopy.	('variants', 'Var', (30, 38))	('CDH1', 'Gene', (14, 18))	('CDH1', 'Gene', '999', (14, 18))	('pathogenic', 'Reg', (19, 29))	('SRCC', 'Disease', (63, 67))
1493	31249446	Those without a CDH1 pathogenic variant had a much lower detection rate of SRCC, 3 of 31 (9.7%) patients.	('CDH1', 'Gene', '999', (16, 20))	('variant', 'Var', (32, 39))	('SRCC', 'Disease', (75, 79))	('lower', 'NegReg', (51, 56))	('CDH1', 'Gene', (16, 20))	('patients', 'Species', '9606', (96, 104))
1497	31249446	Mi et al suggested that risk stratification using allelic expression imbalance (as a marker for progression to neoplasia) may be helpful to better determine the risk for these individuals.	('allelic expression imbalance', 'Var', (50, 78))	('neoplasia', 'Disease', 'MESH:D009369', (111, 120))	('neoplasia', 'Phenotype', 'HP:0002664', (111, 120))	('neoplasia', 'Disease', (111, 120))	('imbalance', 'Phenotype', 'HP:0002172', (69, 78))
1498	31249446	Ideally in the future, enhanced understanding of the genetic basis for HDGC families currently without detectable CDH1 pathogenic variants (such as via improved CDH1 variant detection or identification of additional gastric cancer risk genes) may enable better risk stratification in this population.	('CDH1', 'Gene', '999', (161, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (216, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('improved', 'PosReg', (152, 160))	('CDH1', 'Gene', (114, 118))	('CDH1', 'Gene', '999', (114, 118))	('gastric cancer', 'Disease', 'MESH:D013274', (216, 230))	('gastric cancer', 'Disease', (216, 230))	('CDH1', 'Gene', (161, 165))	('variant', 'Var', (166, 173))
1499	31249446	Currently, endoscopic surveillance at a referral center is suggested for individuals from families meeting HDGC criteria and who lack a CDH1 pathogenic variant.	('CDH1', 'Gene', '999', (136, 140))	('CDH1', 'Gene', (136, 140))	('variant', 'Var', (152, 159))
1501	31249446	Management of patients with HDGC, both with and without pathogenic variants in CDH1, remains challenging given our lack of understanding about the critical drivers of penetrance, differential anatomical location of SRCC, and the imperfect sensitivity of endoscopy to detect early foci of SRCC.	('patients', 'Species', '9606', (14, 22))	('CDH1', 'Gene', '999', (79, 83))	('variants', 'Var', (67, 75))	('CDH1', 'Gene', (79, 83))
1517	25283075	Although it has been suggested that low levels of E-cad are associated with poorer prognosis, its potential as a prognostic marker in ILC has not been clarified.	('low levels', 'Var', (36, 46))	('E-cad', 'Gene', (50, 55))	('E-cad', 'Gene', '999', (50, 55))	('ILC', 'Disease', (134, 137))
1540	25283075	Grade 2 ILC and IDC were compared for each of the following biomarker categories separately: ER+, Ki67low and HER2-.	('IDC', 'Gene', (16, 19))	('ER+', 'Disease', (93, 96))	('Ki67low', 'Var', (98, 105))	('HER2', 'Gene', (110, 114))	('HER2', 'Gene', '2064', (110, 114))	('IDC', 'Gene', '4000', (16, 19))
1541	25283075	Comparison was made between ILC and IDC grade 2 tumours with the favourable biomarker profile (ER+ and HER2- and Ki67low).	('IDC', 'Gene', (36, 39))	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('Ki67low', 'Var', (113, 120))	('ER+', 'Var', (95, 98))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('HER2', 'Gene', (103, 107))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('IDC', 'Gene', '4000', (36, 39))	('HER2', 'Gene', '2064', (103, 107))
1545	25283075	The number of cases with an unfavourable biomarker profile (ER-, HER2+ and Ki67high) was too small for separate analysis (n = 39).	('ER-', 'Var', (60, 63))	('HER2', 'Gene', (65, 69))	('Ki67high', 'Var', (75, 83))	('HER2', 'Gene', '2064', (65, 69))
1561	25283075	For each marker status (ER+, HER2-, Ki67low), respectively, there was a significantly higher risk of death from ILC compared to IDC.	('ER+', 'Var', (24, 27))	('HER2', 'Gene', (29, 33))	('Ki67low', 'Var', (36, 43))	('HER2', 'Gene', '2064', (29, 33))	('ILC', 'Disease', (112, 115))	('IDC', 'Gene', '4000', (128, 131))	('death', 'Disease', 'MESH:D003643', (101, 106))	('death', 'Disease', (101, 106))	('IDC', 'Gene', (128, 131))
1562	25283075	Similarly, risk of death from breast cancer for patients with grade 2 tumours expressing a complete favourable biomarker profile (ER+, HER2- and Ki67low) was higher for ILC than for IDC (HR: 2.16, 95% CI: 1.34-3.49).	('death', 'Disease', (19, 24))	('Ki67low', 'Var', (145, 152))	('HER2', 'Gene', (135, 139))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('ILC', 'Disease', (169, 172))	('tumours', 'Disease', (70, 77))	('IDC', 'Gene', '4000', (182, 185))	('breast cancer', 'Disease', (30, 43))	('HER2', 'Gene', '2064', (135, 139))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('IDC', 'Gene', (182, 185))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('patients', 'Species', '9606', (48, 56))	('ER+', 'Var', (130, 133))	('death', 'Disease', 'MESH:D003643', (19, 24))
1566	25283075	Table6 shows that risk of death from grade 2 breast cancer was higher for luminal A ILC, luminal B (HER2-) ILC and luminal B (HER2-) IDC compared to luminal A IDC.	('luminal', 'Var', (115, 122))	('death', 'Disease', 'MESH:D003643', (26, 31))	('IDC', 'Gene', '4000', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('luminal', 'Var', (89, 96))	('death', 'Disease', (26, 31))	('IDC', 'Gene', (133, 136))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('IDC', 'Gene', '4000', (159, 162))	('IDC', 'Gene', (159, 162))	('HER2', 'Gene', (126, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('HER2', 'Gene', (100, 104))	('HER2', 'Gene', '2064', (126, 130))	('HER2', 'Gene', '2064', (100, 104))
1576	25283075	A similar pattern was observed when the analyses were restricted to tumours with positive prognostic marker profiles (ER+, HER2- and Ki67low).	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('HER2', 'Gene', (123, 127))	('ER+', 'Var', (118, 121))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('Ki67low', 'Var', (133, 140))	('tumours', 'Disease', (68, 75))	('HER2', 'Gene', '2064', (123, 127))
1581	25283075	ER, HER2 and Ki67 are important prognostic and/or predictive markers.	('Ki67', 'Var', (13, 17))	('HER2', 'Gene', '2064', (4, 8))	('HER2', 'Gene', (4, 8))
1589	25283075	The loss of E-cad expression is shown to promote invasion and metastasis of epithelial cancers, including breast cancer.	('expression', 'Protein', (18, 28))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('E-cad', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('metastasis of epithelial cancers', 'Disease', 'MESH:D009362', (62, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('promote', 'PosReg', (41, 48))	('invasion', 'CPA', (49, 57))	('metastasis of epithelial cancers', 'Disease', (62, 94))	('E-cad', 'Gene', '999', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('loss', 'Var', (4, 8))
1620	32256585	Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('HER2', 'Gene', '2064', (62, 66))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('HER2', 'Gene', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
1621	32256585	In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes.	('patients', 'Species', '9606', (201, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('HER2-positive breast cancer', 'Disease', (173, 200))	('single-nucleotide polymorphisms', 'Var', (108, 139))	('HER2', 'Gene', (173, 177))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (173, 200))	('HER2', 'Gene', '2064', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('HER2', 'Gene', (154, 158))	('HER2', 'Gene', (69, 73))	('HER2', 'Gene', '2064', (154, 158))	('HER2', 'Gene', '2064', (69, 73))
1624	32256585	HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments.	('S310Y', 'Var', (39, 44))	('S310F', 'Var', (32, 37))	('HER2', 'Gene', (109, 113))	('D769H', 'Var', (53, 58))	('S310F', 'Mutation', 'rs1057519816', (32, 37))	('HER2', 'Gene', '2064', (109, 113))	('D769H', 'Mutation', 'rs121913468', (53, 58))	('R678Q', 'Mutation', 'rs1057519862', (46, 51))	('HER2', 'Gene', (0, 4))	('S310Y', 'Mutation', 'rs1057519816', (39, 44))	('I767M', 'Mutation', 'p.I767M', (63, 68))	('HER2', 'Gene', '2064', (0, 4))	('patients', 'Species', '9606', (14, 22))	('R678Q', 'Var', (46, 51))	('I767M', 'Var', (63, 68))
1625	32256585	Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib.	('D769Y', 'Mutation', 'rs121913468', (22, 27))	('D769Y', 'Var', (22, 27))	('neratinib', 'Chemical', 'MESH:C487932', (79, 88))	('benefits', 'PosReg', (55, 63))	('afatinib', 'Chemical', 'MESH:D000077716', (92, 100))	('L755S', 'Mutation', 'rs121913470', (13, 18))	('L755S', 'Var', (13, 18))
1626	32256585	By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab.	('D769Y', 'Mutation', 'rs121913468', (61, 66))	('trastuzumab', 'Chemical', 'MESH:D000068878', (95, 106))	('V842I', 'Chemical', '-', (44, 49))	('K753I', 'Mutation', 'p.K753I', (51, 56))	('patients', 'Species', '9606', (13, 21))	('D769Y', 'Var', (61, 66))	('V842I', 'Var', (44, 49))	('L755S', 'Var', (37, 42))	('L755S', 'Mutation', 'rs121913470', (37, 42))	('K753I', 'Var', (51, 56))
1627	32256585	Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I.	('Resistance to lapatinib', 'MPA', (0, 23))	('L755S', 'Mutation', 'rs121913470', (59, 64))	('K753I', 'Var', (77, 82))	('K753I', 'Mutation', 'p.K753I', (77, 82))	('V842I', 'Chemical', '-', (66, 71))	('patients', 'Species', '9606', (45, 53))	('reported', 'Reg', (33, 41))	('V842I', 'Var', (66, 71))	('L755S', 'Var', (59, 64))	('lapatinib', 'Chemical', 'MESH:D000077341', (14, 23))
1636	32256585	However, recent data suggest the presence of oncogenic mutations in HER2 affects clinical outcome in HER2-positive breast cancer patients.	('clinical', 'MPA', (81, 89))	('HER2-positive breast cancer', 'Disease', (101, 128))	('HER2', 'Gene', (101, 105))	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (129, 137))	('HER2', 'Gene', '2064', (101, 105))	('HER2', 'Gene', (68, 72))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (101, 128))	('HER2', 'Gene', '2064', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('affects', 'Reg', (73, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
1649	32256585	HER2 gene amplification, or protein overexpression, is still considered a major mechanism of HER2-driven tumorigenesis and is used as a main predictive biomarker to identify patients who might benefit from therapy with anti-HER2 agents.	('HER2', 'Gene', '2064', (93, 97))	('overexpression', 'PosReg', (36, 50))	('protein', 'Protein', (28, 35))	('HER2', 'Gene', '2064', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', (224, 228))	('HER2', 'Gene', '2064', (0, 4))	('tumor', 'Disease', (105, 110))	('gene amplification', 'Var', (5, 23))	('HER2', 'Gene', (93, 97))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
1652	32256585	Furthermore, HER2 mutations are identified in 4% of breast cancer patients; these mutations are independently associated with HER2 amplification status, occurring in both hormone receptor (HR)-positive/HER2-negative and HER2-positive.	('hormone receptor', 'Gene', '3164', (171, 187))	('hormone receptor', 'Gene', (171, 187))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('HR', 'Gene', '3164', (189, 191))	('HER2', 'Gene', (202, 206))	('HER2', 'Gene', (13, 17))	('associated', 'Reg', (110, 120))	('HER2', 'Gene', (220, 224))	('HER2', 'Gene', '2064', (13, 17))	('HER2', 'Gene', (126, 130))	('HER2', 'Gene', '2064', (202, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('HER2', 'Gene', '2064', (220, 224))	('HER2', 'Gene', '2064', (126, 130))	('amplification status', 'Var', (131, 151))	('patients', 'Species', '9606', (66, 74))
1653	32256585	Some authors suggest that the prevalence of HER2 mutations changes according to certain histological subtypes in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('mutations', 'Var', (49, 58))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('HER2', 'Gene', (44, 48))	('changes', 'Reg', (59, 66))	('HER2', 'Gene', '2064', (44, 48))
1655	32256585	Such mutations therefore undermine the clinical benefits of HER2-targeted treatment in HER2-positive breast cancer patients.	('HER2', 'Gene', '2064', (87, 91))	('patients', 'Species', '9606', (115, 123))	('HER2', 'Gene', (60, 64))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (87, 114))	('mutations', 'Var', (5, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('HER2', 'Gene', '2064', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('undermine', 'NegReg', (25, 34))	('HER2', 'Gene', (87, 91))	('HER2-positive breast cancer', 'Disease', (87, 114))
1656	32256585	Besides, different mutations in HER2 have been found in several tumors although their role in tumorigenesis is not fully understood.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (64, 69))	('HER2', 'Gene', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('HER2', 'Gene', '2064', (32, 36))	('found', 'Reg', (47, 52))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
1657	32256585	To assess the possible clinical implications of HER2 mutations in HER2-positive breast cancer patients, we here review the spectrum of single nucleotide polymorphisms (SNPs) produced in the HER2 gene.	('HER2', 'Gene', '2064', (48, 52))	('HER2', 'Gene', (190, 194))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (66, 93))	('HER2', 'Gene', '2064', (66, 70))	('patients', 'Species', '9606', (94, 102))	('HER2', 'Gene', '2064', (190, 194))	('single nucleotide polymorphisms', 'Var', (135, 166))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('HER2-positive breast cancer', 'Disease', (66, 93))	('HER2', 'Gene', (48, 52))	('HER2', 'Gene', (66, 70))
1658	32256585	Our working hypothesis was that recurrent mutations in specific HER2 domains in these patients could be good biomarkers of the efficacy of anti-HER2 therapy.	('HER2', 'Gene', (64, 68))	('HER2', 'Gene', (144, 148))	('HER2', 'Gene', '2064', (64, 68))	('HER2', 'Gene', '2064', (144, 148))	('mutations', 'Var', (42, 51))	('patients', 'Species', '9606', (86, 94))
1659	32256585	To identify mutations in the HER2 gene in HER2-positive breast cancer patients, two databases were searched: cBioPortal and COSMIC.	('HER2', 'Gene', '2064', (42, 46))	('patients', 'Species', '9606', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (12, 21))	('HER2', 'Gene', (29, 33))	('HER2', 'Gene', '2064', (29, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('HER2-positive breast cancer', 'Disease', (42, 69))	('HER2', 'Gene', (42, 46))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (42, 69))
1660	32256585	These websites provide information regarding the largest number of studies and HER2 mutations across different cancer types.	('HER2', 'Gene', '2064', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (84, 93))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('HER2', 'Gene', (79, 83))
1661	32256585	To identify mutations reoccurring in HER2-positive breast cancer, the following keywords were used: HER2+ BREAST CANCER, ER-HER2+ BREAST CANCER, and ER-PR-HER2+ BREAST CANCER.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('HER2', 'Gene', (37, 41))	('BREAST CANCER', 'Phenotype', 'HP:0003002', (130, 143))	('BREAST CANCER', 'Disease', (130, 143))	('CANCER', 'Phenotype', 'HP:0002664', (113, 119))	('BREAST CANCER', 'Phenotype', 'HP:0003002', (106, 119))	('BREAST CANCER', 'Phenotype', 'HP:0003002', (161, 174))	('CANCER', 'Phenotype', 'HP:0002664', (137, 143))	('CANCER', 'Phenotype', 'HP:0002664', (168, 174))	('HER2', 'Gene', (155, 159))	('HER2', 'Gene', '2064', (100, 104))	('HER2', 'Gene', '2064', (124, 128))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (37, 64))	('HER2', 'Gene', '2064', (37, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('HER2', 'Gene', '2064', (155, 159))	('HER2-positive breast cancer', 'Disease', (37, 64))	('mutations', 'Var', (12, 21))	('HER2', 'Gene', (100, 104))	('HER2', 'Gene', (124, 128))
1662	32256585	To obtain functional data for the different mutations, we also undertook a PubMed search for articles written in English using the keywords: BREAST CANCER, CANCER RISK, HER2/ERBB2, HER2 POSITIVE, HER2-TYROSINE KINASE DOMAIN, HER2, HER2-TRANSMEMBRANE DOMAIN, HER2-EXTRACELLULAR DOMAIN, and HER2 MUTATIONS.	('HER2', 'Gene', '2064', (169, 173))	('EXTRACELLULAR', 'cellular_component', 'GO:0005576', ('263', '276'))	('HER2', 'Gene', '2064', (231, 235))	('HER2', 'Gene', (258, 262))	('HER2', 'Gene', (289, 293))	('HER2', 'Gene', (225, 229))	('ERBB2', 'Gene', (174, 179))	('TYROSINE KINASE', 'Gene', (201, 216))	('HER2', 'Gene', '2064', (196, 200))	('HER2', 'Gene', '2064', (181, 185))	('HER2', 'Gene', (169, 173))	('HER2', 'Gene', (231, 235))	('ERBB2', 'Gene', '2064', (174, 179))	('TYROSINE KINASE', 'Gene', '7294', (201, 216))	('HER2', 'Gene', '2064', (258, 262))	('MUTATIONS', 'Var', (294, 303))	('HER2', 'Gene', '2064', (289, 293))	('CANCER', 'Phenotype', 'HP:0002664', (148, 154))	('BREAST CANCER', 'Disease', (141, 154))	('HER2', 'Gene', '2064', (225, 229))	('BREAST CANCER', 'Phenotype', 'HP:0003002', (141, 154))	('CANCER', 'Phenotype', 'HP:0002664', (156, 162))	('HER2', 'Gene', (196, 200))	('HER2', 'Gene', (181, 185))
1663	32256585	Mutations in the ERBB2 receptor described in this study according to the tumor type were found in invasive lobular carcinoma (ILC), invasive ductal carcinoma (IDC), and mixed ductal and lobular carcinoma (MDLC) (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (132, 157))	('ERBB2', 'Gene', (17, 22))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (107, 124))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (98, 124))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (186, 203))	('invasive ductal carcinoma', 'Disease', (132, 157))	('ERBB2', 'Gene', '2064', (17, 22))	('invasive lobular carcinoma', 'Disease', (98, 124))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (89, 94))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (141, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('lobular carcinoma', 'Disease', 'MESH:D018275', (107, 124))	('lobular carcinoma', 'Disease', 'MESH:D018275', (186, 203))	('tumor', 'Disease', (73, 78))	('lobular carcinoma', 'Disease', (186, 203))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))
1665	32256585	Seven of the eleven mutations were present in both types of carcinomas or even in mixed carcinomas (MDLC); however, some of these mutations are mainly found in IDC or others in ILC (Table 2).	('carcinomas', 'Disease', 'MESH:D009369', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Disease', 'MESH:D009369', (60, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('IDC', 'Disease', (160, 163))	('mutations', 'Var', (130, 139))	('carcinomas', 'Disease', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('found', 'Reg', (151, 156))	('carcinomas', 'Disease', (60, 70))
1666	32256585	Thus, mutations located mainly in IDC were D769H, V842I, K753E, R678Q, and S310F I655V.	('S310F', 'Var', (75, 80))	('I655V', 'SUBSTITUTION', 'None', (81, 86))	('V842I', 'Chemical', '-', (50, 55))	('V842I', 'Var', (50, 55))	('R678Q', 'Mutation', 'rs1057519862', (64, 69))	('R678Q', 'Var', (64, 69))	('I655V', 'Var', (81, 86))	('S310F', 'SUBSTITUTION', 'None', (75, 80))	('D769H', 'Mutation', 'rs121913468', (43, 48))	('K753E', 'Mutation', 'rs754652044', (57, 62))	('D769H', 'Var', (43, 48))	('K753E', 'Var', (57, 62))
1667	32256585	In the other side, mutations more prevalent in ILC were L755S, V777L, D769Y, and S310Y.	('D769Y', 'Var', (70, 75))	('S310Y', 'Var', (81, 86))	('L755S', 'Var', (56, 61))	('L755S', 'Mutation', 'rs121913470', (56, 61))	('D769Y', 'Mutation', 'rs121913468', (70, 75))	('V777L', 'Mutation', 'rs121913471', (63, 68))	('ILC', 'Disease', (47, 50))	('S310Y', 'Mutation', 'rs1057519816', (81, 86))	('prevalent', 'Reg', (34, 43))	('V777L', 'Var', (63, 68))
1668	32256585	Previous studies suggest that HER2 mutations are enriched in certain histological subtypes, as example, some authors have indicated that invasive lobular breast cancer (ILC), which composes about 15% of estrogen receptor- (ER-) positive subtype, the prevalence of HER2 mutations is higher (cBioPortal-21, 27, 56-ILC).	('HER2', 'Gene', (264, 268))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('estrogen receptor', 'Gene', (203, 220))	('mutations', 'Var', (269, 278))	('estrogen receptor', 'Gene', '2099', (203, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('HER2', 'Gene', (30, 34))	('invasive lobular breast cancer', 'Disease', (137, 167))	('HER2', 'Gene', '2064', (30, 34))	('invasive lobular breast cancer', 'Disease', 'MESH:D001943', (137, 167))	('HER2', 'Gene', '2064', (264, 268))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (146, 167))
1669	32256585	No quantitative analysis of the presence of specific mutations according to tumor type has been performed in this study, but the HER2 mutations described here located in IDC and ILC are in agreement with other studies.	('HER2', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('HER2', 'Gene', '2064', (129, 133))	('mutations', 'Var', (134, 143))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
1670	32256585	Interestingly, in silico analysis suggests that some HER2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes with estrogen receptor-positive, ERBB2 nonamplified primary lobular.	('primary ILC', 'Disease', (84, 95))	('mutations', 'Var', (58, 67))	('estrogen receptor', 'Gene', (202, 219))	('ERBB2', 'Gene', (230, 235))	('ERBB2', 'Gene', '2064', (230, 235))	('estrogen receptor', 'Gene', '2099', (202, 219))	('improve', 'PosReg', (172, 179))	('HER2', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (53, 57))	('patient', 'Species', '9606', (180, 187))
1671	32256585	Overall, more quantitative studies are needed for the identification of co-occurring and mutually exclusive HER2 mutations according to histology subtype in order to identify patient that could potentially be targeted with HER2-directed therapies.	('HER2', 'Gene', (108, 112))	('HER2', 'Gene', '2064', (223, 227))	('HER2', 'Gene', '2064', (108, 112))	('patient', 'Species', '9606', (175, 182))	('mutations', 'Var', (113, 122))	('HER2', 'Gene', (223, 227))
1672	32256585	Most mutations in the HER2 gene have been detected in exons 19 and 20 of the tyrosine kinase (TK) domain, at the C-alpha helix position of the protein (Table 2).	('C-alpha', 'Species', '342041', (113, 120))	('tyrosine kinase', 'Gene', (77, 92))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('HER2', 'Gene', (22, 26))	('mutations', 'Var', (5, 14))	('HER2', 'Gene', '2064', (22, 26))	('tyrosine kinase', 'Gene', '7294', (77, 92))
1673	32256585	Several authors propose that mutations in this domain could be an alternative mechanism to HER2 activation and affect sensitivity to anti-HER2 therapy, as an acquired resistance mechanism to this form of therapy.	('HER2', 'Gene', '2064', (138, 142))	('affect', 'Reg', (111, 117))	('mutations in', 'Var', (29, 41))	('HER2', 'Gene', (91, 95))	('HER2', 'Gene', '2064', (91, 95))	('activation', 'PosReg', (96, 106))	('HER2', 'Gene', (138, 142))
1674	32256585	The TKD mutations described to date in HER2+ breast cancer promote the activation of the functionality of the protein and increase the oncogenicity of HER2, besides inducing the phosphorylation of other cell signaling proteins (Table 2).	('phosphorylation', 'biological_process', 'GO:0016310', ('178', '193'))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inducing', 'Reg', (165, 173))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('phosphorylation', 'MPA', (178, 193))	('activation', 'PosReg', (71, 81))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('HER2', 'Gene', (39, 43))	('mutations', 'Var', (8, 17))	('breast cancer', 'Disease', (45, 58))	('HER2', 'Gene', '2064', (39, 43))	('functionality', 'MPA', (89, 102))	('HER2', 'Gene', (151, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('oncogenicity', 'MPA', (135, 147))	('HER2', 'Gene', '2064', (151, 155))	('increase', 'PosReg', (122, 130))
1675	32256585	This is because this domain contains the ATP binding site and its mutations are related to the enhanced phosphorylation of receptors HER2, HER3, and HER1, which causes receptor HER2 dimerization along with protein ERK (extracellular signal-regulated kinase) and AKT phosphorylation, with consequent activation of the PI3K/Akt and MAPK pathways, finally enhancing cell proliferation and angiogenesis (Figure 2).	('mutations', 'Var', (66, 75))	('PI3K', 'molecular_function', 'GO:0016303', ('317', '321'))	('activation', 'PosReg', (299, 309))	('HER1', 'Gene', (149, 153))	('AKT', 'Gene', (262, 265))	('causes', 'Reg', (161, 167))	('HER3', 'Gene', (139, 143))	('HER2', 'Gene', '2064', (177, 181))	('phosphorylation', 'MPA', (104, 119))	('dimerization', 'MPA', (182, 194))	('ERK', 'molecular_function', 'GO:0004707', ('214', '217'))	('enhanced', 'PosReg', (95, 103))	('extracellular signal-regulated kinase', 'Gene', (219, 256))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('HER2', 'Gene', '2064', (133, 137))	('Akt', 'Gene', (322, 325))	('HER1', 'Gene', '1956', (149, 153))	('extracellular signal-regulated kinase', 'Gene', '5594', (219, 256))	('AKT', 'Gene', '207', (262, 265))	('extracellular', 'cellular_component', 'GO:0005576', ('219', '232'))	('Akt', 'Gene', '207', (322, 325))	('ERK', 'Gene', '5594', (214, 217))	('ATP', 'Chemical', 'MESH:D000255', (41, 44))	('HER2', 'Gene', (177, 181))	('HER3', 'Gene', '2065', (139, 143))	('ATP binding', 'molecular_function', 'GO:0005524', ('41', '52'))	('angiogenesis', 'biological_process', 'GO:0001525', ('386', '398'))	('phosphorylation', 'biological_process', 'GO:0016310', ('266', '281'))	('phosphorylation', 'MPA', (266, 281))	('cell proliferation', 'biological_process', 'GO:0008283', ('363', '381'))	('angiogenesis', 'CPA', (386, 398))	('cell proliferation', 'CPA', (363, 381))	('enhancing', 'PosReg', (353, 362))	('HER2', 'Gene', (133, 137))	('MAPK', 'molecular_function', 'GO:0004707', ('330', '334'))	('MAPK pathways', 'Pathway', (330, 343))	('ERK', 'Gene', (214, 217))
1676	32256585	The binding site of ATP with the receptor protein forms a conformational structure with other important structures such as phosphate activation and binding loops, which could be affected by such modifications.	('modifications', 'Var', (195, 208))	('binding', 'molecular_function', 'GO:0005488', ('148', '155'))	('binding', 'Interaction', (4, 11))	('ATP', 'Chemical', 'MESH:D000255', (20, 23))	('phosphate activation', 'MPA', (123, 143))	('binding', 'Interaction', (148, 155))	('conformational structure', 'MPA', (58, 82))	('phosphate', 'Chemical', 'MESH:D010710', (123, 132))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
1677	32256585	Missense substitutions usually occur at the C-alpha helix, which is essential for HER2 protein activation.	('occur', 'Reg', (31, 36))	('HER2', 'Gene', (82, 86))	('HER2', 'Gene', '2064', (82, 86))	('Missense substitutions', 'Var', (0, 22))	('C-alpha', 'Species', '342041', (44, 51))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
1678	32256585	These alterations can promote tumorigenesis and phosphorylation of signaling proteins such as phospholipases gammaC1 and Cgamma (PLCgamma) MAPK.	('alterations', 'Var', (6, 17))	('promote', 'PosReg', (22, 29))	('MAPK', 'molecular_function', 'GO:0004707', ('139', '143'))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('phospholipases', 'Protein', (94, 108))	('phosphorylation', 'MPA', (48, 63))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('tumor', 'Disease', (30, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))
1679	32256585	Many of these activating mutations have proved resistant to anti-HER2, such as those found at codons 755 or 798.	('activating', 'PosReg', (14, 24))	('mutations', 'Var', (25, 34))	('HER2', 'Gene', (65, 69))	('HER2', 'Gene', '2064', (65, 69))
1680	32256585	Most authors have described the appearance of both intrinsic and acquired resistance to trastuzumab therapy in mutations L755S, V777L, D769Y, and K753E.	('intrinsic', 'MPA', (51, 60))	('D769Y', 'Var', (135, 140))	('K753E', 'Mutation', 'rs754652044', (146, 151))	('K753E', 'Var', (146, 151))	('L755S', 'Var', (121, 126))	('V777L', 'Var', (128, 133))	('L755S', 'Mutation', 'rs121913470', (121, 126))	('D769Y', 'Mutation', 'rs121913468', (135, 140))	('trastuzumab', 'Chemical', 'MESH:D000068878', (88, 99))	('V777L', 'Mutation', 'rs121913471', (128, 133))	('acquired resistance', 'MPA', (65, 84))
1681	32256585	All these mutations as well as D769H share the feature of sensitivity to the actions of the irreversible TK inhibitor, neratinib.	('D769H', 'Mutation', 'rs121913468', (31, 36))	('neratinib', 'Chemical', 'MESH:C487932', (119, 128))	('D769H', 'Var', (31, 36))	('sensitivity', 'MPA', (58, 69))
1684	32256585	Most authors agree that resistance to lapatinib, both intrinsic and acquired, appears in L755S, D769Y, V842I, and K753E.	('L755S', 'Mutation', 'rs121913470', (89, 94))	('lapatinib', 'Chemical', 'MESH:D000077341', (38, 47))	('K753E', 'Var', (114, 119))	('appears', 'Reg', (78, 85))	('K753E', 'Mutation', 'rs754652044', (114, 119))	('D769Y', 'Mutation', 'rs121913468', (96, 101))	('V842I', 'Chemical', '-', (103, 108))	('L755S', 'Var', (89, 94))	('V842I', 'Var', (103, 108))	('D769Y', 'Var', (96, 101))
1686	32256585	Moreover, depending on the changes produced by the amino acid substitutions, a protein conformation may arise that promotes either the active state of HER2's kinase domain impairing proper drug binding or this binding increases sensitivity toward the drug.	('amino acid substitutions', 'Var', (51, 75))	('impairing', 'NegReg', (172, 181))	('substitutions', 'Var', (62, 75))	('drug binding', 'molecular_function', 'GO:0008144', ('189', '201'))	('proper drug', 'MPA', (182, 193))	('binding', 'Interaction', (210, 217))	('binding', 'molecular_function', 'GO:0005488', ('210', '217'))	('sensitivity toward the drug', 'MPA', (228, 255))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('active state', 'MPA', (135, 147))	('increases', 'PosReg', (218, 227))	('HER2', 'Gene', (151, 155))	('promotes', 'PosReg', (115, 123))	('HER2', 'Gene', '2064', (151, 155))
1687	32256585	The L755S mutation is the most common in HER2 gene and is considered a hotspot mutation.	('L755S', 'Mutation', 'rs121913470', (4, 9))	('HER2', 'Gene', (41, 45))	('L755S', 'Var', (4, 9))	('HER2', 'Gene', '2064', (41, 45))
1691	32256585	As this mutation induces resistance to trastuzumab alone or in combination with pertuzumab, despite its location far from the drugs' binding sites on the receptor, it could be that kinase activity is so enhanced that it is able to continue signaling despite the nondimerization of the receptor after the binding of these drugs.	('continue signaling', 'MPA', (231, 249))	('induces', 'Reg', (17, 24))	('pertuzumab', 'Chemical', 'MESH:C485206', (80, 90))	('binding', 'molecular_function', 'GO:0005488', ('304', '311'))	('signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('enhanced', 'PosReg', (203, 211))	('kinase activity', 'molecular_function', 'GO:0016301', ('181', '196'))	('binding', 'molecular_function', 'GO:0005488', ('133', '140'))	('nondimerization', 'MPA', (262, 277))	('mutation', 'Var', (8, 16))	('resistance', 'MPA', (25, 35))	('trastuzumab', 'Chemical', 'MESH:D000068878', (39, 50))	('kinase activity', 'MPA', (181, 196))
1692	32256585	Resistance to lapatinib can be explained by the fact that Leu 755 participates in hydrophobic interactions with the C-alpha helix of the TKD in the active state of HER2, while in the inactive form, L755 is found far from this helix.	('Leu 755', 'Var', (58, 65))	('C-alpha', 'Species', '342041', (116, 123))	('participates', 'Reg', (66, 78))	('C-alpha helix', 'Protein', (116, 129))	('HER2', 'Gene', (164, 168))	('HER2', 'Gene', '2064', (164, 168))	('Leu', 'Chemical', 'MESH:D007930', (58, 61))	('hydrophobic interactions', 'MPA', (82, 106))	('lapatinib', 'Chemical', 'MESH:D000077341', (14, 23))
1693	32256585	The L755S polymorphism induces the appearance of polar interactions that stabilize the active form; this would help explain resistance to lapatinib, which only binds to the inactive conformation of HER2.	('HER2', 'Gene', (198, 202))	('lapatinib', 'Chemical', 'MESH:D000077341', (138, 147))	('active', 'MPA', (87, 93))	('HER2', 'Gene', '2064', (198, 202))	('L755S', 'Mutation', 'rs121913470', (4, 9))	('stabilize', 'Reg', (73, 82))	('polar interactions', 'MPA', (49, 67))	('L755S', 'Var', (4, 9))
1695	32256585	In effect, in vitro studies have shown the sensitivity of cells with the L755S mutation to afatinib plus neratinib.	('neratinib', 'Chemical', 'MESH:C487932', (105, 114))	('L755S', 'Var', (73, 78))	('L755S', 'Mutation', 'rs121913470', (73, 78))	('afatinib', 'Chemical', 'MESH:D000077716', (91, 99))	('sensitivity', 'MPA', (43, 54))
1696	32256585	Besides intrinsic resistance, mutation L755S has been associated with resistance acquired to trastuzumab therapy in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('resistance acquired', 'MPA', (70, 89))	('L755S', 'Var', (39, 44))	('L755S', 'Mutation', 'rs121913470', (39, 44))	('trastuzumab', 'Chemical', 'MESH:D000068878', (93, 104))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('associated', 'Reg', (54, 64))
1700	32256585	Residue V777L, located in exon 20 (at the C-terminal tail of the C-alpha helix), is involved in TK activity.	('C-alpha', 'Species', '342041', (65, 72))	('TK activity', 'MPA', (96, 107))	('V777L', 'Var', (8, 13))	('involved', 'Reg', (84, 92))	('V777L', 'Mutation', 'rs121913471', (8, 13))
1701	32256585	This activating mutation promotes the TK activity of HER2, increasing the phosphorylation of signaling proteins such as HER2, HER3, EGFR, and ERK, and the transformation of breast epithelial cells.	('phosphorylation', 'MPA', (74, 89))	('HER2', 'Gene', (53, 57))	('ERK', 'molecular_function', 'GO:0004707', ('142', '145'))	('HER2', 'Gene', '2064', (120, 124))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('HER3', 'Gene', '2065', (126, 130))	('EGFR', 'Gene', '1956', (132, 136))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('EGFR', 'molecular_function', 'GO:0005006', ('132', '136'))	('ERK', 'Gene', '5594', (142, 145))	('transformation', 'CPA', (155, 169))	('promotes', 'PosReg', (25, 33))	('HER2', 'Gene', (120, 124))	('increasing', 'PosReg', (59, 69))	('HER2', 'Gene', '2064', (53, 57))	('HER3', 'Gene', (126, 130))	('TK activity', 'MPA', (38, 49))	('mutation', 'Var', (16, 24))	('ERK', 'Gene', (142, 145))	('EGFR', 'Gene', (132, 136))
1702	32256585	This mutation causes transcriptional activation in most tumors affected by this mutation, which usually occurs independently of HER2 gene activation.	('HER2', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HER2', 'Gene', '2064', (128, 132))	('tumors', 'Disease', (56, 62))	('mutation', 'Var', (5, 13))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('transcriptional activation', 'MPA', (21, 47))	('mutation', 'Var', (80, 88))
1703	32256585	In effect, cases have been described in breast cancer cell lines in which increased endogenous expression levels of HER2 V777L activated signal transduction pathways, but this did not significantly increase tumor growth.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('increase tumor', 'Disease', (198, 212))	('breast cancer', 'Disease', (40, 53))	('V777L', 'Var', (121, 126))	('signal transduction pathways', 'Pathway', (137, 165))	('HER2', 'Gene', '2064', (116, 120))	('increase tumor', 'Disease', 'MESH:D006974', (198, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('signal transduction', 'biological_process', 'GO:0007165', ('137', '156'))	('increased', 'PosReg', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('HER2', 'Gene', (116, 120))	('V777L', 'Mutation', 'rs121913471', (121, 126))	('activated', 'PosReg', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('endogenous expression levels', 'MPA', (84, 112))
1704	32256585	The effects of V777L seem enhanced by mutations in the PIK3CA gene given that, in the presence of mutation PIK3CA E545K, V777L gives rise to enhanced interaction between p58 and HER3.	('V777L', 'Mutation', 'rs121913471', (15, 20))	('HER3', 'Gene', '2065', (178, 182))	('E545K', 'Mutation', 'rs104886003', (114, 119))	('V777L', 'Var', (121, 126))	('p58', 'Gene', (170, 173))	('p58', 'Gene', '984', (170, 173))	('PIK3CA', 'Gene', (107, 113))	('PIK3CA', 'Gene', (55, 61))	('V777L', 'Mutation', 'rs121913471', (121, 126))	('enhanced', 'PosReg', (141, 149))	('PIK3CA', 'Gene', '5290', (107, 113))	('PIK3CA', 'Gene', '5290', (55, 61))	('interaction', 'Interaction', (150, 161))	('E545K', 'Var', (114, 119))	('HER3', 'Gene', (178, 182))
1705	32256585	This suggests that reverse mutations of the HER2 gene could require other genetic alterations to promote cellular transformation and enhance interactions between signaling partners.	('enhance', 'PosReg', (133, 140))	('mutations', 'Var', (27, 36))	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('cellular transformation', 'CPA', (105, 128))	('interactions between', 'Interaction', (141, 161))	('HER2', 'Gene', (44, 48))	('HER2', 'Gene', '2064', (44, 48))	('promote', 'PosReg', (97, 104))
1707	32256585	Although the mutation has been associated in some preclinical studies with a diminished response to lapatinib, afatinib, and neratinib, several studies have shown reduced tumor growth and signaling activity in tumors with the V777L mutation treated with lapatinib.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('afatinib', 'Chemical', 'MESH:D000077716', (111, 119))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('lapatinib', 'Chemical', 'MESH:D000077341', (100, 109))	('V777L', 'Mutation', 'rs121913471', (226, 231))	('tumor', 'Disease', (210, 215))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('V777L', 'Var', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('response to lapatinib', 'biological_process', 'GO:0036274', ('88', '109'))	('lapatinib', 'Chemical', 'MESH:D000077341', (254, 263))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('reduced', 'NegReg', (163, 170))	('tumor', 'Disease', (171, 176))	('neratinib', 'Chemical', 'MESH:C487932', (125, 134))	('signaling activity', 'CPA', (188, 206))
1708	32256585	A response has been observed to combined treatment with neratinib and other drugs in patients with ER + V777L breast carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('patients', 'Species', '9606', (85, 93))	('breast carcinoma', 'Disease', 'MESH:D001943', (110, 126))	('breast carcinoma', 'Disease', (110, 126))	('neratinib', 'Chemical', 'MESH:C487932', (56, 65))	('ER + V777L', 'Var', (99, 109))	('V777L', 'Mutation', 'rs121913471', (104, 109))	('breast carcinoma', 'Phenotype', 'HP:0003002', (110, 126))
1711	32256585	As occurs with the L755S mutation, HER2 V777L shows strong activation of the receptor's kinase that could preserve its signaling activity even with trastuzumab and pertuzumab bound to the extracellular domain of the protein.	('HER2', 'Gene', (35, 39))	('V777L', 'Mutation', 'rs121913471', (40, 45))	('HER2', 'Gene', '2064', (35, 39))	('signaling activity', 'MPA', (119, 137))	('extracellular', 'cellular_component', 'GO:0005576', ('188', '201'))	('trastuzumab', 'Chemical', 'MESH:D000068878', (148, 159))	('L755S', 'Var', (19, 24))	('kinase', 'Enzyme', (88, 94))	('V777L', 'Var', (40, 45))	('L755S', 'Mutation', 'rs121913470', (19, 24))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('pertuzumab', 'Chemical', 'MESH:C485206', (164, 174))	('activation', 'PosReg', (59, 69))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))
1712	32256585	Interestingly, V777L and L755S mutants have been characterized using molecular dynamics simulations and in vitro studies in Ba/F3 cells expressing these mutants, showing that these mutants have a larger binding pocket volumes and therefore are more sensitive to tyrosine kinase inhibitors (TKIs) of quinazoline (afatinib and poziotinib) and indole (osimertinib and nazartinib) groups.	('V777L', 'Mutation', 'rs121913471', (15, 20))	('sensitive', 'MPA', (249, 258))	('nazartinib', 'Chemical', 'MESH:C000619734', (365, 375))	('tyrosine kinase', 'Gene', '7294', (262, 277))	('L755S', 'Var', (25, 30))	('L755S', 'Mutation', 'rs121913470', (25, 30))	('quinazoline', 'Chemical', 'MESH:D011799', (299, 310))	('binding', 'Interaction', (203, 210))	('poziotinib', 'Chemical', 'MESH:C557213', (325, 335))	('V777L', 'Var', (15, 20))	('more', 'PosReg', (244, 248))	('binding', 'molecular_function', 'GO:0005488', ('203', '210'))	('indole', 'Chemical', 'MESH:C030374', (341, 347))	('larger', 'PosReg', (196, 202))	('afatinib', 'Chemical', 'MESH:D000077716', (312, 320))	('tyrosine kinase', 'Gene', (262, 277))	('Ba/F3', 'CellLine', 'CVCL:0161', (124, 129))	('osimertinib', 'Chemical', '-', (349, 360))
1713	32256585	Furthermore, in preclinical models, poziotinib upregulates HER2 cell surface expression and potentiates the activity of T-DM1, inducing a complete tumor regression with combination treatment.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('activity', 'MPA', (108, 116))	('poziotinib', 'Var', (36, 46))	('poziotinib', 'Chemical', 'MESH:C557213', (36, 46))	('cell surface', 'cellular_component', 'GO:0009986', ('64', '76'))	('DM1', 'Gene', (122, 125))	('potentiates', 'PosReg', (92, 103))	('upregulates', 'PosReg', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('HER2', 'Gene', (59, 63))	('HER2', 'Gene', '2064', (59, 63))	('DM1', 'Gene', '1760', (122, 125))	('inducing', 'PosReg', (127, 135))
1714	32256585	The authors of this study suggest that poziotinib in combination with T-DMI could be a good candidate treatment for not only non-small cell lung cancer; in fact, one ongoing trial in phase II is studying the efficacy of poziotinib in metastatic breast cancer harboring HER2 mutations.	('poziotinib', 'Chemical', 'MESH:C557213', (39, 49))	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('HER2', 'Gene', (269, 273))	('HER2', 'Gene', '2064', (269, 273))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (125, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('T-DMI', 'Chemical', '-', (70, 75))	('poziotinib', 'Chemical', 'MESH:C557213', (220, 230))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (129, 151))	('mutations', 'Var', (274, 283))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('breast cancer', 'Disease', (245, 258))
1716	32256585	In SUMMIT trial, neratinib was most effective in breast cancer patients, with patients containing L755S and V777L, but the same mutations were associated with resistance in other cancer types, suggesting that more research is needed to identify the mechanism involved in tumor-type-specific sensitivities.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('patients', 'Species', '9606', (78, 86))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('cancer', 'Disease', (56, 62))	('associated', 'Reg', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('V777L', 'Mutation', 'rs121913471', (108, 113))	('V777L', 'Var', (108, 113))	('tumor', 'Disease', (271, 276))	('neratinib', 'Chemical', 'MESH:C487932', (17, 26))	('L755S', 'Var', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('L755S', 'Mutation', 'rs121913470', (98, 103))	('patients', 'Species', '9606', (63, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cancer', 'Disease', (179, 185))
1717	32256585	Recently, using isogenic knock-in HER2 mutations in ER + MCF7 cells and xenografts, two activating HER2 mutations located in the kinase domain (L755S and V777L) emerged as resistance to anti-ER therapy progression.	('L755S', 'Var', (144, 149))	('L755S', 'Mutation', 'rs121913470', (144, 149))	('V777L', 'Mutation', 'rs121913471', (154, 159))	('mutations', 'Var', (39, 48))	('MCF7', 'CellLine', 'CVCL:0031', (57, 61))	('HER2', 'Gene', (99, 103))	('activating', 'PosReg', (88, 98))	('HER2', 'Gene', (34, 38))	('HER2', 'Gene', '2064', (99, 103))	('HER2', 'Gene', '2064', (34, 38))	('V777L', 'Var', (154, 159))
1720	32256585	These data suggest that the prevalence of HER2 mutations might increase in metastatic ER+ breast cancer treated with anti-ER therapy, and these mutations are a distinct mechanism of acquired resistance to ER-directed therapy in metastatic breast cancer that could be solved by the treatment with an irreversible HER2 inhibitor.	('HER2', 'Gene', '2064', (42, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('increase', 'PosReg', (63, 71))	('breast cancer', 'Disease', (239, 252))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('HER2', 'Gene', (312, 316))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('HER2', 'Gene', '2064', (312, 316))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('HER2', 'Gene', (42, 46))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
1721	32256585	Overall, these data suggest that patients with ER+/HER2 mutations would benefit from HER2-targeted therapies in combination with hormonal therapy.	('mutations', 'Var', (56, 65))	('patients', 'Species', '9606', (33, 41))	('benefit', 'PosReg', (72, 79))	('HER2', 'Gene', (85, 89))	('HER2', 'Gene', (51, 55))	('HER2', 'Gene', '2064', (85, 89))	('HER2', 'Gene', '2064', (51, 55))
1723	32256585	Mutation V842I has been detected in various types of tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('V842I', 'Chemical', '-', (9, 14))	('V842I', 'Var', (9, 14))
1724	32256585	This is also an activating mutation associated with HER2 gene amplification and increased phosphorylation of different signaling proteins and also represents a hotspot in HER2.	('HER2', 'Gene', '2064', (52, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('increased', 'PosReg', (80, 89))	('HER2', 'Gene', (171, 175))	('HER2', 'Gene', '2064', (171, 175))	('amplification', 'Var', (62, 75))	('phosphorylation of different signaling proteins', 'MPA', (90, 137))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('HER2', 'Gene', (52, 56))
1725	32256585	The effects of V842I on the response to anti-HER2 therapy in patients with HER2+ breast cancer have not been yet explored.	('V842I', 'Var', (15, 20))	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('patients', 'Species', '9606', (61, 69))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', '2064', (45, 49))	('HER2', 'Gene', '2064', (75, 79))	('HER2', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('V842I', 'Chemical', '-', (15, 20))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
1726	32256585	Some in vitro studies indicate the resistance to trastuzumab and lapatinib of cell lines with this mutation.	('trastuzumab', 'Chemical', 'MESH:D000068878', (49, 60))	('lapatinib', 'Chemical', 'MESH:D000077341', (65, 74))	('resistance to trastuzumab', 'MPA', (35, 60))	('mutation', 'Var', (99, 107))
1728	32256585	However, given its recurrent expression in different tumor tissues and its association with amplification of the gene, studies are warranted to clarify its impact on the receptor's kinase activity.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('kinase activity', 'molecular_function', 'GO:0016301', ('181', '196'))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', (53, 58))
1729	32256585	The nonsynonymous mutations D769Y and D769H are among the most frequent somatic mutations of the HER2 gene.	('HER2', 'Gene', (97, 101))	('HER2', 'Gene', '2064', (97, 101))	('D769Y', 'Mutation', 'rs121913468', (28, 33))	('D769H', 'Mutation', 'rs121913468', (38, 43))	('D769H', 'Var', (38, 43))	('D769Y', 'Var', (28, 33))
1731	32256585	Both mutations have been characterized as activators in mammary epithelium cell lines, and in vivo studies have revealed neratinib as effective at blocking tumor growth in HER2+ breast carcinomas with these mutations.	('breast carcinomas', 'Disease', 'MESH:D001943', (178, 195))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('breast carcinomas', 'Disease', (178, 195))	('neratinib', 'Chemical', 'MESH:C487932', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutations', 'Var', (207, 216))	('breast carcinoma', 'Phenotype', 'HP:0003002', (178, 194))	('breast carcinomas', 'Phenotype', 'HP:0003002', (178, 195))	('tumor', 'Disease', (156, 161))	('HER2', 'Gene', (172, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))	('blocking', 'NegReg', (147, 155))	('HER2', 'Gene', '2064', (172, 176))
1732	32256585	Cases have been described of xenografts acquiring the D769Y mutation following treatment with trastuzumab, along with their subsequent resistance to trastuzumab and lapatinib, suggesting its possible role in acquired resistance to anti-HER2 therapy.	('D769Y', 'Mutation', 'rs121913468', (54, 59))	('HER2', 'Gene', (236, 240))	('trastuzumab', 'Chemical', 'MESH:D000068878', (149, 160))	('HER2', 'Gene', '2064', (236, 240))	('D769Y', 'Var', (54, 59))	('trastuzumab', 'Chemical', 'MESH:D000068878', (94, 105))	('lapatinib', 'Chemical', 'MESH:D000077341', (165, 174))
1733	32256585	In mutation D769Y, the change from aspartic acid to tyrosine could lead to changes in electrostatic interactions, due to the substitution of a negatively charged acid side chain at physiological pH with the capacity to form hydrogen bridges and bind phosphate groups.	('lead', 'Reg', (67, 71))	('changes', 'Reg', (75, 82))	('electrostatic interactions', 'MPA', (86, 112))	('D769Y', 'Var', (12, 17))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('hydrogen bridges', 'MPA', (224, 240))	('bind', 'Interaction', (245, 249))	('hydrogen', 'Chemical', 'MESH:D006859', (224, 232))	('phosphate', 'Chemical', 'MESH:D010710', (250, 259))	('aspartic acid', 'Chemical', 'MESH:D001224', (35, 48))	('D769Y', 'Mutation', 'rs121913468', (12, 17))
1734	32256585	As this mutation occurs at an important position for ATP binding to the receptor, this change could benefit this binding and thus diminish the impacts of lapatinib and neratinib therapy, whose mechanism of action is to impair this binding of ATP to HER2.	('ATP', 'Chemical', 'MESH:D000255', (242, 245))	('impacts', 'MPA', (143, 150))	('ATP', 'Chemical', 'MESH:D000255', (53, 56))	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('ATP binding', 'molecular_function', 'GO:0005524', ('53', '64'))	('impair', 'NegReg', (219, 225))	('HER2', 'Gene', (249, 253))	('diminish', 'NegReg', (130, 138))	('mutation', 'Var', (8, 16))	('lapatinib', 'Chemical', 'MESH:D000077341', (154, 163))	('binding', 'Interaction', (113, 120))	('ATP', 'Protein', (242, 245))	('neratinib', 'Chemical', 'MESH:C487932', (168, 177))	('binding', 'Interaction', (231, 238))	('binding', 'Interaction', (57, 64))	('benefit', 'PosReg', (100, 107))	('HER2', 'Gene', '2064', (249, 253))	('change', 'Var', (87, 93))	('binding', 'molecular_function', 'GO:0005488', ('231', '238'))
1735	32256585	The D769Y mutation promotes the phosphorylation of HER2, EGFR, HER3, and ERK and transformation of mammary epithelial cells.	('promotes', 'PosReg', (19, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('HER3', 'Gene', (63, 67))	('HER2', 'Gene', '2064', (51, 55))	('ERK', 'molecular_function', 'GO:0004707', ('73', '76'))	('ERK', 'Gene', (73, 76))	('HER3', 'Gene', '2065', (63, 67))	('D769Y', 'Mutation', 'rs121913468', (4, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGFR', 'Gene', '1956', (57, 61))	('HER2', 'Gene', (51, 55))	('D769Y', 'Var', (4, 9))	('phosphorylation', 'MPA', (32, 47))	('EGFR', 'Gene', (57, 61))	('transformation of mammary epithelial cells', 'CPA', (81, 123))	('ERK', 'Gene', '5594', (73, 76))
1736	32256585	Cell lines with this mutation display sensitivity to neratinib, in smaller measure to lapatinib and resistance to trastuzumab, although Nagano et al.	('sensitivity', 'MPA', (38, 49))	('neratinib', 'Chemical', 'MESH:C487932', (53, 62))	('lapatinib', 'Chemical', 'MESH:D000077341', (86, 95))	('mutation', 'Var', (21, 29))	('trastuzumab', 'Chemical', 'MESH:D000068878', (114, 125))	('lapatinib', 'MPA', (86, 95))
1738	32256585	Some authors report that loss of the acid side chain or addition of an aromatic ring to amino acid 769 could increase HER2's TK activity due to dimeric interactions between the kinase domains of HER2 and HER3.	('loss', 'Var', (25, 29))	('HER2', 'Gene', (118, 122))	('increase', 'PosReg', (109, 117))	('HER3', 'Gene', (204, 208))	('HER2', 'Gene', '2064', (118, 122))	('dimeric interactions', 'MPA', (144, 164))	('HER3', 'Gene', '2065', (204, 208))	('HER2', 'Gene', (195, 199))	('TK activity', 'MPA', (125, 136))	('HER2', 'Gene', '2064', (195, 199))	('acid', 'Protein', (37, 41))
1739	32256585	Mutations D769H/Y may enhance hydrophobic contacts and heterodimerization of HER2.	('heterodimerization', 'MPA', (55, 73))	('D769H', 'SUBSTITUTION', 'None', (10, 15))	('hydrophobic contacts', 'MPA', (30, 50))	('HER2', 'Gene', (77, 81))	('HER2', 'Gene', '2064', (77, 81))	('enhance', 'PosReg', (22, 29))	('D769H', 'Var', (10, 15))
1740	32256585	Besides, the D769H alteration could lead to activation within the HER2 monomer, adding hydrogen bonds to its own activation A-loop.	('lead to', 'Reg', (36, 43))	('HER2', 'Gene', '2064', (66, 70))	('activation', 'MPA', (44, 54))	('hydrogen', 'Chemical', 'MESH:D006859', (87, 95))	('D769H', 'Mutation', 'rs121913468', (13, 18))	('adding', 'PosReg', (80, 86))	('hydrogen bonds', 'MPA', (87, 101))	('D769H', 'Var', (13, 18))	('activation A-loop', 'MPA', (113, 130))	('HER2', 'Gene', (66, 70))
1741	32256585	Mutation K753E leads to a shift in charge of the amino acid's side chain, which goes from being basic to acidic, thus possibly affecting the electrostatic interactions of the protein.	('protein', 'Protein', (175, 182))	('shift', 'Reg', (26, 31))	('electrostatic interactions', 'MPA', (141, 167))	('K753E', 'Mutation', 'rs754652044', (9, 14))	('affecting', 'Reg', (127, 136))	('K753E', 'Var', (9, 14))	('charge', 'MPA', (35, 41))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))
1742	32256585	Several authors have related this mutation with lapatinib resistance, and this could be attributed to its close proximity with the L755S mutation which confers resistance to this drug.	('lapatinib', 'Chemical', 'MESH:D000077341', (48, 57))	('L755S', 'Var', (131, 136))	('lapatinib resistance', 'MPA', (48, 68))	('L755S', 'Mutation', 'rs121913470', (131, 136))	('related', 'Reg', (21, 28))
1743	32256585	Recently, the effect of this mutation has been observed in cell lines overexpressing HER2 K753E.	('K753E', 'Var', (90, 95))	('HER2', 'Gene', (85, 89))	('K753E', 'Mutation', 'rs754652044', (90, 95))	('HER2', 'Gene', '2064', (85, 89))
1744	32256585	In HER2 K753E mutant cells resistant to lapatinib, a greater affinity of the drug for the HER2 protein was observed compared to wild-type cells and other variants.	('HER2', 'Gene', '2064', (3, 7))	('HER2', 'Gene', (90, 94))	('HER2', 'Gene', '2064', (90, 94))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('K753E', 'Mutation', 'rs754652044', (8, 13))	('K753E', 'Var', (8, 13))	('affinity', 'Interaction', (61, 69))	('lapatinib', 'Chemical', 'MESH:D000077341', (40, 49))	('greater', 'PosReg', (53, 60))	('HER2', 'Gene', (3, 7))
1747	32256585	Following trastuzumab therapy, the appearance of K753E and L755S mutants could suggest their potential role as drivers of developing trastuzumab resistance during HER2+ tumor progression.	('L755S', 'Mutation', 'rs121913470', (59, 64))	('HER2', 'Gene', (163, 167))	('trastuzumab', 'Chemical', 'MESH:D000068878', (133, 144))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('K753E', 'Mutation', 'rs754652044', (49, 54))	('HER2', 'Gene', '2064', (163, 167))	('K753E', 'Var', (49, 54))	('trastuzumab', 'Chemical', 'MESH:D000068878', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('L755S', 'Var', (59, 64))
1748	32256585	Mutation I767M is a hotspot in gene HER2 identified in patients with HER2+ breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('I767M', 'Var', (9, 14))	('HER2', 'Gene', (36, 40))	('I767M', 'Mutation', 'p.I767M', (9, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('HER2', 'Gene', '2064', (36, 40))	('patients', 'Species', '9606', (55, 63))	('HER2', 'Gene', (69, 73))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('HER2', 'Gene', '2064', (69, 73))
1750	32256585	In the former cells, the presence of this mutation along with mutations in the genes PIK3CA and TP53 conferred a significant growth benefit over cells with the wild-type HER2 gene.	('HER2', 'Gene', (170, 174))	('HER2', 'Gene', '2064', (170, 174))	('TP53', 'Gene', (96, 100))	('PIK3CA', 'Gene', '5290', (85, 91))	('mutation', 'Var', (42, 50))	('growth', 'MPA', (125, 131))	('presence', 'Var', (25, 33))	('TP53', 'Gene', '7157', (96, 100))	('PIK3CA', 'Gene', (85, 91))
1751	32256585	Further, both the mutant and wild-type protein featured similar AKT and MAPK signaling levels, although the AKT pathway remained active over time for longer in the cells expressing HER2 I767M.	('AKT', 'Gene', '207', (108, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('72', '76'))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('I767M', 'Mutation', 'p.I767M', (186, 191))	('MAPK signaling levels', 'MPA', (72, 93))	('I767M', 'Var', (186, 191))	('AKT', 'Gene', (108, 111))	('AKT', 'Gene', '207', (64, 67))	('HER2', 'Gene', (181, 185))	('HER2', 'Gene', '2064', (181, 185))	('AKT', 'Gene', (64, 67))	('MAPK signaling', 'biological_process', 'GO:0000165', ('72', '86'))
1753	32256585	According to the data from COSMIC and cBioPortal, while other mutations in this kinase domain have been described (i.e., V797A, D808E, D873G, and M889I), there are still no data regarding their role in HER2+ breast cancer.	('D873G', 'Mutation', 'p.D873G', (135, 140))	('D808E', 'Var', (128, 133))	('M889I', 'Mutation', 'p.M889I', (146, 151))	('V797A', 'Var', (121, 126))	('M889I', 'Var', (146, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('V797A', 'Mutation', 'p.V797A', (121, 126))	('HER2', 'Gene', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('HER2', 'Gene', '2064', (202, 206))	('D808E', 'Mutation', 'rs146603731', (128, 133))	('breast cancer', 'Disease', (208, 221))	('D873G', 'Var', (135, 140))
1754	32256585	Several authors have described reoccurring mutations in this domain with a functional activating effect in different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('activating effect', 'PosReg', (86, 103))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
1756	32256585	In our search of mutations in the COSMIC and cBioPortal databases, we found two mutations, R678Q and V697L, present in HER2-positive breast carcinoma.	('breast carcinoma', 'Disease', (133, 149))	('R678Q', 'Mutation', 'rs1057519862', (91, 96))	('V697L', 'Var', (101, 106))	('V697L', 'Mutation', 'p.V697L', (101, 106))	('breast carcinoma', 'Disease', 'MESH:D001943', (133, 149))	('R678Q', 'Var', (91, 96))	('HER2', 'Gene', (119, 123))	('HER2', 'Gene', '2064', (119, 123))	('breast carcinoma', 'Phenotype', 'HP:0003002', (133, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
1757	32256585	In vitro studies indicate that R678Q is an activating mutation that confers sensitivity towards treatment with trastuzumab, lapatinib, afatinib, and neratinib (Table 2) and has been classified as a hotspot.	('lapatinib', 'Chemical', 'MESH:D000077341', (124, 133))	('sensitivity', 'MPA', (76, 87))	('R678Q', 'Mutation', 'rs1057519862', (31, 36))	('afatinib', 'Chemical', 'MESH:D000077716', (135, 143))	('trastuzumab', 'Chemical', 'MESH:D000068878', (111, 122))	('R678Q', 'Var', (31, 36))	('neratinib', 'Chemical', 'MESH:C487932', (149, 158))
1758	32256585	No functional data exist for mutation V697L, but it has been described as a mutational hotspot and data available for other cancer types suggest its oncogenic effect.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('V697L', 'Var', (38, 43))	('V697L', 'Mutation', 'p.V697L', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
1761	32256585	However, the data sources COSMIC and cBioPortal reveal that no mutations in this domain occur in HER2-positive breast cancer.	('mutations', 'Var', (63, 72))	('HER2-positive breast cancer', 'Disease', (97, 124))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (97, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))
1762	32256585	In the present study, we identified only one mutation, I655V (Table 2), in HER2-positive patients, which, according to Fleishman et al., involves an altered receptor conformation that renders it a constitutively activated state, promoting the homodimerization and autophosphorylation of HER2 and activation of the TK domain.	('homodimerization', 'MPA', (243, 259))	('I655V', 'Mutation', 'rs1136201', (55, 60))	('altered', 'Reg', (149, 156))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', (287, 291))	('promoting', 'PosReg', (229, 238))	('HER2', 'Gene', '2064', (75, 79))	('patients', 'Species', '9606', (89, 97))	('HER2', 'Gene', '2064', (287, 291))	('TK domain', 'MPA', (314, 323))	('autophosphorylation', 'MPA', (264, 283))	('activation', 'PosReg', (296, 306))	('I655V', 'Var', (55, 60))
1763	32256585	found, among patients in Indian hospitals, a positive significant association between HER2 I655V and the susceptibility of developing breast cancer, while other authors have detected negative correlation when examining patients in Brazil.	('HER2', 'Gene', (86, 90))	('HER2', 'Gene', '2064', (86, 90))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('patients', 'Species', '9606', (13, 21))	('I655V', 'Var', (91, 96))	('I655V', 'Mutation', 'rs1136201', (91, 96))	('patients', 'Species', '9606', (219, 227))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
1764	32256585	A meta-analysis conducted in 2019 revealed the impacts of ethnicity on the association between mutation HER2 I655V and breast cancer risk, observing positive correlation in Asia and Africa but not the other continents.	('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))	('I655V', 'Var', (109, 114))	('HER2', 'Gene', (104, 108))	('I655V', 'Mutation', 'rs1136201', (109, 114))	('HER2', 'Gene', '2064', (104, 108))	('association', 'Interaction', (75, 86))
1766	32256585	In some studies, disease-free survival (DFS) and delayed DFS (DDFS) were improved in patients with this mutation and the genotypes HER2 Val/Val or Val/Ile compared to the genotype Ile/Ile.	('delayed DFS', 'MPA', (49, 60))	('HER2', 'Gene', (131, 135))	('disease-free survival', 'CPA', (17, 38))	('HER2', 'Gene', '2064', (131, 135))	('improved', 'PosReg', (73, 81))	('patients', 'Species', '9606', (85, 93))	('Val/Val', 'Var', (136, 143))	('mutation', 'Var', (104, 112))	('Val/Ile', 'Var', (147, 154))
1769	32256585	The effect of trastuzumab and other antibodies may be limited in tumors that show mutations in the TMD, as HER2 dimerization seems stable despite trastuzumab binding to its extracellular domain.	('binding', 'molecular_function', 'GO:0005488', ('158', '165'))	('HER2', 'Gene', '2064', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TMD', 'Disease', (99, 102))	('trastuzumab', 'Chemical', 'MESH:D000068878', (14, 25))	('tumors', 'Disease', (65, 71))	('mutations', 'Var', (82, 91))	('dimerization', 'MPA', (112, 124))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('trastuzumab', 'Chemical', 'MESH:D000068878', (146, 157))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('TMD', 'Disease', 'MESH:D049310', (99, 102))	('extracellular', 'cellular_component', 'GO:0005576', ('173', '186'))	('HER2', 'Gene', (107, 111))	('binding', 'Interaction', (158, 165))
1770	32256585	Neratinib, which binds to the HER2 receptor's kinase domain and inhibits its phosphorylation and activity, can exert antitumor effects irrespective of the domain affected by mutations and has an impact on this HER2 I655V mutation in different lung cancer cell lines.	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('activity', 'MPA', (97, 105))	('I655V', 'Mutation', 'rs1136201', (215, 220))	('HER2', 'Gene', (30, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('HER2', 'Gene', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Disease', (121, 126))	('I655V', 'Var', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('phosphorylation', 'MPA', (77, 92))	('lung cancer', 'Disease', (243, 254))	('HER2', 'Gene', '2064', (30, 34))	('Neratinib', 'Chemical', 'MESH:C487932', (0, 9))	('HER2', 'Gene', '2064', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('impact', 'Reg', (195, 201))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('inhibits', 'NegReg', (64, 72))
1772	32256585	Despite initial proposals that being a carrier of the mutant allele, genotypes HER2 Val/Val or Val/Ile, was a possible predictor of this adverse effect of the drug, this relation could not be later confirmed.	('mutant', 'Var', (54, 60))	('HER2', 'Gene', '2064', (79, 83))	('carrier', 'molecular_function', 'GO:0005215', ('39', '46'))	('HER2', 'Gene', (79, 83))
1775	32256585	Several mutations in the ECD domain have been described in patients with HER2-positive breast cancer both in PubMed and the databases COSMIC and cBioPortal, as described below.	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (73, 100))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (59, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('HER2-positive breast cancer', 'Disease', (73, 100))
1776	32256585	The most common mutations in the ECD of the HER2 receptor, S310F and S310Y, corresponding to the gene hotspot (Table 2), have been related to the increased dimerization of the receptor, kinase activation, and malignant cell transformation.	('kinase activation', 'MPA', (186, 203))	('S310Y', 'Mutation', 'rs1057519816', (69, 74))	('malignant cell transformation', 'CPA', (209, 238))	('increased', 'PosReg', (146, 155))	('S310F', 'Var', (59, 64))	('dimerization', 'MPA', (156, 168))	('HER2', 'Gene', (44, 48))	('S310Y', 'Var', (69, 74))	('HER2', 'Gene', '2064', (44, 48))	('S310F', 'Mutation', 'rs1057519816', (59, 64))
1777	32256585	Of the two, S310F has been most studied in different tumor tissues (both HER2-positive breast and HER2-negative lobular breast, lung, colorectal, ovarian, bladder, micropapillary urothelial, and endometrial) while S310Y has been more commonly associated with pulmonary adenocarcinoma while it has been also found in HER2-positive and HER2-negative breast cancer.	('HER2', 'Gene', '2064', (73, 77))	('HER2', 'Gene', (316, 320))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('S310Y', 'Mutation', 'rs1057519816', (214, 219))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (259, 283))	('breast cancer', 'Phenotype', 'HP:0003002', (348, 361))	('colorectal, ovarian, bladder, micropapillary urothelial', 'Disease', 'MESH:D001749', (134, 189))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (259, 283))	('HER2', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('pulmonary adenocarcinoma', 'Disease', (259, 283))	('breast cancer', 'Disease', 'MESH:D001943', (348, 361))	('HER2', 'Gene', (334, 338))	('HER2', 'Gene', (73, 77))	('breast cancer', 'Disease', (348, 361))	('HER2', 'Gene', '2064', (316, 320))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('S310Y', 'Var', (214, 219))	('associated', 'Reg', (243, 253))	('S310F', 'Mutation', 'rs1057519816', (12, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('HER2', 'Gene', '2064', (98, 102))	('tumor', 'Disease', (53, 58))	('HER2', 'Gene', '2064', (334, 338))
1778	32256585	The fact that mutations in this position are present in different cancers suggests it could be an oncogenic mutation.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('mutations', 'Var', (14, 23))
1779	32256585	They are therefore mutations that activate HER2 protein via elevated phosphorylation of the C-terminal tail, as is the case of mutation S310F/Y, or inducing covalent dimerization sustained by intermolecular disulfide bridges, as in the case of mutations G309E/A, only described in HER2-negative breast cancer and other cancers.	('breast cancer', 'Disease', (295, 308))	('elevated', 'PosReg', (60, 68))	('cancers', 'Phenotype', 'HP:0002664', (319, 326))	('cancers', 'Disease', (319, 326))	('G309E', 'Var', (254, 259))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('phosphorylation of the C-terminal tail', 'MPA', (69, 107))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('HER2', 'Gene', (43, 47))	('disulfide', 'Chemical', 'MESH:D004220', (207, 216))	('HER2', 'Gene', (281, 285))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('activate', 'PosReg', (34, 42))	('cancers', 'Disease', 'MESH:D009369', (319, 326))	('G309E', 'SUBSTITUTION', 'None', (254, 259))	('inducing', 'Reg', (148, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (295, 308))	('S310F', 'Var', (136, 141))	('HER2', 'Gene', '2064', (43, 47))	('S310F', 'SUBSTITUTION', 'None', (136, 141))	('HER2', 'Gene', '2064', (281, 285))	('breast cancer', 'Disease', 'MESH:D001943', (295, 308))
1780	32256585	In the presence of an S310F/Y mutation, it has been noted that protein HER2 seems more sensitive to anti-HER2 therapy containing neratinib and possibly trastuzumab in patients with HER2+ breast cancer.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('S310F', 'Var', (22, 27))	('neratinib', 'Chemical', 'MESH:C487932', (129, 138))	('HER2', 'Gene', (105, 109))	('HER2', 'Gene', (71, 75))	('HER2', 'Gene', '2064', (105, 109))	('patients', 'Species', '9606', (167, 175))	('HER2', 'Gene', '2064', (71, 75))	('S310F', 'SUBSTITUTION', 'None', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('HER2', 'Gene', (181, 185))	('sensitive', 'MPA', (87, 96))	('trastuzumab', 'Chemical', 'MESH:D000068878', (152, 163))	('HER2', 'Gene', '2064', (181, 185))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Disease', (187, 200))
1781	32256585	Accordingly, in cells featuring ECD mutations, trastuzumab may bind to this region and prevent homodimerization and activation of the receptor.	('bind', 'Interaction', (63, 67))	('trastuzumab', 'Chemical', 'MESH:D000068878', (47, 58))	('mutations', 'Var', (36, 45))	('prevent', 'NegReg', (87, 94))	('homodimerization', 'MPA', (95, 111))	('activation', 'MPA', (116, 126))
1782	32256585	However, because of the constant activation of the TKD in tumors with mutations at this domain, the antiproliferative effects of monoclonal antibodies may be limited despite inhibiting dimerization.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (70, 79))	('inhibiting', 'NegReg', (174, 184))	('tumors', 'Disease', (58, 64))	('activation', 'PosReg', (33, 43))	('antiproliferative', 'CPA', (100, 117))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('TKD', 'MPA', (51, 54))	('dimerization', 'MPA', (185, 197))
1784	32256585	The overexpressed S310F as well as G309A, G309E, and S310Y HER2 mutants reacted to trastuzumab, but S310F mutant did not react to pertuzumab along with S310Y or G309E mutants.	('G309E', 'Mutation', 'rs1057519787', (161, 166))	('G309A', 'Var', (35, 40))	('G309E', 'Mutation', 'rs1057519787', (42, 47))	('HER2', 'Gene', '2064', (59, 63))	('S310Y', 'Mutation', 'rs1057519816', (152, 157))	('reacted to trastuzumab', 'MPA', (72, 94))	('S310F', 'Var', (18, 23))	('trastuzumab', 'Chemical', 'MESH:D000068878', (83, 94))	('pertuzumab', 'Chemical', 'MESH:C485206', (130, 140))	('S310Y', 'Mutation', 'rs1057519816', (53, 58))	('HER2', 'Gene', (59, 63))	('S310F', 'Var', (100, 105))	('G309A', 'Mutation', 'rs1057519787', (35, 40))	('S310F', 'Mutation', 'rs1057519816', (18, 23))	('G309E', 'Var', (42, 47))	('S310F', 'Mutation', 'rs1057519816', (100, 105))	('S310Y', 'Var', (53, 58))
1785	32256585	Thereafter, authors tested the effects of trastuzumab and pertuzumab using both wild-type HER2 and S310F mutant.	('HER2', 'Gene', (90, 94))	('S310F', 'Var', (99, 104))	('HER2', 'Gene', '2064', (90, 94))	('trastuzumab', 'Chemical', 'MESH:D000068878', (42, 53))	('tested', 'Reg', (20, 26))	('S310F', 'Mutation', 'rs1057519816', (99, 104))	('pertuzumab', 'Chemical', 'MESH:C485206', (58, 68))
1786	32256585	In this case, trastuzumab did not inhibit the activation of the HER2 receptor, suggesting that the S310F HER2 mutant did not form homodimers or heterodimers with wild-type HER2.	('HER2', 'Gene', (105, 109))	('S310F', 'Var', (99, 104))	('HER2', 'Gene', '2064', (105, 109))	('trastuzumab', 'Chemical', 'MESH:D000068878', (14, 25))	('HER2', 'Gene', (64, 68))	('S310F', 'Mutation', 'rs1057519816', (99, 104))	('HER2', 'Gene', '2064', (64, 68))	('HER2', 'Gene', (172, 176))	('HER2', 'Gene', '2064', (172, 176))
1787	32256585	Because pertuzumab did not inhibit the phosphorylation of HER2 while it bound to wild-type HER2, EGFR-mediated phosphorylation is expected to occur on the S310F mutant; therefore, trastuzumab in combination with pertuzumab is not effective.	('S310F', 'Mutation', 'rs1057519816', (155, 160))	('pertuzumab', 'Chemical', 'MESH:C485206', (8, 18))	('EGFR', 'Gene', '1956', (97, 101))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('EGFR', 'Gene', (97, 101))	('HER2', 'Gene', (91, 95))	('S310F', 'Var', (155, 160))	('trastuzumab', 'Chemical', 'MESH:D000068878', (180, 191))	('HER2', 'Gene', '2064', (91, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('111', '126'))	('HER2', 'Gene', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))	('pertuzumab', 'Chemical', 'MESH:C485206', (212, 222))	('HER2', 'Gene', '2064', (58, 62))
1788	32256585	This residue is located close to one of the key residues, K311, for receptor-antibody binding whose replacement with alanine, via targeted mutagenesis, leads to a drastic reduction in the response to this drug in cells expressing the mutation.	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('mutation', 'Var', (234, 242))	('alanine', 'Chemical', 'MESH:D000409', (117, 124))	('response to this drug', 'MPA', (188, 209))	('reduction', 'NegReg', (171, 180))	('mutagenesis', 'biological_process', 'GO:0006280', ('139', '150'))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('binding', 'molecular_function', 'GO:0005488', ('86', '93'))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))	('K311', 'Var', (58, 62))
1789	32256585	Amino acid substitutions in these residues could provoke changes in electrostatic interactions or even give rise to a stearic impediment possibly affecting pertuzumab binding to the HER2 receptor.	('HER2', 'Gene', '2064', (182, 186))	('Amino acid substitutions', 'Var', (0, 24))	('binding', 'molecular_function', 'GO:0005488', ('167', '174'))	('pertuzumab', 'Chemical', 'MESH:C485206', (156, 166))	('stearic impediment', 'MPA', (118, 136))	('affecting', 'Reg', (146, 155))	('give rise to', 'Reg', (103, 115))	('provoke changes', 'Reg', (49, 64))	('electrostatic interactions', 'MPA', (68, 94))	('HER2', 'Gene', (182, 186))	('binding', 'Interaction', (167, 174))
1790	32256585	Other less frequent mutations in the ECD have been described, such as R190Q, P523S, and Q548R, in patients with breast cancer without specifying HER2 amplification, in which no relationship has been found between the mutations and prognosis.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('Q548R', 'Var', (88, 93))	('HER2', 'Gene', (145, 149))	('P523S', 'Var', (77, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('R190Q', 'Var', (70, 75))	('R190Q', 'Mutation', 'rs531563820', (70, 75))	('HER2', 'Gene', '2064', (145, 149))	('patients', 'Species', '9606', (98, 106))	('Q548R', 'Mutation', 'p.Q548R', (88, 93))	('P523S', 'Mutation', 'rs202202058', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
1791	32256585	Even rarer are L313I and R456C, observed in two patients with HER2+ breast cancer effectively treated with neratinib.	('L313I', 'Mutation', 'p.L313I', (15, 20))	('HER2', 'Gene', '2064', (62, 66))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('R456C', 'Mutation', 'rs200497646', (25, 30))	('breast cancer', 'Disease', (68, 81))	('neratinib', 'Chemical', 'MESH:C487932', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('patients', 'Species', '9606', (48, 56))	('HER2', 'Gene', (62, 66))	('R456C', 'Var', (25, 30))	('L313I', 'Var', (15, 20))
1792	32256585	The COSMIC and cBioPortal databases also describe other mutations in this domain about which there are no published data for HER2-positive breast cancer: A37T, P232S, D277H (also described in bladder cancer, enhances its activation together with S310F, de Martino et al.	('D277H', 'Var', (167, 172))	('A37T', 'Mutation', 'c.37A>T', (154, 158))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (125, 152))	('enhances', 'PosReg', (208, 216))	('A37T', 'Var', (154, 158))	('S310F', 'Mutation', 'rs1057519816', (246, 251))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('bladder cancer', 'Phenotype', 'HP:0009725', (192, 206))	('D277H', 'Mutation', 'p.D277H', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('bladder cancer', 'Disease', 'MESH:D001749', (192, 206))	('bladder cancer', 'Disease', (192, 206))	('P232S', 'Mutation', 'p.P232S', (160, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('HER2-positive breast cancer', 'Disease', (125, 152))	('activation', 'MPA', (221, 231))	('P232S', 'Var', (160, 165))
1793	32256585	), T297I, E405D, and H470Q.	('T297I', 'Var', (3, 8))	('T297I', 'Mutation', 'p.T297I', (3, 8))	('H470Q', 'Var', (21, 26))	('E405D', 'Mutation', 'p.E405D', (10, 15))	('E405D', 'Var', (10, 15))	('H470Q', 'Mutation', 'p.H470Q', (21, 26))
1794	32256585	Around sixteen clinical trials investigating the efficacy of HER2-directed therapy in HER2 mutant cancers are currently active.	('HER2', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HER2', 'Gene', '2064', (86, 90))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('HER2', 'Gene', (61, 65))	('cancers', 'Disease', (98, 105))	('HER2', 'Gene', '2064', (61, 65))	('mutant', 'Var', (91, 97))
1795	32256585	Four phase II studies are studying the efficacy of different pharmacological products (afatinib, neratinib plus trastuzumab, poziotinib, and pyrotinib) in different types of metastatic HER2 nonamplified but with HER2 mutant breast cancer.	('trastuzumab', 'Chemical', 'MESH:D000068878', (112, 123))	('neratinib', 'Chemical', 'MESH:C487932', (97, 106))	('mutant', 'Var', (217, 223))	('HER2', 'Gene', '2064', (212, 216))	('nonamplified', 'Var', (190, 202))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('pyrotinib', 'Chemical', 'MESH:C000622954', (141, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('breast cancer', 'Disease', (224, 237))	('afatinib', 'Chemical', 'MESH:D000077716', (87, 95))	('metastatic', 'Disease', (174, 184))	('HER2', 'Gene', (212, 216))	('HER2', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('poziotinib', 'Chemical', 'MESH:C557213', (125, 135))	('HER2', 'Gene', '2064', (185, 189))
1796	32256585	There are a relatively large number of pharmacological approaches for breast cancer carrying HER2 mutants.	('HER2', 'Gene', '2064', (93, 97))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutants', 'Var', (98, 105))	('HER2', 'Gene', (93, 97))
1798	32256585	Some mutations are sensitive in a specific type of cancer and in others could be associated with resistance, suggesting that there may be other mechanisms specific with the tumor that requires further research.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('resistance', 'Disease', (97, 107))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('associated', 'Reg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
1799	32256585	The focus of this review is to assess the possible clinical implications of HER2 mutations in HER2-positive breast cancer patients; in this study, we have described that the most prevalent mutations found in HER2 gene in HER2-positive breast cancer (Table 2) are present also in HER2-negative breast cancer.	('HER2', 'Gene', '2064', (279, 283))	('HER2', 'Gene', '2064', (208, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (293, 306))	('breast cancer', 'Phenotype', 'HP:0003002', (235, 248))	('HER2', 'Gene', (76, 80))	('HER2', 'Gene', '2064', (221, 225))	('breast cancer', 'Disease', 'MESH:D001943', (235, 248))	('breast cancer', 'Disease', (293, 306))	('breast cancer', 'Disease', 'MESH:D001943', (293, 306))	('mutations', 'Var', (189, 198))	('HER2', 'Gene', (279, 283))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('HER2', 'Gene', '2064', (94, 98))	('HER2', 'Gene', (208, 212))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (94, 121))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (221, 248))	('patients', 'Species', '9606', (122, 130))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('HER2-positive breast cancer', 'Disease', (94, 121))	('HER2', 'Gene', (221, 225))	('HER2-positive breast cancer', 'Disease', (221, 248))	('HER2', 'Gene', '2064', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('HER2', 'Gene', (94, 98))
1801	32256585	The first patient diagnosed with triple-negative breast cancer, carrying two HER mutations (V777L and S310F), respond to lapatinib and trastuzumab-based therapies during 6 months.	('V777L', 'Mutation', 'rs121913471', (92, 97))	('S310F', 'Var', (102, 107))	('lapatinib', 'Chemical', 'MESH:D000077341', (121, 130))	('S310F', 'Mutation', 'rs1057519816', (102, 107))	('patient', 'Species', '9606', (10, 17))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('respond', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('V777L', 'Var', (92, 97))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('trastuzumab', 'Chemical', 'MESH:D000068878', (135, 146))
1802	32256585	A second case diagnosed with ER + HER-negative breast cancer, carrying a HER2 S310F mutation, was treated during 12 months with the combination of trastuzumab, pertuzumab, and fulvestrant.	('HER2', 'Gene', '2064', (73, 77))	('S310F', 'Var', (78, 83))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('S310F', 'Mutation', 'rs1057519816', (78, 83))	('trastuzumab', 'Chemical', 'MESH:D000068878', (147, 158))	('pertuzumab', 'Chemical', 'MESH:C485206', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('HER2', 'Gene', (73, 77))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
1803	32256585	An additional case with ER+, HER2-negative metastatic breast cancer with HER L755S mutation was treated with neratinib monotherapy experiencing improvement in symptoms and tumor markers.	('breast cancer', 'Disease', (54, 67))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('neratinib', 'Chemical', 'MESH:C487932', (109, 118))	('tumor', 'Disease', (172, 177))	('HER2', 'Gene', (29, 33))	('L755S', 'Mutation', 'rs121913470', (77, 82))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('HER2', 'Gene', '2064', (29, 33))	('improvement', 'PosReg', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('L755S', 'Var', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
1806	32256585	In the phase II MutHER trial, the activity of neratinib in HER2 mutant nonamplified metastatic breast cancer was investigated (Table 3); the patients obtained clinical benefit over 24 months.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('HER2', 'Gene', (59, 63))	('HER2', 'Gene', '2064', (59, 63))	('mutant', 'Var', (64, 70))	('patients', 'Species', '9606', (141, 149))	('neratinib', 'Chemical', 'MESH:C487932', (46, 55))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
1807	32256585	A case report was a HER2-negative breast cancer patient with two detected mutations in ERBB2 (S310F and D769Y mutations) who benefited from lapatinib combined with endocrine therapies.	('lapatinib', 'Chemical', 'MESH:D000077341', (140, 149))	('S310F', 'Mutation', 'rs1057519816', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('D769Y mutations', 'Var', (104, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('patient', 'Species', '9606', (48, 55))	('ERBB2', 'Gene', (87, 92))	('HER2', 'Gene', (20, 24))	('ERBB2', 'Gene', '2064', (87, 92))	('D769Y', 'Mutation', 'rs121913468', (104, 109))	('HER2', 'Gene', '2064', (20, 24))	('S310F', 'Var', (94, 99))	('benefited', 'PosReg', (125, 134))
1808	32256585	Based on clinical data available for HER2-negative breast cancer patients (Table 3), functional activating HER2 mutations, V777L, L755S, S310F, D769H/Y, and V842I, may similarly confer sensitivity to HER2-directed pharmacological products.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('HER2', 'Gene', (37, 41))	('HER2', 'Gene', '2064', (200, 204))	('activating', 'PosReg', (96, 106))	('S310F', 'Mutation', 'rs1057519816', (137, 142))	('D769H', 'Var', (144, 149))	('HER2', 'Gene', (107, 111))	('V842I', 'Chemical', '-', (157, 162))	('sensitivity', 'MPA', (185, 196))	('D769H', 'SUBSTITUTION', 'None', (144, 149))	('HER2', 'Gene', (200, 204))	('V777L', 'Mutation', 'rs121913471', (123, 128))	('HER2', 'Gene', '2064', (37, 41))	('patients', 'Species', '9606', (65, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('L755S', 'Var', (130, 135))	('V777L', 'Var', (123, 128))	('HER2', 'Gene', '2064', (107, 111))	('S310F', 'Var', (137, 142))	('V842I', 'Var', (157, 162))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('L755S', 'Mutation', 'rs121913470', (130, 135))	('breast cancer', 'Disease', (51, 64))
1810	32256585	Overall, HER2-negative breast cancer patients carrying the above mutations can benefit from HER2-targeted therapy; this is in agreement with data previously published by other authors.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('patients', 'Species', '9606', (37, 45))	('HER2', 'Gene', (9, 13))	('benefit', 'PosReg', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))	('HER2', 'Gene', '2064', (9, 13))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('mutations', 'Var', (65, 74))
1812	32256585	Further, in vitro and in vivo studies indicate that the presence of somatic HER2 mutations could influence the clinical outcome of HER2-positive patients under currently approved treatments (Table 1).	('patients', 'Species', '9606', (145, 153))	('HER2', 'Gene', (76, 80))	('HER2', 'Gene', (131, 135))	('HER2', 'Gene', '2064', (76, 80))	('HER2', 'Gene', '2064', (131, 135))	('clinical', 'MPA', (111, 119))	('mutations', 'Var', (81, 90))	('influence', 'Reg', (97, 106))
1815	32256585	Recently, in vitro and in vivo studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy opening new options of treatments in patients with ER + MBC.	('patients', 'Species', '9606', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('MBC', 'Disease', (220, 223))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (88, 97))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('MBC', 'Disease', 'MESH:D001943', (220, 223))	('HER2', 'Gene', (83, 87))	('HER2', 'Gene', '2064', (83, 87))
1816	32256585	In this review, we identify the more prevalent somatic HER2 SNP mutations appearing in HER2-positive breast cancer patients and summarize their possible implications for current HER2-targeted therapy (Figure 4).	('HER2', 'Gene', '2064', (87, 91))	('patients', 'Species', '9606', (115, 123))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (87, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('SNP', 'Gene', (60, 63))	('mutations', 'Var', (64, 73))	('HER2', 'Gene', (55, 59))	('HER2', 'Gene', (178, 182))	('HER2', 'Gene', (87, 91))	('HER2-positive breast cancer', 'Disease', (87, 114))	('HER2', 'Gene', '2064', (55, 59))	('HER2', 'Gene', '2064', (178, 182))
1817	32256585	We found that somatic HER2 mutations occur in low frequency in HER2-positive breast cancer patients.	('mutations', 'Var', (27, 36))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (63, 90))	('patients', 'Species', '9606', (91, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('HER2', 'Gene', (22, 26))	('HER2', 'Gene', '2064', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('HER2', 'Gene', (63, 67))	('HER2-positive breast cancer', 'Disease', (63, 90))	('HER2', 'Gene', '2064', (63, 67))
1818	32256585	In total, 11 somatic mutations have been identified, and according to information available from in vitro and in vivo studies, 9/11 are classified as oncogenic and hotspot (see Table 2), and several authors have identified the presence of these mutations also in HER2-negative breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('breast cancer', 'Disease', (277, 290))	('mutations', 'Var', (245, 254))	('HER2', 'Gene', (263, 267))	('HER2', 'Gene', '2064', (263, 267))	('patients', 'Species', '9606', (291, 299))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('mutations', 'Var', (21, 30))
1819	32256585	For two mutations, I767M and K753E, there is insufficient information so far to classify them as oncogenic and/or hotspot.	('I767M', 'Var', (19, 24))	('K753E', 'Mutation', 'rs754652044', (29, 34))	('I767M', 'Mutation', 'p.I767M', (19, 24))	('K753E', 'Var', (29, 34))
1821	32256585	For the reviewed somatic HER2 mutations, no sensitivity or resistance data are available for pertuzumab, with the exception of mutation D769H.	('pertuzumab', 'Chemical', 'MESH:C485206', (93, 103))	('D769H', 'Mutation', 'rs121913468', (136, 141))	('mutations', 'Var', (30, 39))	('HER2', 'Gene', (25, 29))	('D769H', 'Var', (136, 141))	('HER2', 'Gene', '2064', (25, 29))
1822	32256585	HER2-positive patients carrying S310F, S310Y, R678Q, D769H, I767M, or V777L emerged as potentially good candidates for HER2-targeted therapy and could have a favorable outcome because of sensitivity to current pharmacological treatments with the exception of inconclusive data for the impacts of trastuzumab in V777L (Figure 3).	('S310F', 'Var', (32, 37))	('D769H', 'Mutation', 'rs121913468', (53, 58))	('HER2', 'Gene', '2064', (119, 123))	('V777L', 'Mutation', 'rs121913471', (70, 75))	('S310Y', 'Mutation', 'rs1057519816', (39, 44))	('I767M', 'Var', (60, 65))	('HER2', 'Gene', '2064', (0, 4))	('patients', 'Species', '9606', (14, 22))	('V777L', 'Var', (70, 75))	('S310F', 'Mutation', 'rs1057519816', (32, 37))	('D769H', 'Var', (53, 58))	('HER2', 'Gene', (119, 123))	('trastuzumab', 'Chemical', 'MESH:D000068878', (296, 307))	('HER2', 'Gene', (0, 4))	('S310Y', 'Var', (39, 44))	('V777L', 'Mutation', 'rs121913471', (311, 316))	('I767M', 'Mutation', 'p.I767M', (60, 65))	('R678Q', 'Mutation', 'rs1057519862', (46, 51))	('R678Q', 'Var', (46, 51))
1823	32256585	Patients with L755S or D769Y might also benefit from neratinib or afatinib treatment.	('L755S', 'Var', (14, 19))	('L755S', 'Mutation', 'rs121913470', (14, 19))	('neratinib', 'Chemical', 'MESH:C487932', (53, 62))	('D769Y', 'Var', (23, 28))	('afatinib', 'Chemical', 'MESH:D000077716', (66, 74))	('Patients', 'Species', '9606', (0, 8))	('benefit', 'PosReg', (40, 47))	('D769Y', 'Mutation', 'rs121913468', (23, 28))
1824	32256585	In contrast, patients with the somatic mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab.	('L755S', 'Var', (49, 54))	('D769Y', 'Var', (73, 78))	('patients', 'Species', '9606', (13, 21))	('L755S', 'Mutation', 'rs121913470', (49, 54))	('V842I', 'Chemical', '-', (56, 61))	('K753I', 'Var', (63, 68))	('D769Y', 'Mutation', 'rs121913468', (73, 78))	('trastuzumab', 'Chemical', 'MESH:D000068878', (107, 118))	('K753I', 'Mutation', 'p.K753I', (63, 68))	('V842I', 'Var', (56, 61))
1825	32256585	Similar negative results have been observed for lapatinib in patients carrying the L755S, V842I, and K753I mutations.	('K753I', 'Var', (101, 106))	('K753I', 'Mutation', 'p.K753I', (101, 106))	('L755S', 'Var', (83, 88))	('L755S', 'Mutation', 'rs121913470', (83, 88))	('lapatinib', 'Chemical', 'MESH:D000077341', (48, 57))	('patients', 'Species', '9606', (61, 69))	('V842I', 'Chemical', '-', (90, 95))	('lapatinib', 'MPA', (48, 57))	('V842I', 'Var', (90, 95))
1826	32256585	L755S and V777L mutations emerge as a distinct mechanism of acquired resistance to anti-ER therapies in ER+ metastatic breast cancer that was overcome by combining fulvestrant with the irreversible inhibitor neratinib.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('L755S', 'Mutation', 'rs121913470', (0, 5))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('V777L', 'Mutation', 'rs121913471', (10, 15))	('L755S', 'Var', (0, 5))	('V777L', 'Var', (10, 15))	('neratinib', 'Chemical', 'MESH:C487932', (208, 217))
1827	32256585	Furthermore, patients with metastatic breast cancer HER2+ with L755S and V777L could benefit of treatment with a new TKI, poziotinib, that is in phase II of clinical trials.	('L755S', 'Mutation', 'rs121913470', (63, 68))	('HER2', 'Gene', '2064', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('benefit', 'PosReg', (85, 92))	('patients', 'Species', '9606', (13, 21))	('poziotinib', 'Chemical', 'MESH:C557213', (122, 132))	('V777L', 'Var', (73, 78))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('L755S', 'Var', (63, 68))	('V777L', 'Mutation', 'rs121913471', (73, 78))	('HER2', 'Gene', (52, 56))
1828	32256585	Clinical studies suggest that HER2-negative breast cancer patients carrying the HER2 mutations reviewed here can benefit from HER2-targeted therapy.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('benefit', 'Reg', (113, 120))	('HER2', 'Gene', (80, 84))	('HER2', 'Gene', '2064', (80, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('breast cancer', 'Disease', (44, 57))	('HER2', 'Gene', '2064', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (85, 94))	('HER2', 'Gene', (30, 34))	('HER2', 'Gene', (126, 130))	('patients', 'Species', '9606', (58, 66))	('HER2', 'Gene', '2064', (126, 130))
1844	31342363	The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial randomized women with T1-T2, cN0 tumors undergoing breast-conserving surgery followed by whole-breast irradiation (BCT) with fewer than 3 positive sentinel lymph nodes (SLNs) to either SLNB alone or SLNB and axillary lymph node dissection (ALND).	('ALND', 'Chemical', '-', (309, 313))	('T1-T2', 'Var', (91, 96))	('women', 'Species', '9606', (80, 85))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('Oncology', 'Phenotype', 'HP:0002664', (33, 41))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('SLN', 'Gene', (254, 257))	('SLN', 'Gene', (238, 241))	('SLN', 'Gene', '6588', (254, 257))	('SLN', 'Gene', (268, 271))	('SLN', 'Gene', '6588', (268, 271))	('SLN', 'Gene', '6588', (238, 241))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
1852	31342363	Starting in August 2010, consecutive patients with T1-T2 cN0 invasive breast cancer undergoing BCT who were found to have SLN metastases on routine hematoxylin and eosin (H&E) staining were managed with ALND if metastases were present in 3 or more SLNs, or if noted to have gross extracapsular (ECE), defined as matted nodes or macroscopically evident extranodal disease at the time of SLNB.	('ALND', 'Chemical', '-', (203, 207))	('metastases', 'Disease', (211, 221))	('hematoxylin', 'Chemical', 'MESH:D006416', (148, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('SLN metastases', 'Disease', (122, 136))	('invasive breast cancer', 'Disease', (61, 83))	('SLN', 'Gene', '6588', (386, 389))	('nodal disease', 'Disease', (357, 370))	('SLN', 'Gene', (122, 125))	('patients', 'Species', '9606', (37, 45))	('SLN', 'Gene', (386, 389))	('invasive breast cancer', 'Disease', 'MESH:D001943', (61, 83))	('SLN', 'Gene', (248, 251))	('T1-T2', 'Var', (51, 56))	('eosin', 'Chemical', 'MESH:D004801', (164, 169))	('metastases', 'Disease', 'MESH:D009362', (126, 136))	('metastases', 'Disease', (126, 136))	('have gross', 'Disease', (269, 279))	('SLN', 'Gene', '6588', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SLN', 'Gene', '6588', (248, 251))	('nodal disease', 'Disease', 'MESH:D013611', (357, 370))	('SLN metastases', 'Disease', 'MESH:D009362', (122, 136))	('metastases', 'Disease', 'MESH:D009362', (211, 221))
1876	31342363	On multivariable analysis, lobular histology (odds ratio [OR] 3.37, 95% confidence interval [CI] 0.29-6.45, p = 0.03) and increasing pathologic tumor size (OR 1.25, 95% CI 0.11-2.38, p = 0.03) were independently associated with additional positive lymph nodes at ALND, after additionally adjusting for both ER status and HER2 status.	('tumor', 'Disease', (144, 149))	('HER2', 'Gene', (321, 325))	('ER', 'Gene', '2099', (307, 309))	('ALND', 'Chemical', '-', (263, 267))	('HER2', 'Gene', '2064', (321, 325))	('lobular', 'Var', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('ER', 'Gene', '2099', (322, 324))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
1991	24386009	In the high Recurrence Score group, approximately two-thirds of patients received chemotherapy, which is considerably less than optimal given the MHS eligibility criteria with request to discuss chemotherapy use in cases found to be at high recurrence risk.	('patients', 'Species', '9606', (64, 72))	('high', 'Var', (7, 11))	('chemotherapy', 'Disease', (82, 94))
2009	28575524	Depending on the location and orientation of their reintegration, these integrations can activate oncogenes or inactivate tumor suppressors, thereby inducing tumor development and progression.	('tumor', 'Disease', (158, 163))	('activate', 'PosReg', (89, 97))	('inducing', 'PosReg', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('oncogenes', 'Protein', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('inactivate', 'NegReg', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (122, 127))	('integrations', 'Var', (72, 84))	('progression', 'CPA', (180, 191))
2010	28575524	By identifying genomic loci that are recurrently affected by transposon insertions in multiple independent tumors, this approach can be used to identify candidate cancer genes.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('transposon insertions', 'Var', (61, 82))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
2011	28575524	These insights may be key to ultimately understanding the biological effect of insertions and how they may contribute to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('insertions', 'Var', (79, 89))	('tumor', 'Disease', (121, 126))	('contribute', 'Reg', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
2017	28575524	To identify cases in which insertions lead to the expression of non-canonical transcripts, IM-Fusion provides an optional step which uses StringTie to perform a reference-guided assembly of novel transcripts using the read alignment from STAR.	('STAR', 'Gene', (238, 242))	('insertions', 'Var', (27, 37))	('STAR', 'Gene', '20845', (238, 242))	('lead to', 'Reg', (38, 45))	('expression', 'MPA', (50, 60))
2025	28575524	The current implementation supports the use of STAR or Tophat-Fusion to detect fusions, although support for additional fusion-aware aligners may be added in the future.	('STAR', 'Gene', '20845', (47, 51))	('STAR', 'Gene', (47, 51))	('fusions', 'Var', (79, 86))
2027	28575524	Optionally, STAR-Fusion can also be used to detect endogenous gene fusions as part of the STAR insertion detection pipeline.	('STAR', 'Gene', '20845', (90, 94))	('STAR', 'Gene', '20845', (12, 16))	('endogenous', 'Var', (51, 61))	('STAR', 'Gene', (90, 94))	('STAR', 'Gene', (12, 16))
2033	28575524	Finally, identified insertions are assigned to their predicted target genes using the windows outlined in KC-RBM.	('RBM', 'Gene', '19657', (109, 112))	('RBM', 'Gene', (109, 112))	('insertions', 'Var', (20, 30))
2053	28575524	To determine why certain CTGs/candidates were not identified by Fusion Finder, we visualized the distribution of the used transposon features and compared the alignments of reads supporting insertions unique to IM-Fusion between the Tophat2 and STAR alignments using pysam.	('insertions', 'Var', (190, 200))	('CTGs', 'Chemical', '-', (25, 29))	('STAR', 'Gene', (245, 249))	('STAR', 'Gene', '20845', (245, 249))
2054	28575524	Transposon insertions can affect the expression of nearby genes, potentially leading to the activation of oncogenes or the inactivation of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('activation', 'PosReg', (92, 102))	('insertions', 'Var', (11, 21))	('Transposon insertions', 'Var', (0, 21))	('affect', 'Reg', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('oncogenes', 'Protein', (106, 115))	('expression', 'MPA', (37, 47))	('inactivation', 'NegReg', (123, 135))
2055	28575524	When integrated in the vicinity of a gene, this transposon can induce (over)expression of nearby genes by initiating transcription from its promoter sequence (MSCV) and then splicing into the gene using the SD sequence (Figure 1B).	('SD', 'Chemical', '-', (207, 209))	('initiating', 'Reg', (106, 116))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('MSCV', 'Species', '258023', (159, 163))	('transcription', 'MPA', (117, 130))	('splicing', 'Var', (174, 182))	('induce', 'PosReg', (63, 69))	('splicing', 'biological_process', 'GO:0045292', ('174', '182'))
2056	28575524	Alternatively, the transposon can truncate transcripts using either of its SA sites (SA/En2SA) and their corresponding polyA (pA) sites (Figure 1C).	('truncate', 'NegReg', (34, 42))	('SA', 'Chemical', '-', (75, 77))	('transposon', 'Var', (19, 29))	('SA', 'Chemical', '-', (91, 93))	('SA', 'Chemical', '-', (85, 87))	('transcripts', 'MPA', (43, 54))
2059	28575524	To establish whether the expression of a CTG is significantly altered by its insertions, we test for differential expression over the insertion sites in the gene.	('expression', 'MPA', (25, 35))	('insertions', 'Var', (77, 87))	('altered', 'Reg', (62, 69))	('CTG', 'Chemical', '-', (41, 44))
2060	28575524	We tested our approach by using IM-Fusion to identify SB transposon insertions in 123 tumors from a mouse model of invasive lobular breast cancer (ILC).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('invasive lobular breast cancer', 'Disease', (115, 145))	('insertions', 'Var', (68, 78))	('mouse', 'Species', '10090', (100, 105))	('transposon insertions', 'Var', (57, 78))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (115, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', (86, 92))	('SB', 'Chemical', '-', (54, 56))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (124, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
2061	28575524	From these fusions, IM-Fusion identified a total of 2057 transposon insertion sites across all tumors, with a median of 12 insertions per tumor (Supplementary Table S2).	('transposon insertion', 'Var', (57, 77))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('insertion', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
2062	28575524	A total of 1043 genes were affected by at least one insertion, 14 of which were selected as differentially expressed (DE) CTGs (Supplementary Table S3).	('affected', 'Reg', (27, 35))	('genes', 'Gene', (16, 21))	('CTGs', 'Chemical', '-', (122, 126))	('insertion', 'Var', (52, 61))
2063	28575524	An example is shown in Figure 3A, which shows an antisense insertion in the Trps1 gene.	('antisense insertion', 'Var', (49, 68))	('Trps1', 'Gene', (76, 81))	('Trps1', 'Gene', '83925', (76, 81))
2065	28575524	The first fusion, between the SA site of the transposon and exon 12 of the gene, indicated that the insertion truncated gene transcription after this exon.	('truncated', 'NegReg', (110, 119))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('SA', 'Chemical', '-', (30, 32))	('insertion', 'Var', (100, 109))	('gene transcription', 'MPA', (120, 138))
2066	28575524	However, the second fusion, between the SD site and exon 13, indicated that the insertion also drove overexpression of a partial gene transcript downstream of the insertion.	('SD', 'Chemical', '-', (40, 42))	('overexpression', 'PosReg', (101, 115))	('partial gene transcript', 'MPA', (121, 144))	('insertion', 'Var', (80, 89))
2069	28575524	In this analysis, a bias to SD insertions would indicate the gene is mainly overexpressed by insertions in the gene (Figure 1B).	('SD', 'Chemical', '-', (28, 30))	('insertions', 'Var', (93, 103))	('overexpressed', 'PosReg', (76, 89))
2072	28575524	This analysis showed that most top CTGs (Ppp1r12a, Trps1, Myh9, Tgfbr2 and Runx1) were clearly biased toward SA/En2SA insertions (Figure 3E), indicating that transcripts of these genes were being truncated by the transposon insertions.	('Myh9', 'Gene', '17886', (58, 62))	('Runx1', 'Gene', '12394', (75, 80))	('Tgfbr2', 'Gene', '21813', (64, 70))	('SA', 'Chemical', '-', (115, 117))	('Ppp1r12a', 'Gene', (41, 49))	('Runx1', 'Gene', (75, 80))	('Trps1', 'Gene', '83925', (51, 56))	('insertions', 'Var', (118, 128))	('Myh9', 'Gene', (58, 62))	('CTGs', 'Chemical', '-', (35, 39))	('biased', 'Reg', (95, 101))	('SA/En2SA', 'Gene', (109, 117))	('SA', 'Chemical', '-', (109, 111))	('Tgfbr2', 'Gene', (64, 70))	('transcripts', 'MPA', (158, 169))	('Trps1', 'Gene', (51, 56))	('Ppp1r12a', 'Gene', '17931', (41, 49))
2073	28575524	Conversely, for one top CTG, Trp53bp2, we saw a clear bias toward SD insertions, indicating that this gene is overexpressed by its insertions.	('Trp53bp2', 'Gene', (29, 37))	('Trp53bp2', 'Gene', '209456', (29, 37))	('insertions', 'Var', (69, 79))	('SD', 'Chemical', '-', (66, 68))	('CTG', 'Chemical', '-', (24, 27))
2078	28575524	For example, insertions within the Arfip1/Fbxw7 locus were frequently assigned by ShearSplink to both Fbxw7 and Arfip1.	('Fbxw7', 'Gene', (102, 107))	('insertions', 'Var', (13, 23))	('Arfip1', 'Gene', '99889', (35, 41))	('Arfip1', 'Gene', (35, 41))	('Fbxw7', 'Gene', (42, 47))	('Arfip1', 'Gene', '99889', (112, 118))	('Arfip1', 'Gene', (112, 118))	('Fbxw7', 'Gene', '50754', (102, 107))	('Fbxw7', 'Gene', '50754', (42, 47))
2079	28575524	Closer inspection of these insertions indicated that these insertions are in fact closely clustered in Fbxw7 and are therefore unlikely to affect the Arfip1 transcript that overlaps with Fbxw7.	('affect', 'Reg', (139, 145))	('Fbxw7', 'Gene', '50754', (187, 192))	('insertions', 'Var', (59, 69))	('Fbxw7', 'Gene', (103, 108))	('Arfip1', 'Gene', '99889', (150, 156))	('Arfip1', 'Gene', (150, 156))	('Fbxw7', 'Gene', (187, 192))	('Fbxw7', 'Gene', '50754', (103, 108))
2080	28575524	This hypothesis was supported by the IM-Fusion results, which only identified insertions in Fbxw7, indicating that Arfip1 is a false positive of the heuristic assignment by ShearSplink.	('Arfip1', 'Gene', '99889', (115, 121))	('Arfip1', 'Gene', (115, 121))	('insertions', 'Var', (78, 88))	('false', 'biological_process', 'GO:0071878', ('127', '132'))	('Fbxw7', 'Gene', '50754', (92, 97))	('false', 'biological_process', 'GO:0071877', ('127', '132'))	('Fbxw7', 'Gene', (92, 97))
2083	28575524	Five genes (Arfip1, Gm26836, Gm14798, Ppp2r2a and Bach2) were not identified at all by IM-Fusion, suggesting that these are either false positives of the ShearSplink analysis, as we have already argued for Arfip1, or are weak/subclonal insertions that were not picked up by IM-Fusion.	('Arfip1', 'Gene', (206, 212))	('Arfip1', 'Gene', '99889', (12, 18))	('Arfip1', 'Gene', (12, 18))	('false', 'biological_process', 'GO:0071878', ('131', '136'))	('Ppp2r2a', 'Gene', (38, 45))	('Gm14798', 'Var', (29, 36))	('Gm26836', 'Var', (20, 27))	('Ppp2r2a', 'Gene', '71978', (38, 45))	('Bach2', 'Gene', (50, 55))	('Bach2', 'Gene', '12014', (50, 55))	('false', 'biological_process', 'GO:0071877', ('131', '136'))	('Arfip1', 'Gene', '99889', (206, 212))
2086	28575524	However, closer inspection showed that Nf1 insertions were generally supported by few reads in the ShearSplink data, thereby explaining their omission by IM-Fusion.	('Nf1', 'Gene', (39, 42))	('insertions', 'Var', (43, 53))	('ShearSplink', 'Protein', (99, 110))	('Nf1', 'Gene', '18015', (39, 42))
2092	28575524	This can, for example, be done by grouping samples based on the orientation of their insertions (as done here) or on the involved SD/SA sites if these are expected to have different effects on expression.	('insertions', 'Var', (85, 95))	('effects', 'Reg', (182, 189))	('SD', 'Chemical', '-', (130, 132))	('SA', 'Chemical', '-', (133, 135))
2103	28575524	Although the analysis of the single-end dataset identified the same DE CTGs as the paired-end analysis (Figure 5C), the paired-end data yielded on average two times higher support scores for insertions due to the higher effective depth of paired-end sequencing, and identified a number of insertions that were not detected in the single-end sequencing data (Supplementary Table S8).	('higher', 'PosReg', (165, 171))	('CTGs', 'Chemical', '-', (71, 75))	('insertions', 'Var', (191, 201))	('higher', 'PosReg', (213, 219))
2104	28575524	Comparison of the identified insertions showed that Fusion Finder identified recurrent insertions in Cblb and Dlx3, but was only able to identify insertions in a single sample for Jak1 and Bmi1, and was unable to detect insertions in any of the other DE CTGs identified by IM-Fusion (Supplementary Table S9).	('Dlx3', 'Gene', (110, 114))	('Bmi1', 'Gene', '12151', (189, 193))	('Jak1', 'Gene', (180, 184))	('Cblb', 'Gene', '208650', (101, 105))	('Dlx3', 'Gene', '13393', (110, 114))	('Bmi1', 'Gene', (189, 193))	('Jak', 'molecular_function', 'GO:0004713', ('180', '183'))	('insertions', 'Var', (87, 97))	('Cblb', 'Gene', (101, 105))	('CTGs', 'Chemical', '-', (254, 258))	('Jak1', 'Gene', '16451', (180, 184))
2105	28575524	More detailed analyses of the results showed that the insertions in CTGs missed by Fusion Finder are (i) biased toward SD insertions and (ii) mainly supported by chimeric reads overlapping the fusion boundary, rather than mate pairs that span the fusion (with one mate on either side of the fusion).	('supported', 'Reg', (149, 158))	('insertions', 'Var', (54, 64))	('CTGs', 'Chemical', '-', (68, 72))	('SD', 'Chemical', '-', (119, 121))
2108	28575524	The same expression data may also be used to identify more global changes in gene expression associated with tumor subtypes or with specific insertions, or be used to detect single nucleotide variants and somatic gene fusions that contribute to tumorigenesis.	('gene expression', 'MPA', (77, 92))	('contribute', 'Reg', (231, 241))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('insertions', 'Var', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('changes', 'Reg', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (245, 250))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))	('tumor', 'Disease', (109, 114))
2109	28575524	As an example of the latter, we have identified several endogenous fusions in the ILC and B-ALL datasets (Supplementary Figure S7 and Table S10), including several Fgfr2 fusions that reflect known oncogenic fusions previously identified in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('S10', 'Gene', (140, 143))	('fusions', 'Var', (170, 177))	('cancers', 'Disease', (246, 253))	('human', 'Species', '9606', (240, 245))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('S10', 'Gene', '6204', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('B-ALL', 'Phenotype', 'HP:0004812', (90, 95))	('Fgfr2', 'Gene', (164, 169))	('Fgfr', 'molecular_function', 'GO:0005007', ('164', '168'))
2112	28575524	Although we do not observe evidence pointing to transcript degradation in the presence of (clonal) SB insertions (Supplementary Figure S8), other transposons might have different effects on transcript stability.	('SB', 'Chemical', '-', (99, 101))	('transcript stability', 'MPA', (190, 210))	('insertions', 'Var', (102, 112))	('degradation', 'biological_process', 'GO:0009056', ('59', '70'))
2164	25601220	These genes were also confirmed as targets of genomic alterations (i.e., somatic mutations or copy number alterations) in >4% of all breast cancers according to TCGA.	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('breast cancers', 'Disease', 'MESH:D001943', (133, 147))	('breast cancers', 'Disease', (133, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('copy number alterations', 'Var', (94, 117))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancers', 'Phenotype', 'HP:0003002', (133, 147))
2176	25601220	Heterozygous deletions of 16q may result in haploinsufficiency of several genes mapping to 16q with secondary influence in expression of genes mapped to other locations, including NAT1 (8p23.1) and EVL (14q32), two genes reported as differentially expressed on 16q deleted invasive breast cancers by Hungermann et al and also part of our potential precursor gene list.	('genes', 'Gene', (74, 79))	('NAT1', 'Gene', '9', (180, 184))	('EVL', 'Gene', '51466', (198, 201))	('haploinsufficiency', 'Disease', 'MESH:D058495', (44, 62))	('invasive breast cancers', 'Disease', 'MESH:D001943', (273, 296))	('result', 'Reg', (34, 40))	('breast cancers', 'Phenotype', 'HP:0003002', (282, 296))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('Heterozygous', 'Var', (0, 12))	('16q', 'Gene', (26, 29))	('haploinsufficiency', 'Disease', (44, 62))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('breast cancer', 'Phenotype', 'HP:0003002', (282, 295))	('invasive breast cancers', 'Disease', (273, 296))	('EVL', 'Gene', (198, 201))	('NAT1', 'Gene', (180, 184))
2179	25601220	According to the reported TCGA breast cancer dataset, PIK3R1 is altered in 5.1% of all breast cancers, including 0.2% with homozygous deletions and 1.6% with somatic mutations.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('deletions', 'Var', (134, 143))	('breast cancers', 'Phenotype', 'HP:0003002', (87, 101))	('breast cancers', 'Disease', 'MESH:D001943', (87, 101))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('breast cancers', 'Disease', (87, 101))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('altered', 'Reg', (64, 71))	('PIK3R1', 'Gene', (54, 60))	('PIK3R1', 'Gene', '5295', (54, 60))
2182	25601220	The fact that PIK3R1 mutations are relatively uncommon in breast cancer suggests that PIK3R1 regulation in lobular lesions involves mechanisms other than somatic genetic alterations.	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('PIK3R1', 'Gene', '5295', (86, 92))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('PIK3R1', 'Gene', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('PIK3R1', 'Gene', '5295', (14, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('PIK3R1', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
2193	25601220	Genes whose gene expression changes likely play a role in the genesis and/or progression of LCIS were identified, and these segregate LCIS into two clusters that differ in terms of proliferation, as defined by the mRNA expression levels of MKI67.	('MKI67', 'Gene', (240, 245))	('MKI67', 'Gene', '4288', (240, 245))	('changes', 'Var', (28, 35))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('LCIS', 'Disease', (92, 96))
2196	25601220	LCIS lobular carcinoma in situ ILC invasive lobular carcinoma ER estrogen receptor MSKCC Memorial Sloan Kettering Cancer Center H&E hematoxylin and eosin LCM laser capture microdissection DAVID Database for Annotation, Visualization and Integrated Discovery FFPE formalin-fixed paraffin-embedded TCGA The Cancer Genome Atlas Lobular carcinoma in situ (LCIS) is a non-obligate precursor to breast cancer We demonstrate that LCIS is heterogeneous at the level of the transcriptome Copy number alterations in LCIS and ILC result in gene expression changes Candidate precursor genes may play a role in the progression of LCIS	('carcinoma in situ', 'Phenotype', 'HP:0030075', (333, 350))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (5, 22))	('Memorial Sloan Kettering Cancer', 'Disease', (89, 120))	('Cancer', 'Phenotype', 'HP:0002664', (305, 311))	('estrogen receptor', 'Gene', '2099', (65, 82))	('breast cancer', 'Disease', 'MESH:D001943', (389, 402))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (5, 30))	('Lobular carcinoma', 'Disease', 'MESH:D018275', (325, 342))	('breast cancer', 'Disease', (389, 402))	('hematoxylin', 'Chemical', 'MESH:D006416', (132, 143))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (13, 30))	('eosin', 'Chemical', 'MESH:D004801', (148, 153))	('ER', 'Gene', '2099', (62, 64))	('formalin', 'Chemical', 'MESH:D005557', (263, 271))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (44, 61))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (35, 61))	('H&E', 'Chemical', '-', (128, 131))	('lobular carcinoma', 'Disease', 'MESH:D018275', (5, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('lobular carcinoma', 'Disease', (5, 22))	('number', 'Var', (484, 490))	('gene expression', 'biological_process', 'GO:0010467', ('529', '544'))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (89, 120))	('invasive lobular carcinoma', 'Disease', (35, 61))	('estrogen receptor', 'Gene', (65, 82))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (305, 324))	('in gene', 'MPA', (526, 533))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('may', 'Reg', (579, 582))	('lobular carcinoma', 'Disease', 'MESH:D018275', (44, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Cancer Genome Atlas', 'Disease', (305, 324))	('paraffin', 'Chemical', 'MESH:D010232', (278, 286))	('Lobular carcinoma', 'Disease', (325, 342))	('expression', 'Reg', (534, 544))	('Lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (325, 350))	('breast cancer', 'Phenotype', 'HP:0003002', (389, 402))
2203	33919581	We show that while CDH1 (E-cadherin) and PIK3CA mutations do not significantly impact survival, overall survival is significantly poorer for patients with a higher tumour mutation burden; this is also true for grade 3 tumours, and those carrying a somatic TP53 mutation (and these cases were more likely to be ER-negative).	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('ER', 'Gene', '2099', (310, 312))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumours', 'Disease', (218, 225))	('tumour', 'Disease', (164, 170))	('TP53', 'Gene', '7157', (256, 260))	('PIK3CA', 'Gene', '5290', (41, 47))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('poorer', 'NegReg', (130, 136))	('mutations', 'Var', (48, 57))	('patients', 'Species', '9606', (141, 149))	('tumour', 'Disease', 'MESH:D009369', (218, 224))	('tumours', 'Phenotype', 'HP:0002664', (218, 225))	('tumours', 'Disease', 'MESH:D009369', (218, 225))	('tumour', 'Disease', (218, 224))	('CDH1', 'Gene', '999', (19, 23))	('PIK3CA', 'Gene', (41, 47))	('mutation', 'Var', (261, 269))	('CDH1', 'Gene', (19, 23))	('E-cadherin', 'Gene', (25, 35))	('E-cadherin', 'Gene', '999', (25, 35))	('TP53', 'Gene', (256, 260))	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))
2218	33919581	As described by early cohort studies (, reviewed in), the most commonly altered driver mutations in ILC are in CDH1, TP53, PIK3CA, FOXA1, PTEN, TBX3, FGFR2, ERBB2, and ERBB3.	('altered', 'Reg', (72, 79))	('TP53', 'Gene', (117, 121))	('CDH1', 'Gene', (111, 115))	('mutations', 'Var', (87, 96))	('PTEN', 'Gene', (138, 142))	('ERBB2', 'Gene', (157, 162))	('PIK3CA', 'Gene', (123, 129))	('ERBB3', 'Gene', (168, 173))	('TBX3', 'Gene', '6926', (144, 148))	('FOXA1', 'Gene', '3169', (131, 136))	('PTEN', 'Gene', '5728', (138, 142))	('TP53', 'Gene', '7157', (117, 121))	('ERBB2', 'Gene', '2064', (157, 162))	('ILC', 'Gene', (100, 103))	('FOXA1', 'Gene', (131, 136))	('TBX3', 'Gene', (144, 148))	('FGFR2', 'Gene', (150, 155))	('FGFR', 'molecular_function', 'GO:0005007', ('150', '154'))	('ERBB3', 'Gene', '2065', (168, 173))	('PIK3CA', 'Gene', '5290', (123, 129))	('CDH1', 'Gene', '999', (111, 115))	('FGFR2', 'Gene', '2263', (150, 155))
2220	33919581	Here, we investigated the distribution of these alterations across the different cohorts, and then we used the combined cohort to investigate the associations between various pathological and genomic features (i.e., grade, ER status, gene mutations and tumour mutation burden).	('gene mutations', 'Var', (234, 248))	('ER', 'Gene', '2099', (223, 225))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('associations', 'Interaction', (146, 158))	('tumour', 'Disease', (253, 259))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))
2221	33919581	As shown in Table 1, the distribution of mutations in CDH1, TP53, ERBB2, BRCA1/2 and TBX3 differs across the four cohorts.	('mutations', 'Var', (41, 50))	('BRCA1/2', 'Gene', (73, 80))	('TBX3', 'Gene', '6926', (85, 89))	('BRCA1/2', 'Gene', '672;675', (73, 80))	('TP53', 'Gene', '7157', (60, 64))	('ERBB2', 'Gene', '2064', (66, 71))	('TBX3', 'Gene', (85, 89))	('CDH1', 'Gene', (54, 58))	('ERBB2', 'Gene', (66, 71))	('CDH1', 'Gene', '999', (54, 58))	('differs', 'Reg', (90, 97))	('TP53', 'Gene', (60, 64))
2222	33919581	Importantly, CDH1 alterations were variably reported across the cohorts (37-64%), being highest in the EURO set (p < 0.001).	('CDH1', 'Gene', '999', (13, 17))	('alterations', 'Var', (18, 29))	('CDH1', 'Gene', (13, 17))	('highest', 'Reg', (88, 95))
2223	33919581	Significant enrichments for alterations in TP53 (p < 0.001) and ERBB2 (p = 0.0084) were noted for the METABRIC cohort, as a likely consequence of there being more grade 3 tumours in this dataset.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('alterations', 'Var', (28, 39))	('METABRIC', 'Gene', '5205', (102, 110))	('TP53', 'Gene', '7157', (43, 47))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('ERBB2', 'Gene', (64, 69))	('ERBB2', 'Gene', '2064', (64, 69))	('tumours', 'Disease', 'MESH:D009369', (171, 178))	('METABRIC', 'Gene', (102, 110))	('tumours', 'Disease', (171, 178))	('TP53', 'Gene', (43, 47))
2224	33919581	Overall, ERBB2 alterations were present in approximately 10% of the ILC cases, supporting recent work from Memorial Sloane Kettering, which also pointed to an enrichment for ERBB2 alterations in the metastatic setting of ILC, as did.	('alterations', 'Var', (180, 191))	('ERBB2', 'Gene', '2064', (174, 179))	('ERBB2', 'Gene', (174, 179))	('ILC', 'Disease', (68, 71))	('ERBB2', 'Gene', (9, 14))	('ERBB2', 'Gene', '2064', (9, 14))
2226	33919581	Given the cohort size and the high number of grade 3 and ER-negative tumours, we observed significant associations (Chi-squared/Fisher's exact tests; Table S2; Table 2) between both increasing grade and ER-negative status and the enrichment of TP53 (p < 0.00000001) and ERBB2 mutations (p < 0.02).	('tumours', 'Disease', (69, 76))	('ER', 'Gene', '2099', (203, 205))	('ERBB2', 'Gene', (270, 275))	('ERBB2', 'Gene', '2064', (270, 275))	('TP53', 'Gene', (244, 248))	('mutations', 'Var', (276, 285))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('ER', 'Gene', '2099', (57, 59))	('ER', 'Gene', '2099', (270, 272))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))	('TP53', 'Gene', '7157', (244, 248))
2227	33919581	Interestingly, there was a significant association between the absence of CDH1 mutations and ER negativity (p = 0.0204).	('ER', 'Gene', '2099', (93, 95))	('absence', 'NegReg', (63, 70))	('CDH1', 'Gene', (74, 78))	('CDH1', 'Gene', '999', (74, 78))	('mutations', 'Var', (79, 88))
2234	33919581	Higher mutation burden was also associated with ER-negative and triple negative states (Figure S1C; p = 0.0038), and with negative LN status (Figure S1D; p = 0.0038), older patient age at diagnosis (Figure S1E; p = 0.0001) and smaller tumour size (Figure S1F; p = 0.0241).	('ER', 'Gene', '2099', (48, 50))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('mutation burden', 'Var', (7, 22))	('tumour', 'Disease', (235, 241))	('patient', 'Species', '9606', (173, 180))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('triple negative states', 'MPA', (64, 86))
2235	33919581	TP53, PIK3CA and ERBB2 mutations were significantly associated with mutation burden (Figure S1H, p = 0.0002; Figure S1I, p = 0.0012; Figure S1K, p < 0.0001), while there was no association with CDH1 mutations (Figure S1J).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (52, 62))	('ERBB2', 'Gene', '2064', (17, 22))	('CDH1', 'Gene', (194, 198))	('PIK3CA', 'Gene', (6, 12))	('mutations', 'Var', (23, 32))	('ERBB2', 'Gene', (17, 22))	('PIK3CA', 'Gene', '5290', (6, 12))	('mutation burden', 'MPA', (68, 83))	('CDH1', 'Gene', '999', (194, 198))
2238	33919581	Neither the CDH1 nor PIK3CA gene mutation status had an impact on prognosis (Figure 2; p = 0.923 and p = 0.1233, respectively), while the presence of TP53 mutations (p < 0.0001; Figure 2), and ERBB2 alterations (mutations and amplifications) (p = 0.0222; Figure 2) were both associated with a significantly poorer outcome.	('presence', 'Var', (138, 146))	('alterations', 'Var', (199, 210))	('TP53', 'Gene', (150, 154))	('ERBB2', 'Gene', '2064', (193, 198))	('mutations', 'Var', (155, 164))	('ERBB2', 'Gene', (193, 198))	('PIK3CA', 'Gene', '5290', (21, 27))	('PIK3CA', 'Gene', (21, 27))	('CDH1', 'Gene', (12, 16))	('CDH1', 'Gene', '999', (12, 16))	('TP53', 'Gene', '7157', (150, 154))
2239	33919581	This corroborates the recent meta-analysis of TCGA data reported by Kurozumi et al., which showed a survival disadvantage in the presence of ERBB2 alterations, and contrasting with Deniziaut et al., which reported no prognostic impact.	('ERBB2', 'Gene', '2064', (141, 146))	('presence', 'Reg', (129, 137))	('disadvantage', 'NegReg', (109, 121))	('ERBB2', 'Gene', (141, 146))	('alterations', 'Var', (147, 158))
2240	33919581	We await the results of the SUMMIT trial (ClinicalTrials.gov Identifier: NCT01953926 , accessed on 16 April 2021) and the mutHER trial (ClinicalTrials.gov Identifier: NCT01670877 , accessed on 16 April 2021, among others) to determine the benefit of anti-HER2 therapy on a background of ERBB2 mutations.	('ERBB2', 'Gene', '2064', (287, 292))	('ERBB2', 'Gene', (287, 292))	('HER2', 'Gene', '2064', (255, 259))	('mutations', 'Var', (293, 302))	('ER', 'Gene', '2099', (256, 258))	('ER', 'Gene', '2099', (287, 289))	('HER2', 'Gene', (255, 259))	('ER', 'Gene', '2099', (126, 128))
2242	33919581	Here, we accessed cases and associated mutational data from (i) the International Cancer Genome Consortium (ICGC) project involving the sequencing of 560 whole genomes (n = 38 ILC); (ii) ILC sequenced as part of an in-house cohort of familial breast cancers (FBC; n = 5), which involved mutation signatures calculated using the same COSMIC substitution signatures V2 and rearrangement signatures as the ICGC; and (iii) ILC sequenced as part of TCGA (n = 4), for which data were re-mapped and analysed using the same in-house pipelines as used for the familial breast cancer cohort (Figure 3, Figure S2, Figure S3 and Table S3).	('breast cancers', 'Phenotype', 'HP:0003002', (243, 257))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('familial breast cancers', 'Disease', 'MESH:D001943', (234, 257))	('mutation', 'Var', (287, 295))	('familial breast cancer', 'Disease', (551, 573))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (567, 573))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (560, 573))	('familial breast cancer', 'Disease', 'MESH:D001943', (234, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('familial breast cancer', 'Disease', 'MESH:D001943', (551, 573))	('familial breast cancers', 'Disease', (234, 257))
2246	33919581	Tumours with low levels of genome complexity were characterised by substitution mutation signatures previously correlated with aging and reported in many different cancer types (signatures 1 and 5; green and dark blue annotations in Figure 3D).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('aging', 'biological_process', 'GO:0007568', ('127', '132'))	('substitution mutation', 'Var', (67, 88))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
2247	33919581	The tumours with the highest numbers of mutations in each cohort exhibited >25,000 substitutions, and these variants were categorised predominantly as C > T substitutions attributed to hyperactivity of the AID/APOBEC family of cytidine deaminases (substitution signatures 2 and 13).	('hyperactivity of the AID', 'Disease', 'MESH:D006948', (185, 209))	('APOBEC', 'cellular_component', 'GO:0030895', ('210', '216'))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('C > T', 'Var', (151, 156))	('mutations', 'Var', (40, 49))	('hyperactivity of the AID', 'Disease', (185, 209))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('hyperactivity', 'Phenotype', 'HP:0000752', (185, 198))	('substitutions', 'Var', (83, 96))	('tumours', 'Disease', (4, 11))
2250	33919581	These tumours harboured germline mutations in either BRCA1 or BRCA2, and tumours were considered homologous recombination deficient according to HRDetect analysis.	('tumours', 'Disease', (73, 80))	('tumours', 'Disease', (6, 13))	('BRCA2', 'Gene', '675', (62, 67))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('BRCA1', 'Gene', (53, 58))	('harboured', 'Reg', (14, 23))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('homologous recombination', 'biological_process', 'GO:0035825', ('97', '121'))	('BRCA1', 'Gene', '672', (53, 58))	('germline mutations', 'Var', (24, 42))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('BRCA2', 'Gene', (62, 67))
2251	33919581	Indeed, in our experience, most ILC variants exhibit multiple variant types (e.g., solid and pleomorphic), as opposed to being a pure variant, akin to mixed metaplastic carcinomas, and therefore classification and associating clinical and/or genomic parameters to a single variant classification status may be limited.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Disease', 'MESH:D009369', (169, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('solid', 'Disease', (83, 88))	('pure', 'molecular_function', 'GO:0034023', ('129', '133'))	('carcinomas', 'Disease', (169, 179))	('variants', 'Var', (36, 44))	('ILC', 'Gene', (32, 35))
2260	33919581	Nevertheless, it is clear that while ILC exhibit recurrent mutations in CDH1 and PIK3CA and have broadly quiet genomes, there persists a subset of 'non-conforming' ILC cases in which interesting genomic features are hidden beneath this curious morphological growth pattern.	('PIK3CA', 'Gene', (81, 87))	("'non-conforming' ILC", 'Disease', (147, 167))	('PIK3CA', 'Gene', '5290', (81, 87))	('CDH1', 'Gene', (72, 76))	('growth pattern', 'biological_process', 'GO:0007150', ('258', '272'))	('ILC', 'Disease', (164, 167))	('mutations', 'Var', (59, 68))	('CDH1', 'Gene', '999', (72, 76))	('growth pattern', 'biological_process', 'GO:0040007', ('258', '272'))
2261	33919581	CDH1 mutations are pathognomonic for ILC and occur in the majority of tumours; loss of E-cadherin has been shown to unequivocally drive the ILC phenotype.	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('loss', 'Var', (79, 83))	('drive', 'PosReg', (130, 135))	('CDH1', 'Gene', '999', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (5, 14))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('ILC', 'Disease', (37, 40))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('pathognomonic', 'Reg', (19, 32))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('ILC', 'Disease', (140, 143))	('tumours', 'Disease', (70, 77))	('CDH1', 'Gene', (0, 4))
2262	33919581	The frequency in which CDH1 mutations are reported in lobular lesions in the literature is highly variable (42-82%,, and is highest in microdissected lobular in situ carcinoma lesions, 81-94%), suggesting that mutation reporting is likely impacted by (i) the tumour cellularity of the individual specimens analysed, for what is described as a diffusely infiltrating tumour type; and (ii) the quality and sensitivity of sequencing technology used (panel, exome, whole genome).	('tumour', 'Disease', (259, 265))	('tumour', 'Phenotype', 'HP:0002664', (366, 372))	('situ carcinoma lesions', 'Disease', 'MESH:D002278', (161, 183))	('tumour', 'Disease', 'MESH:D009369', (366, 372))	('situ carcinoma lesions', 'Disease', (161, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('impacted', 'Reg', (239, 247))	('lobular in situ carcinoma', 'Phenotype', 'HP:0030076', (150, 175))	('tumour', 'Disease', (366, 372))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('CDH1', 'Gene', (23, 27))	('tumour', 'Disease', 'MESH:D009369', (259, 265))	('mutations', 'Var', (28, 37))	('CDH1', 'Gene', '999', (23, 27))
2263	33919581	PIK3CA mutations are the second most common alteration in ILC, and these mutations may provide an important therapeutic target for patients.	('patients', 'Species', '9606', (131, 139))	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
2264	33919581	While the PIK3CA mutations do not impact prognosis in these historical cohorts not exposed to therapies targeting these mutations, this may change in the future with more widespread use of PI3K/MTOR inhibitors.	('PIK3CA', 'Gene', '5290', (10, 16))	('MTOR', 'Gene', (194, 198))	('PIK3CA', 'Gene', (10, 16))	('MTOR', 'Gene', '2475', (194, 198))	('mutations', 'Var', (17, 26))	('PI3K', 'molecular_function', 'GO:0016303', ('189', '193'))
2266	33919581	Together with data from indicating the importance of AKT mutations (although infrequent), this shows the potential therapeutic importance of this pathway in ILC, as does the sensitivity of ILC models to the therapeutic targeting of AKT.	('AKT', 'Gene', '207', (232, 235))	('AKT', 'Gene', '207', (53, 56))	('AKT', 'Gene', (232, 235))	('mutations', 'Var', (57, 66))	('ILC', 'Disease', (157, 160))	('AKT', 'Gene', (53, 56))
2268	33919581	Additional features that were associated with poor prognosis in the large case series studied by panel and exome sequencing included grade 3 ILC, an ER-negative phenotype, mutations in TP53 or ERBB2, and a high tumour substitution mutation burden (>5 mutations/Mb).	('ILC', 'Disease', (141, 144))	('mutations', 'Var', (172, 181))	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('ERBB2', 'Gene', '2064', (193, 198))	('tumour', 'Disease', (211, 217))	('TP53', 'Gene', (185, 189))	('ERBB2', 'Gene', (193, 198))	('ER', 'Gene', '2099', (149, 151))	('ER', 'Gene', '2099', (193, 195))	('grade 3 ILC', 'Disease', (133, 144))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('TP53', 'Gene', '7157', (185, 189))
2271	33919581	However, in each dataset there are tumours with considerable genome complexity, which are associated with (i) a low number of structural rearrangements but a hypermutation genotype linked to APOBEC mutagenesis; or (ii) tumours with highly rearranged genomes affecting clustered sets of chromosomes, which would fit with a previous description of complex 'firestorm' rearrangements and have been associated with complex high level amplifications (and indeed co-amplification) of 11q13 and 8p12 in ER-positive breast cancer and ILC; or (iii) tumours exhibiting tumour genomes characteristic of homologous recombination (HR) DNA repair deficiency, which is associated with treatment opportunities involving platinum-based chemotherapy or PARP-inhibitors.	('tumours', 'Disease', (35, 42))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Disease', 'MESH:D001943', (508, 521))	('breast cancer', 'Disease', (508, 521))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('tumour', 'Disease', (219, 225))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('deficiency', 'Var', (633, 643))	('tumour', 'Phenotype', 'HP:0002664', (559, 565))	('mutagenesis', 'biological_process', 'GO:0006280', ('198', '209'))	('tumour', 'Disease', 'MESH:D009369', (559, 565))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('APOBEC', 'cellular_component', 'GO:0030895', ('191', '197'))	('tumour', 'Disease', (559, 565))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('tumour', 'Disease', (35, 41))	('DNA repair', 'biological_process', 'GO:0006281', ('622', '632'))	('tumours', 'Disease', (540, 547))	('cancer', 'Phenotype', 'HP:0002664', (515, 521))	('tumour', 'Phenotype', 'HP:0002664', (540, 546))	('ER', 'Gene', '2099', (496, 498))	('DNA', 'cellular_component', 'GO:0005574', ('622', '625'))	('tumours', 'Disease', (219, 226))	('tumours', 'Phenotype', 'HP:0002664', (540, 547))	('tumour', 'Disease', 'MESH:D009369', (540, 546))	('homologous recombination', 'biological_process', 'GO:0035825', ('592', '616'))	('tumour', 'Disease', (540, 546))	('tumours', 'Disease', 'MESH:D009369', (540, 547))	('tumours', 'Phenotype', 'HP:0002664', (219, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (508, 521))	('tumours', 'Disease', 'MESH:D009369', (219, 226))
2276	33919581	The findings specific to metastatic ILC are consistent with those genomic features that were associated with poor prognosis in primary ILC: higher mutation burden and frequency of mutations affecting driver genes TP53 and ERBB2, as well as mutations in ESR1.	('ERBB2', 'Gene', (222, 227))	('mutations', 'Var', (180, 189))	('TP53', 'Gene', (213, 217))	('higher', 'PosReg', (140, 146))	('ESR1', 'Gene', '2099', (253, 257))	('mutation burden', 'MPA', (147, 162))	('ESR1', 'Gene', (253, 257))	('mutations', 'Var', (240, 249))	('TP53', 'Gene', '7157', (213, 217))	('ERBB2', 'Gene', '2064', (222, 227))
2277	33919581	These analyses also confirmed the prevalence of NF1 mutations, as an emerging mechanism of endocrine resistance, as well as FAT1, which confers resistance to CDK4/6 inhibitors when inactive.	('mutations', 'Var', (52, 61))	('FAT1', 'Gene', (124, 128))	('NF1', 'Gene', '4763', (48, 51))	('CDK4/6', 'Gene', '1019;1021', (158, 164))	('CDK', 'molecular_function', 'GO:0004693', ('158', '161'))	('CDK4/6', 'Gene', (158, 164))	('FAT1', 'Gene', '2195', (124, 128))	('NF1', 'Gene', (48, 51))
2279	33919581	Taken together, these data and those of the collective large papers suggest that there are some very important morphological and molecular findings which could impact the variable clinical behaviour of ILC: grade 3, morphological variants, ER-negativity, alterations in PIK3CA, TP53, and ERBB2, and signatures associated with APOBEC, complex structural rearrangements, and HR deficiency.	('PIK3CA', 'Gene', (270, 276))	('impact', 'Reg', (160, 166))	('APOBEC', 'cellular_component', 'GO:0030895', ('326', '332'))	('variants', 'Var', (230, 238))	('TP53', 'Gene', '7157', (278, 282))	('TP53', 'Gene', (278, 282))	('HR deficiency', 'Disease', (373, 386))	('ERBB2', 'Gene', '2064', (288, 293))	('ER', 'Gene', '2099', (240, 242))	('PIK3CA', 'Gene', '5290', (270, 276))	('behaviour', 'biological_process', 'GO:0007610', ('189', '198'))	('ERBB2', 'Gene', (288, 293))	('associated', 'Reg', (310, 320))	('HR deficiency', 'Disease', 'MESH:D001919', (373, 386))	('ER', 'Gene', '2099', (288, 290))	('alterations', 'Var', (255, 266))	('APOBEC', 'Disease', (326, 332))
2317	33923191	All cases with score of 3+ were defined as HER2 IHC positive and score of 0 or 1+ were HER2 negative; no HER2 FISH was performed on these cases.	('HER2', 'Gene', '2064', (87, 91))	('HER2', 'Gene', (105, 109))	('HER2', 'Gene', (43, 47))	('HER2', 'Gene', '2064', (105, 109))	('HER2', 'Gene', '2064', (43, 47))	('score', 'Var', (15, 20))	('HER2', 'Gene', (87, 91))
2382	33923191	Interestingly, this patient also had BCRA1 mutation, which is uncommon in ER/PR positive ILC with typical lobular histology.	('mutation', 'Var', (43, 51))	('BCRA1', 'Gene', (37, 42))	('PR', 'Gene', '140738', (77, 79))	('patient', 'Species', '9606', (20, 27))	('ER', 'Gene', '2099', (74, 76))
2383	33923191	ILC is rare in other hereditary tumor syndromes and only accounts for a minority of cancers associated with well-established susceptibility genes, for example, comprising less than 10% of cancers in patients with BRCA2 mutations, and less than 5% of cancers in patients with BRCA1 or TP53 mutations.	('BRCA1', 'Gene', '672', (275, 280))	('hereditary tumor syndromes', 'Disease', 'MESH:D009386', (21, 47))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('BRCA1', 'Gene', (275, 280))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ILC', 'Disease', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('hereditary tumor syndromes', 'Disease', (21, 47))	('TP53', 'Gene', '7157', (284, 288))	('BRCA2', 'Gene', (213, 218))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (219, 228))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('BRCA2', 'Gene', '675', (213, 218))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (250, 257))	('cancers', 'Disease', (84, 91))	('patients', 'Species', '9606', (199, 207))	('TP53', 'Gene', (284, 288))	('patients', 'Species', '9606', (261, 269))
2384	33923191	BRCA1 mutation has also been found to be more commonly associated with basal-like or triple negative ILC.	('BRCA1', 'Gene', (0, 5))	('basal-like', 'Disease', (71, 81))	('triple negative ILC', 'Disease', (85, 104))	('mutation', 'Var', (6, 14))	('associated', 'Reg', (55, 65))	('BRCA1', 'Gene', '672', (0, 5))
2387	33923191	Its dysregulation results from somatic mutations in the CDH1 gene on chromosome 16q22.1, reported in 30% to 80% ILCs, as well as by loss of heterozygosity at the CDH2 locus.	('CDH2', 'Gene', '1000', (162, 166))	('loss', 'NegReg', (132, 136))	('CDH1', 'Gene', (56, 60))	('mutations', 'Var', (39, 48))	('CDH1', 'Gene', '999', (56, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('dysregulation', 'MPA', (4, 17))	('CDH2', 'Gene', (162, 166))
2388	33923191	In addition to CDH1 gene mutation, ILC and IDC differed in the FOXA1 and GATA3 mutational spectra, PTEN loss, and AKT1 activation and alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases in the Cancer Genome Analysis study.	('PTEN', 'Gene', '5728', (230, 234))	('FOXA1', 'Gene', (63, 68))	('Cancer', 'Disease', 'MESH:D009369', (301, 307))	('GATA3', 'Gene', '2625', (73, 78))	('CDH1', 'Gene', (15, 19))	('PTEN loss', 'Disease', 'MESH:D006223', (99, 108))	('GATA3', 'Gene', (73, 78))	('PIK3CA', 'Gene', '5290', (222, 228))	('mutation', 'Var', (25, 33))	('PTEN', 'Gene', (99, 103))	('PTEN loss', 'Disease', (99, 108))	('AKT1', 'Gene', '207', (240, 244))	('Cancer', 'Phenotype', 'HP:0002664', (301, 307))	('activation', 'PosReg', (119, 129))	('alterations', 'Var', (134, 145))	('AKT1', 'Gene', '207', (114, 118))	('PTEN', 'Gene', '5728', (99, 103))	('PTEN', 'Gene', (230, 234))	('rat', 'Species', '10116', (138, 141))	('PIK3CA', 'Gene', (222, 228))	('IDC', 'Gene', '4000', (43, 46))	('Cancer', 'Disease', (301, 307))	('IDC', 'Gene', (43, 46))	('AKT1', 'Gene', (240, 244))	('FOXA1', 'Gene', '3169', (63, 68))	('CDH1', 'Gene', '999', (15, 19))	('AKT1', 'Gene', (114, 118))
2391	33923191	HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, both of which are involved in activating the human epidermal growth factor receptor pathway.	('activating', 'PosReg', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('110', '133'))	('HER3', 'Gene', (9, 13))	('epidermal growth factor receptor', 'Gene', (110, 142))	('mutated', 'Var', (19, 26))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('HER3', 'Gene', '2065', (9, 13))	('HER2', 'Gene', (0, 4))	('human', 'Species', '9606', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('HER2', 'Gene', '2064', (0, 4))	('epidermal growth factor receptor', 'Gene', '1956', (110, 142))
2392	33923191	Further survival analyses in the same study revealed that chromosome 1q and 11p gains have independent prognostic value in ILC and that HER2 and AKT1 mutations were associated with increased risk of early relapse.	('early relapse', 'CPA', (199, 212))	('gains', 'PosReg', (80, 85))	('associated', 'Reg', (165, 175))	('AKT1', 'Gene', '207', (145, 149))	('ILC', 'Disease', (123, 126))	('HER2', 'Gene', (136, 140))	('mutations', 'Var', (150, 159))	('HER2', 'Gene', '2064', (136, 140))	('AKT1', 'Gene', (145, 149))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
2395	33923191	By comparing their molecular features such as HER2 gene mutations and copy number alterations and p53 mutation status to those of HER2(+) high-grade breast cancer will demonstrate if there are any differences to better classify the HER2(+) cILCs to guide management of this rare subset of breast cancer to avoid unnecessary treatment and drug toxicity.	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('p53', 'Gene', (98, 101))	('rat', 'Species', '10116', (175, 178))	('HER2', 'Gene', '2064', (232, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('rat', 'Species', '10116', (86, 89))	('mutations', 'Var', (56, 65))	('HER2', 'Gene', '2064', (46, 50))	('HER2', 'Gene', (130, 134))	('age', 'Gene', (258, 261))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Disease', (149, 162))	('drug toxicity', 'Disease', (338, 351))	('copy number alterations', 'Var', (70, 93))	('HER2', 'Gene', (232, 236))	('breast cancer', 'Phenotype', 'HP:0003002', (289, 302))	('drug toxicity', 'Disease', 'MESH:D064420', (338, 351))	('age', 'Gene', '5973', (258, 261))	('HER2', 'Gene', (46, 50))	('breast cancer', 'Disease', 'MESH:D001943', (289, 302))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', (289, 302))	('HER2', 'Gene', '2064', (130, 134))	('p53', 'Gene', '7157', (98, 101))
2401	33923191	further identified a mechanism for early dissemination in which HER2 aberrantly activates a program similar to mammary ductal branching that generates early disseminated cancer cells that are capable of forming metastasis after a dormancy phase.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('dormancy', 'biological_process', 'GO:0030431', ('230', '238'))	('cancer', 'Disease', (170, 176))	('activates', 'PosReg', (80, 89))	('HER2', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('HER2', 'Gene', '2064', (64, 68))	('rat', 'Species', '10116', (145, 148))	('aberrantly', 'Var', (69, 79))
2412	33923191	ILC, in particular, has more frequent mutations in the PI3K pathway including PIK3CA, PTEN, and AKT1, could potentially have a higher drug resistance rate.	('drug resistance', 'Phenotype', 'HP:0020174', (134, 149))	('PI3K pathway', 'Pathway', (55, 67))	('PIK3CA', 'Gene', (78, 84))	('AKT1', 'Gene', '207', (96, 100))	('PTEN', 'Gene', (86, 90))	('AKT1', 'Gene', (96, 100))	('PTEN', 'Gene', '5728', (86, 90))	('PIK3CA', 'Gene', '5290', (78, 84))	('drug resistance rate', 'MPA', (134, 154))	('rat', 'Species', '10116', (150, 153))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('higher', 'PosReg', (127, 133))	('drug resistance', 'biological_process', 'GO:0009315', ('134', '149'))	('mutations', 'Var', (38, 47))	('drug resistance', 'biological_process', 'GO:0042493', ('134', '149'))
2423	30820448	ESR1 mutations in metastatic lobular breast cancer patients Invasive lobular breast cancer (ILC) represents the second most common histology of breast cancer after invasive ductal breast cancer (IDC), accounts for up to 15% of all invasive cases and generally express the estrogen receptor (ER, coded by the ESR1 gene).	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('estrogen receptor', 'Gene', '2099', (272, 289))	('breast cancer', 'Disease', (144, 157))	('lobular breast cancer', 'Disease', (69, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('lobular breast cancer', 'Disease', (29, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('lobular breast cancer', 'Disease', 'MESH:D013274', (69, 90))	('ER', 'Gene', '2099', (291, 293))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (69, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('lobular breast cancer', 'Disease', 'MESH:D013274', (29, 50))	('estrogen receptor', 'Gene', (272, 289))	('invasive ductal breast cancer', 'Disease', 'MESH:D018270', (164, 193))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (29, 50))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ESR1', 'Gene', '2099', (0, 4))	('express', 'Reg', (260, 267))	('ESR1', 'Gene', (0, 4))	('invasive ductal breast cancer', 'Disease', (164, 193))	('ESR1', 'Gene', '2099', (308, 312))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('ESR1', 'Gene', (308, 312))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
2424	30820448	ESR1 mutations have been associated with resistance to endocrine therapy, however these have not been specifically evaluated in ILC.	('ILC', 'Disease', (128, 131))	('ESR1', 'Gene', (0, 4))	('associated', 'Reg', (25, 35))	('resistance to endocrine therapy', 'MPA', (41, 72))	('mutations', 'Var', (5, 14))	('ESR1', 'Gene', '2099', (0, 4))
2425	30820448	We assessed the frequency of ESR1 mutations by droplet digital PCR in a retrospective multi-centric series of matched primary tumor and recurrence samples (n = 279) from 80 metastatic ER-positive ILC patients.	('patients', 'Species', '9606', (200, 208))	('ER', 'Gene', '2099', (184, 186))	('ESR1', 'Gene', '2099', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('ESR1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('tumor', 'Disease', (126, 131))
2426	30820448	We further compared ESR1 mutations between IDC and ILC patients in metastatic samples from MSKCC-IMPACT (n = 595 IDC and 116 ILC) and in ctDNA from the SoFEA and PALOMA-3 trials (n = 416 IDC and 76 ILC).	('mutations', 'Var', (25, 34))	('compared', 'Reg', (11, 19))	('ESR1', 'Gene', (20, 24))	('ESR1', 'Gene', '2099', (20, 24))	('patients', 'Species', '9606', (55, 63))
2427	30820448	In the retrospective series, the metastases from seven patients (9%) harbored ESR1 mutations, which were absent from the interrogated primary samples.	('mutations', 'Var', (83, 92))	('metastases', 'Disease', (33, 43))	('ESR1', 'Gene', '2099', (78, 82))	('harbored', 'Reg', (69, 77))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('patients', 'Species', '9606', (55, 63))	('ESR1', 'Gene', (78, 82))
2428	30820448	Five patients (6%) had a mutation in the primary tumor or axillary metastasis, which could not be detected in the matched distant metastasis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('patients', 'Species', '9606', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutation', 'Var', (25, 33))	('axillary metastasis', 'CPA', (58, 77))	('tumor', 'Disease', (49, 54))
2429	30820448	In the MSKCC-IMPACT cohort, as well as in the SoFEA and PALOMA-3 trials, there were no differences in prevalence and distribution of the mutations between IDC and ILC, with D538G being the most frequent mutation in both histological subtypes.	('frequent', 'Reg', (194, 202))	('IDC', 'Gene', (155, 158))	('D538G', 'Var', (173, 178))	('D538G', 'Mutation', 'p.D538G', (173, 178))	('ILC', 'Gene', (163, 166))
2430	30820448	To conclude, no patient had an identical ESR1 mutation in the early and metastatic disease in the retrospective ILC series.	('ESR1', 'Gene', (41, 45))	('ESR1', 'Gene', '2099', (41, 45))	('mutation', 'Var', (46, 54))	('patient', 'Species', '9606', (16, 23))
2431	30820448	In the external series, there was no difference in terms of prevalence and type of ESR1 mutations between ILC and IDC.	('IDC', 'Disease', (114, 117))	('ESR1', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('ILC', 'Disease', (106, 109))	('ESR1', 'Gene', '2099', (83, 87))
2433	30820448	ESR1 encodes the estrogen receptor targeted by endocrine therapy : thus, tumors harboring mutations in this gene may require different treatment strategies.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('ESR1', 'Gene', (0, 4))	('mutations', 'Var', (90, 99))	('estrogen receptor', 'Gene', (17, 34))	('estrogen receptor', 'Gene', '2099', (17, 34))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('ESR1', 'Gene', '2099', (0, 4))	('tumors', 'Disease', (73, 79))
2434	30820448	Christine Desmedt :  from KU Leuven, Belgium, and colleagues found that 9% of patients had metastases with ESR1 mutations that were absent in primary breast tumors; another 6% had mutations in the primary tumors or in cancer-invaded lymph nodes that were not detected in distant metastatic sites.	('metastases', 'Disease', (91, 101))	('patients', 'Species', '9606', (78, 86))	('mutations', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('ESR1', 'Gene', '2099', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('KU Leuven', 'Disease', (26, 35))	('ESR1', 'Gene', (107, 111))	('breast tumors', 'Disease', (150, 163))	('breast tumors', 'Disease', 'MESH:D001943', (150, 163))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('mutations', 'Var', (180, 189))	('breast tumors', 'Phenotype', 'HP:0100013', (150, 163))	('primary tumors', 'Disease', (197, 211))	('KU Leuven', 'Disease', 'None', (26, 35))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('primary tumors', 'Disease', 'MESH:D009369', (197, 211))
2435	30820448	Comparisons with other datasets showed that the prevalence and distribution of ESR1 mutations were not significantly different among women with lobular and ductal breast cancer, the two most common subtypes of the disease.	('women', 'Species', '9606', (133, 138))	('ESR1', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('lobular and ductal breast cancer', 'Disease', 'MESH:D013274', (144, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('ESR1', 'Gene', '2099', (79, 83))
2441	30820448	Although several mechanisms of endocrine resistance have been proposed, one of those that has been receiving more attention during the last years thanks to the increasing sequencing initiatives of metastatic breast tumors is represented by the recurrent mutations in the ESR1 gene (reviewed by Jeselsohn et al.).	('breast tumors', 'Disease', 'MESH:D001943', (208, 221))	('ESR1', 'Gene', (271, 275))	('breast tumors', 'Disease', (208, 221))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('ESR1', 'Gene', '2099', (271, 275))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('breast tumors', 'Phenotype', 'HP:0100013', (208, 221))	('mutations', 'Var', (254, 263))
2445	30820448	The majority of the ESR1 mutations are concentrated on two amino acids (Y537, D538) in the ligand-binding domain.	('ligand', 'molecular_function', 'GO:0005488', ('91', '97'))	('ESR1', 'Gene', (20, 24))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('ESR1', 'Gene', '2099', (20, 24))	('Y537', 'Var', (72, 76))	('D538', 'Var', (78, 82))
2446	30820448	Mutations affecting the ESR1 gene have been detected mainly in metastases from ER-positive/HER2-negative breast tumors, at a frequency ranging from 5 to 25%, when considering series with >20 interrogated metastases.	('metastases', 'Disease', (204, 214))	('breast tumors', 'Disease', 'MESH:D001943', (105, 118))	('ESR1', 'Gene', (24, 28))	('ER', 'Gene', '2099', (79, 81))	('breast tumors', 'Disease', (105, 118))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('breast tumors', 'Phenotype', 'HP:0100013', (105, 118))	('metastases', 'Disease', 'MESH:D009362', (204, 214))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('detected', 'Reg', (44, 52))	('HER2', 'Gene', (91, 95))	('Mutations', 'Var', (0, 9))	('HER2', 'Gene', '2064', (91, 95))	('ESR1', 'Gene', '2099', (24, 28))	('ER', 'Gene', '2099', (92, 94))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('metastases', 'Disease', (63, 73))
2447	30820448	The largest cohort of BC metastases with information about the ESR1 mutational status is the one derived from the prospective clinical sequencing initiative from the Memorial Sloan Kettering Cancer Center (MSKCC-IMPACT), which reported mutations in 107/835 (12.5%) metastatic BC patients (source: cbioportal.org).	('metastatic BC', 'Disease', (265, 278))	('Cancer', 'Phenotype', 'HP:0002664', (191, 197))	('BC', 'Phenotype', 'HP:0003002', (22, 24))	('BC', 'Phenotype', 'HP:0003002', (276, 278))	('ESR1', 'Gene', (63, 67))	('metastases', 'Disease', 'MESH:D009362', (25, 35))	('mutations', 'Var', (236, 245))	('patients', 'Species', '9606', (279, 287))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (166, 197))	('ESR1', 'Gene', '2099', (63, 67))	('metastases', 'Disease', (25, 35))	('Memorial Sloan Kettering Cancer', 'Disease', (166, 197))
2448	30820448	Besides the detection in metastatic tissue, several studies have also interrogated the presence of these mutations in circulating tumor DNA (ctDNA) in institutional cohorts or in the context of clinical trials.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mutations', 'Var', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
2449	30820448	The prevalence of ESR1 mutations was much higher here, ranging between 14.8 and 31.5% in the institutional series and between 25.3 and 39.1% in the trials.	('mutations', 'Var', (23, 32))	('ESR1', 'Gene', (18, 22))	('ESR1', 'Gene', '2099', (18, 22))
2450	30820448	Results are consistent across the cohorts in reporting higher ESR1 mutation rates in patients treated with aromatase inhibitors in the metastatic setting.	('mutation', 'Var', (67, 75))	('ESR1', 'Gene', (62, 66))	('patients', 'Species', '9606', (85, 93))	('higher', 'PosReg', (55, 61))	('ESR1', 'Gene', '2099', (62, 66))
2451	30820448	So far the prevalence of these mutations has been extremely low in primary tumors, with 0.5% mutated samples detected by next-generation sequencing (NGS) in the large cohort from The Cancer Genome Atlas (TCGA, source: cbioportal.org).	('primary tumors', 'Disease', 'MESH:D009369', (67, 81))	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Cancer Genome Atlas', 'Disease', (183, 202))	('primary tumors', 'Disease', (67, 81))	('Cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (183, 202))
2453	30820448	Two series of primary cancers from patients who recurred revealed also increased rates of 3 and 3.5% using NGS.	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('NGS', 'Var', (107, 110))
2458	30820448	However, given the higher rates of ESR1 mutations detected with ddPCR, we hypothesized that deeper sequencing methods could maybe identify additional matched mutations.	('mutations', 'Var', (40, 49))	('ESR1', 'Gene', (35, 39))	('ESR1', 'Gene', '2099', (35, 39))
2459	30820448	If the ESR1 mutations were pre-existing in the primary tumor and led to endocrine resistance, this would have important therapeutic and monitoring implications.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('led to', 'Reg', (65, 71))	('ESR1', 'Gene', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('pre', 'molecular_function', 'GO:0003904', ('27', '30'))	('mutations', 'Var', (12, 21))	('endocrine resistance', 'MPA', (72, 92))	('tumor', 'Disease', (55, 60))	('ESR1', 'Gene', '2099', (7, 11))
2460	30820448	Since tumors harboring ESR1 mutations may require a different endocrine treatment strategy, it is of utmost importance to identify these.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('ESR1', 'Gene', '2099', (23, 27))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('ESR1', 'Gene', (23, 27))
2461	30820448	However, no study has ever specifically evaluated the presence and distribution of ESR1 mutations in metastatic ILC.	('ESR1', 'Gene', (83, 87))	('metastatic ILC', 'Disease', (101, 115))	('ESR1', 'Gene', '2099', (83, 87))	('mutations', 'Var', (88, 97))
2462	30820448	In this study, we therefore assembled a retrospective multi-centric cohort of matched normal, primary and metastatic samples from metastatic ER-positive ILC patients and evaluated the most frequent ESR1 mutations using ddPCR.	('ER', 'Gene', '2099', (141, 143))	('ESR1', 'Gene', '2099', (198, 202))	('patients', 'Species', '9606', (157, 165))	('ESR1', 'Gene', (198, 202))	('mutations', 'Var', (203, 212))
2472	30820448	We assessed the presence of five different ESR1 mutations: E380Q, Y537S/C/N, and D538G.	('E380Q', 'Var', (59, 64))	('ESR1', 'Gene', (43, 47))	('Y537S', 'Var', (66, 71))	('ESR1', 'Gene', '2099', (43, 47))	('D538G', 'Var', (81, 86))	('E380Q', 'Mutation', 'rs1057519827', (59, 64))	('D538G', 'Mutation', 'p.D538G', (81, 86))	('Y537S', 'SUBSTITUTION', 'None', (66, 71))
2473	30820448	Five patients (6%) had a unique ESR1 mutation in the primary tumor (n = 3) or axillary lymph node metastasis (n = 2), which was not detected in the matched distant metastasis (Table 2).	('patients', 'Species', '9606', (5, 13))	('axillary lymph node metastasis', 'Disease', (78, 108))	('mutation', 'Var', (37, 45))	('ESR1', 'Gene', '2099', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('axillary lymph node metastasis', 'Disease', 'MESH:D009362', (78, 108))	('ESR1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
2474	30820448	These mutations showed a variant allele fraction ranging between 0.1 and 2.0% and were distributed as follows: D538G (n = 3), Y537S (n = 1), and Y537N (n = 1).	('Y537S', 'Mutation', 'p.Y537S', (126, 131))	('D538G', 'Var', (111, 116))	('Y537N', 'Var', (145, 150))	('Y537N', 'Mutation', 'p.Y537N', (145, 150))	('D538G', 'Mutation', 'p.D538G', (111, 116))	('Y537S', 'Var', (126, 131))
2475	30820448	The metastases from seven patients (9%) harbored ESR1 mutations, which were absent from the interrogated primary samples (Table 3).	('harbored', 'Reg', (40, 48))	('metastases', 'Disease', 'MESH:D009362', (4, 14))	('ESR1', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (26, 34))	('ESR1', 'Gene', '2099', (49, 53))	('metastases', 'Disease', (4, 14))
2476	30820448	Of these, patient #6 harbored the Y537S mutation in the skin metastasis and the D538G mutation in the axillary lymph node metastasis.	('Y537S', 'Var', (34, 39))	('Y537S', 'Mutation', 'p.Y537S', (34, 39))	('D538G', 'Var', (80, 85))	('axillary lymph node metastasis', 'Disease', (102, 132))	('patient', 'Species', '9606', (10, 17))	('axillary lymph node metastasis', 'Disease', 'MESH:D009362', (102, 132))	('D538G', 'Mutation', 'p.D538G', (80, 85))
2477	30820448	Of interest, for two of these patients, two different metastatic samples collected at a different time of disease evolution displayed a different ESR1 mutational status.	('patients', 'Species', '9606', (30, 38))	('mutational', 'Var', (151, 161))	('ESR1', 'Gene', (146, 150))	('ESR1', 'Gene', '2099', (146, 150))
2478	30820448	The first metastatic biopsy of patient #2 was taken at first diagnosis of recurrence and did not harbor an ESR1 mutation, while the second, taken at progression two years later after she had received an aromatase inhibitor, presented the D538G mutation.	('ESR1', 'Gene', (107, 111))	('patient', 'Species', '9606', (31, 38))	('D538G', 'Var', (238, 243))	('D538G', 'Mutation', 'p.D538G', (238, 243))	('ESR1', 'Gene', '2099', (107, 111))
2479	30820448	Patient #78, who was diagnosed with de novo metastatic disease, also had two metastases that were analyzed, the first taken at diagnosis which was negative and the second taken 1.3 years later after being treated with letrozole, which harbored the E380Q mutation.	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('metastases', 'Disease', (77, 87))	('letrozole', 'Chemical', 'MESH:D000077289', (218, 227))	('E380Q', 'Var', (248, 253))	('Patient', 'Species', '9606', (0, 7))	('E380Q', 'Mutation', 'rs1057519827', (248, 253))
2481	30820448	All but one patients with ESR1 mutations were <= 55 years old at diagnosis and had axillary lymph node metastasi(e)s. Also all but one patients were treated with aromatase inhibitors, in the adjuvant and/or metastatic setting before the metastatic biopsy was taken.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (135, 143))	('mutations', 'Var', (31, 40))	('axillary lymph node metastasi', 'Disease', (83, 112))	('ESR1', 'Gene', '2099', (26, 30))	('axillary lymph node metastasi', 'Disease', 'MESH:D009362', (83, 112))	('ESR1', 'Gene', (26, 30))
2484	30820448	Of interest, the metastasis from patient #67 harbored three different ESR1 mutations, however this patient received only adjuvant tamoxifen as endocrine treatment.	('patient', 'Species', '9606', (99, 106))	('ESR1', 'Gene', '2099', (70, 74))	('patient', 'Species', '9606', (33, 40))	('tamoxifen', 'Chemical', 'MESH:D013629', (130, 139))	('harbored', 'Reg', (45, 53))	('ESR1', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))
2485	30820448	We did not observe any association with the specific histologic ILC variants and none of the metastatic samples that lost ER expression presented an ESR1 mutation.	('ER', 'Gene', '2099', (122, 124))	('ESR1', 'Gene', (149, 153))	('mutation', 'Var', (154, 162))	('ESR1', 'Gene', '2099', (149, 153))
2486	30820448	To compare the prevalence and distribution of ESR1 mutations between IDC and ILC patients, we first interrogated the metastases from the MSKCC-IMPACT cohort (Fig.	('mutations', 'Var', (51, 60))	('ESR1', 'Gene', '2099', (46, 50))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('patients', 'Species', '9606', (81, 89))	('ESR1', 'Gene', (46, 50))	('metastases', 'Disease', (117, 127))
2488	30820448	We observed no statistically significant difference in the prevalence of ESR1 mutations, with 11.9% (71/595) of the IDC and 13.8% (16/116) of the ILC patients harboring a mutation in at least one of the investigated metastases (p = 0.540, Fisher's exact test).	('metastases', 'Disease', 'MESH:D009362', (216, 226))	('ILC', 'Disease', (146, 149))	('mutation', 'Var', (171, 179))	('ESR1', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('harboring', 'Reg', (159, 168))	('patients', 'Species', '9606', (150, 158))	('metastases', 'Disease', (216, 226))	('IDC', 'Disease', (116, 119))	('ESR1', 'Gene', '2099', (73, 77))
2489	30820448	We then compared the types of mutations and observed that the most frequent mutation both in IDC and ILC is the D538G mutation, present in 38.5 and 56.3% of the IDC and ILC mutated samples, respectively.	('D538G', 'Var', (112, 117))	('IDC', 'Disease', (161, 164))	('D538G', 'Mutation', 'p.D538G', (112, 117))
2490	30820448	Some of the less commonly reported mutations such as V422del, S463P, L536H/P/R, and Y537N were only observed in metastases from IDC patients.	('L536H', 'Var', (69, 74))	('IDC', 'Disease', (128, 131))	('L536H', 'SUBSTITUTION', 'None', (69, 74))	('V422del', 'Mutation', 'p.422delV', (53, 60))	('S463P', 'Mutation', 'rs1057519714', (62, 67))	('metastases', 'Disease', (112, 122))	('Y537N', 'Var', (84, 89))	('observed', 'Reg', (100, 108))	('V422del', 'Var', (53, 60))	('Y537N', 'Mutation', 'p.Y537N', (84, 89))	('S463P', 'Var', (62, 67))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('patients', 'Species', '9606', (132, 140))
2491	30820448	Of note, in the metastases from the ILC patients, the only additionally detected mutation that we found and that was not part of the five mutations we were interrogating in our series was the L536Q mutation present in one metastasis.	('L536Q', 'Var', (192, 197))	('patients', 'Species', '9606', (40, 48))	('L536Q', 'Mutation', 'p.L536Q', (192, 197))	('metastases', 'Disease', (16, 26))	('metastases', 'Disease', 'MESH:D009362', (16, 26))
2493	30820448	Given the key role of FOXA1 and GATA3 in the transcription factor complex of ER, we aimed at investigating the co-occurrence of mutations present in these genes with ESR1 mutations.	('transcription factor', 'molecular_function', 'GO:0000981', ('45', '65'))	('FOXA1', 'Gene', '3169', (22, 27))	('ESR1', 'Gene', '2099', (166, 170))	('GATA3', 'Gene', (32, 37))	('transcription', 'biological_process', 'GO:0006351', ('45', '58'))	('ER', 'Gene', '2099', (77, 79))	('ESR1', 'Gene', (166, 170))	('GATA3', 'Gene', '2625', (32, 37))	('mutations', 'Var', (171, 180))	('FOXA1', 'Gene', (22, 27))	('transcription factor complex', 'cellular_component', 'GO:0005667', ('45', '73'))
2494	30820448	Consistently with what has been observed in the primary disease, we noticed a higher prevalence of GATA3 mutations in IDC (14.8%) compared to ILC (3.4%) metastases (p < 0.001, Fisher's exact test).	('metastases', 'Disease', (153, 163))	('IDC', 'Disease', (118, 121))	('metastases', 'Disease', 'MESH:D009362', (153, 163))	('mutations', 'Var', (105, 114))	('GATA3', 'Gene', (99, 104))	('GATA3', 'Gene', '2625', (99, 104))
2495	30820448	The only statistically significant association we observed was between ESR1 and GATA3 mutations in IDC metastases, with 28.0% of the ESR1-mutated metastases harboring also GATA3 mutations, compared to only 13.0% of the ESR1 wild-type metastases (p = 0.002, Fisher's exact test).	('mutations', 'Var', (86, 95))	('metastases', 'Disease', (146, 156))	('GATA3', 'Gene', '2625', (172, 177))	('ESR1', 'Gene', (219, 223))	('GATA3', 'Gene', (80, 85))	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('metastases', 'Disease', 'MESH:D009362', (234, 244))	('ESR1', 'Gene', '2099', (71, 75))	('GATA3', 'Gene', '2625', (80, 85))	('ESR1', 'Gene', '2099', (133, 137))	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('mutations', 'Var', (178, 187))	('metastases', 'Disease', (103, 113))	('metastases', 'Disease', (234, 244))	('ESR1', 'Gene', (71, 75))	('ESR1', 'Gene', '2099', (219, 223))	('GATA3', 'Gene', (172, 177))	('ESR1', 'Gene', (133, 137))
2496	30820448	We further compared the prevalence and distribution of ESR1 mutations identified in ctDNA between IDC and ILC patients in the SoFEA (NCT00253422) and PALOMA-3 (NCT01942135) trials (Fig.	('ESR1', 'Gene', (55, 59))	('IDC', 'Disease', (98, 101))	('mutations', 'Var', (60, 69))	('ESR1', 'Gene', '2099', (55, 59))	('patients', 'Species', '9606', (110, 118))
2498	30820448	There was no statistically significant difference in the overall incidence of ESR1 mutations between the two main histologies with 29.6 and 26.3% reported in samples from IDC and ILC patients, respectively (p = 0.680, Fisher's exact test).	('mutations', 'Var', (83, 92))	('IDC', 'Disease', (171, 174))	('ESR1', 'Gene', '2099', (78, 82))	('ILC', 'Disease', (179, 182))	('ESR1', 'Gene', (78, 82))	('patients', 'Species', '9606', (183, 191))
2499	30820448	Consistently with the above results, we further did not observe any difference in the distribution of the ESR1 mutations between the two histologies.	('mutations', 'Var', (111, 120))	('ESR1', 'Gene', (106, 110))	('ESR1', 'Gene', '2099', (106, 110))
2500	30820448	In this study, we aimed first at evaluating ESR1 mutations in a unique retrospective multi-centric cohort of metastatic ILC and second at comparing their prevalence and distribution to metastatic IDC using external cohorts.	('mutations', 'Var', (49, 58))	('ESR1', 'Gene', '2099', (44, 48))	('metastatic ILC', 'Disease', (109, 123))	('metastatic IDC', 'Disease', (185, 199))	('ESR1', 'Gene', (44, 48))
2505	30820448	Globally, these comparisons revealed no difference in prevalence of ESR1 mutations between the two histologies.	('ESR1', 'Gene', (68, 72))	('ESR1', 'Gene', '2099', (68, 72))	('mutations', 'Var', (73, 82))
2506	30820448	reported ESR1 mutations in 11/% (11/118) and 11.4% (14/113) of IDC and ILC metastases, however this study was limited to bone metastases.	('ESR1', 'Gene', '2099', (9, 13))	('bone metastases', 'Disease', (121, 136))	('ILC', 'Disease', (71, 74))	('bone metastases', 'Disease', 'MESH:D009362', (121, 136))	('metastases', 'Disease', (75, 85))	('metastases', 'Disease', 'MESH:D009362', (126, 136))	('metastases', 'Disease', (126, 136))	('ESR1', 'Gene', (9, 13))	('metastases', 'Disease', 'MESH:D009362', (75, 85))	('mutations', 'Var', (14, 23))	('IDC', 'Disease', (63, 66))
2507	30820448	reported ESR1 mutations in 10.3% (72/698) and 14.2% (20/141) of IDC and ILC samples, respectively, however these were a mixture of primary tumors and metastases from recurring patients.	('ILC', 'Disease', (72, 75))	('patients', 'Species', '9606', (176, 184))	('ESR1', 'Gene', '2099', (9, 13))	('primary tumors', 'Disease', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('metastases', 'Disease', (150, 160))	('IDC', 'Disease', (64, 67))	('primary tumors', 'Disease', 'MESH:D009369', (131, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('ESR1', 'Gene', (9, 13))	('metastases', 'Disease', 'MESH:D009362', (150, 160))	('mutations', 'Var', (14, 23))
2508	30820448	With regard to the type of mutations present in ILC, we observed that D538G is the most common mutation, present in the metastatic disease from 57.1%, 56.3%, and 60.0% of the ILC patients with ESR1-mutated metastases from our series, MSKCC-IMPACT, and the SoFEA/PALOMA-3 ctDNA, respectively.	('D538G', 'Var', (70, 75))	('ESR1', 'Gene', '2099', (193, 197))	('metastases', 'Disease', 'MESH:D009362', (206, 216))	('D538G', 'Mutation', 'p.D538G', (70, 75))	('ESR1', 'Gene', (193, 197))	('ILC', 'Disease', (175, 178))	('patients', 'Species', '9606', (179, 187))	('metastases', 'Disease', (206, 216))
2510	30820448	It has recently been demonstrated that the different activating ESR1 mutations do promote a metastatic phenotype but are not similar with regard to the efficacy of ER antagonists.	('mutations', 'Var', (69, 78))	('ER', 'Gene', '2099', (164, 166))	('promote', 'PosReg', (82, 89))	('ESR1', 'Gene', '2099', (64, 68))	('metastatic phenotype', 'CPA', (92, 112))	('activating', 'PosReg', (53, 63))	('ESR1', 'Gene', (64, 68))
2511	30820448	observed that Y537S-mutated tumors, as opposed to tumors harboring D538G, E380Q, or S463P mutations, are associated with in vivo resistance to fulvestrant and should therefore be treated with a more potent ER antagonist.	('Y537S-mutated', 'Var', (14, 27))	('ER', 'Gene', '2099', (206, 208))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('E380Q', 'Var', (74, 79))	('E380Q', 'Mutation', 'rs1057519827', (74, 79))	('resistance to fulvestrant', 'MPA', (129, 154))	('Y537S', 'Mutation', 'p.Y537S', (14, 19))	('S463P', 'Mutation', 'rs1057519714', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('D538G', 'Var', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('S463P', 'Var', (84, 89))	('D538G', 'Mutation', 'p.D538G', (67, 72))
2512	30820448	The fraction of Y537S mutations among all ESR1 mutations was variable across the series: 42% in our series, 18.8% in MSKCC-IMPACT, and 15% in SoFEA/PALOMA-3.	('Y537S', 'Var', (16, 21))	('ESR1', 'Gene', (42, 46))	('ESR1', 'Gene', '2099', (42, 46))	('Y537S', 'Mutation', 'p.Y537S', (16, 21))
2513	30820448	This suggests that the type of ESR1 mutation should be carefully evaluated for optimal endocrine treatment decision.	('ESR1', 'Gene', (31, 35))	('ESR1', 'Gene', '2099', (31, 35))	('mutation', 'Var', (36, 44))
2514	30820448	This study is to the best of our knowledge the largest study of ER-positive BC comparing the presence of ESR1 mutations in matched primary and metastatic samples.	('mutations', 'Var', (110, 119))	('ESR1', 'Gene', '2099', (105, 109))	('ER', 'Gene', '2099', (64, 66))	('BC', 'Phenotype', 'HP:0003002', (76, 78))	('ESR1', 'Gene', (105, 109))
2517	30820448	The full spectrum of ESR1 mutations was however interrogated in the MSKCC-IMPACT cohort.	('ESR1', 'Gene', '2099', (21, 25))	('mutations', 'Var', (26, 35))	('ESR1', 'Gene', (21, 25))
2519	30820448	Indeed a study comparing NGS and ddPCR showed that they could detect three times more ESR1 mutations with ddPCR than NGS.	('ESR1', 'Gene', '2099', (86, 90))	('mutations', 'Var', (91, 100))	('ESR1', 'Gene', (86, 90))
2520	30820448	Finally, the last limitation of this study was that it focused on ESR1 mutations only, and was therefore not reporting on other potential mechanisms of endocrine resistance involving directly (ESR1 gain/amplification/translocation/fusion) or indirectly ESR1 (such as partners from the transcription factor complex).	('ESR1', 'Gene', '2099', (66, 70))	('gain/amplification/translocation/fusion', 'PosReg', (198, 237))	('ESR1', 'Gene', '2099', (193, 197))	('transcription factor', 'molecular_function', 'GO:0000981', ('285', '305'))	('ESR1', 'Gene', (66, 70))	('ESR1', 'Gene', '2099', (253, 257))	('transcription factor complex', 'cellular_component', 'GO:0005667', ('285', '313'))	('transcription', 'biological_process', 'GO:0006351', ('285', '298'))	('mutations', 'Var', (71, 80))	('ESR1', 'Gene', (193, 197))	('ESR1', 'Gene', (253, 257))
2522	30820448	We only observed a positive association between ESR1 and GATA3 mutations in metastases from IDC patients, the biological implications of which should be further investigated through functional studies.	('mutations', 'Var', (63, 72))	('positive association', 'Reg', (19, 39))	('metastases', 'Disease', 'MESH:D009362', (76, 86))	('ESR1', 'Gene', (48, 52))	('GATA3', 'Gene', (57, 62))	('ESR1', 'Gene', '2099', (48, 52))	('IDC', 'Disease', (92, 95))	('patients', 'Species', '9606', (96, 104))	('GATA3', 'Gene', '2625', (57, 62))	('metastases', 'Disease', (76, 86))
2523	30820448	To conclude, we have shown here using the largest series of matched primary/metastasis ILC cohort and an ultra-sensitive technology, that there was no patient presenting an identical ESR1 mutation in the early setting and in metastatic disease.	('mutation', 'Var', (188, 196))	('ESR1', 'Gene', '2099', (183, 187))	('patient', 'Species', '9606', (151, 158))	('ESR1', 'Gene', (183, 187))
2524	30820448	Furthermore, the study did not identify differences in terms of prevalence and type of ESR1 mutations between the two most common BC histological subtypes.	('BC', 'Phenotype', 'HP:0003002', (130, 132))	('ESR1', 'Gene', (87, 91))	('ESR1', 'Gene', '2099', (87, 91))	('mutations', 'Var', (92, 101))
2528	30820448	The presence of the mutations E380Q, Y537S/C/N, and D538G was assessed using custom designed mutation-specific assays in a total reaction volume of 23 microl consisting in 1x ddPCR supermix for probes without dUTP, 0.9 microM each primer, 0.25 microM probe, and 10-100 ng of DNA.	('D538G', 'Var', (52, 57))	('Y537S', 'SUBSTITUTION', 'None', (37, 42))	('Y537S', 'Var', (37, 42))	('D538G', 'Mutation', 'p.D538G', (52, 57))	('E380Q', 'Mutation', 'rs1057519827', (30, 35))	('dUTP', 'Chemical', 'MESH:C027078', (209, 213))	('DNA', 'cellular_component', 'GO:0005574', ('275', '278'))	('E380Q', 'Var', (30, 35))
2534	30820448	With regard to the ESR1 mutations, we only considered those reported to be "Gain-of-function" or "Likely Gain-of-function" according to OncoKB.	('mutations', 'Var', (24, 33))	('ESR1', 'Gene', (19, 23))	('Gain-of-function', 'PosReg', (105, 121))	('ESR1', 'Gene', '2099', (19, 23))
2535	30820448	For the GATA3 and FOXA1 mutations, we considered the mutations annotated as "hotspot" or "3D hotspot" or "Likely Oncogenic" or "Predicted Oncogenic" in cbioportal.org.	('FOXA1', 'Gene', (18, 23))	('GATA3', 'Gene', (8, 13))	('GATA3', 'Gene', '2625', (8, 13))	('FOXA1', 'Gene', '3169', (18, 23))	('mutations', 'Var', (24, 33))
2536	30820448	In these studies, the presence of the ESR1 mutations was assessed by ddPCR.	('ESR1', 'Gene', '2099', (38, 42))	('mutations', 'Var', (43, 52))	('ESR1', 'Gene', (38, 42))
2647	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))
2660	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))
2689	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.	('MCF-7', 'CellLine', 'CVCL:0031', (85, 90))	('human', 'Species', '9606', (79, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('USPIO-PEG-OCT CA', 'Var', (119, 135))	('OCT', 'Chemical', '-', (129, 132))	('bind', 'Interaction', (149, 153))	('PEG', 'Chemical', 'MESH:D011092', (125, 128))	('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))
2693	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))	('CAs', 'cellular_component', 'GO:0005650', ('187', '190'))	('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))
2695	20799509	The tumors showed uptake of P866 and P1048, which decreased with competing free folate.	('uptake', 'MPA', (18, 24))	('P866', 'Var', (28, 32))	('uptake', 'biological_process', 'GO:0098739', ('18', '24'))	('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))	('uptake', 'biological_process', 'GO:0098657', ('18', '24'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
2696	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))
2697	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))
2698	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))
2703	20799509	In contrast, and despite considerable efforts, a clear cut case has not been yet made for the earlier detection of ovarian cancer by either MRI or CA-enhanced MRI.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('MRI', 'Var', (140, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (115, 129))	('ovarian cancer', 'Disease', (115, 129))
2757	24305978	Each patient's tumor histology was classified using International Classification of Diseases for Oncology (ICD-O-3) histologic codes for IDC (M-8500 or M-8521), ILC (M-8520), mixed ductal/lobular carcinoma (IDLC) (M-8522-4), and other histology.	('M-8520', 'Var', (166, 172))	('patient', 'Species', '9606', (5, 12))	('lobular carcinoma', 'Disease', (188, 205))	('IDC', 'Gene', '4000', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('M-8522-4', 'Var', (214, 222))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (188, 205))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('IDC', 'Gene', (137, 140))	('tumor', 'Disease', (15, 20))	('ILC', 'Disease', (161, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('lobular carcinoma', 'Disease', 'MESH:D018275', (188, 205))	('Oncology', 'Phenotype', 'HP:0002664', (97, 105))	('M-8521', 'Var', (152, 158))	('M-8500', 'Var', (142, 148))
2794	24305978	After propensity score adjustment, breast MRI receipt was associated with increased odds of a final mastectomy among all patients (OR: 1.20; 95% CI [1.08, 1.33]) and among patients with IDC (OR: 1.21; 95% CI [1.07, 1.37]) and IDLC (1.43; 95% CI [1.10, 1.85]).	('IDC', 'Gene', (186, 189))	('breast MRI', 'Var', (35, 45))	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (121, 129))	('IDC', 'Gene', '4000', (186, 189))
2842	27642214	Since it resembled a poorly differentiated urothelial carcinoma, immunohistochemistry was performed with markers positive for urothelial carcinoma, such as uroplakin II, GATA3, p63, p40, and 34betaE12.	('p63', 'Gene', '8626', (177, 180))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (43, 63))	('p40', 'cellular_component', 'GO:0043514', ('182', '185'))	('GATA3', 'Gene', (170, 175))	('p40', 'Gene', (182, 185))	('34betaE12', 'Var', (191, 200))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (126, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('urothelial carcinoma', 'Disease', (43, 63))	('uroplakin II', 'Gene', '7379', (156, 168))	('GATA3', 'Gene', '2625', (170, 175))	('p40', 'Gene', '8626', (182, 185))	('p63', 'Gene', (177, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('p40', 'cellular_component', 'GO:0070743', ('182', '185'))	('uroplakin II', 'Gene', (156, 168))	('urothelial carcinoma', 'Disease', (126, 146))
2941	26199779	revealed that RT-PCR of the BM is an independent prognostic factor for disease-free survival of breast cancer patients.	('disease-free survival', 'CPA', (71, 92))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('RT-PCR', 'Var', (14, 20))	('patients', 'Species', '9606', (110, 118))
3034	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))
3042	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))
3089	11305955	A missense mutation in exon 12 of E-cadherin (1774G A; Ala592Thr) was previously found in one family with diffuse gastric cancer, and colon and breast cancer.	('gastric cancer', 'Disease', (114, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('E-cadherin', 'Gene', (34, 44))	('found', 'Reg', (81, 86))	('colon and breast cancer', 'Disease', 'MESH:D001943', (134, 157))	('E-cadherin', 'Gene', '999', (34, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cadherin', 'molecular_function', 'GO:0008014', ('36', '44'))	('Ala592Thr', 'Chemical', '-', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('missense mutation in', 'Var', (2, 22))
3090	11305955	An allelic association study was performed to determine whether the Ala592Thr alteration predisposes to breast cancer.	('Ala592Thr', 'Chemical', '-', (68, 77))	('Ala592Thr', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('predisposes', 'Reg', (89, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
3092	11305955	However, a correlation between the Ala592Thr alteration and ductal comedo-type tumour was seen.	('comedo', 'Phenotype', 'HP:0025249', (67, 73))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('Ala592Thr', 'Chemical', '-', (35, 44))	('Ala592Thr', 'Var', (35, 44))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
3093	11305955	These results, together with previously reported studies, indicate that germline mutations and, more commonly, somatic mutations in E-cadherin may have an influence on the behaviour of the tumours, rather than predispose to breast cancer.	('predispose', 'Reg', (210, 220))	('tumours', 'Disease', (189, 196))	('E-cadherin', 'Gene', (132, 142))	('E-cadherin', 'Gene', '999', (132, 142))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancer', 'Disease', (224, 237))	('have', 'Reg', (147, 151))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('behaviour', 'biological_process', 'GO:0007610', ('172', '181'))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumours', 'Disease', 'MESH:D009369', (189, 196))	('influence', 'Reg', (155, 164))	('germline mutations', 'Var', (72, 90))
3095	11305955	Germline mutations in E-cadherin have been described in families with early-onset diffuse gastric cancer, and loss of function of this gene has been implicated in the pathogenesis of early-onset colorectal and breast cancers.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('implicated', 'Reg', (149, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('pathogenesis', 'biological_process', 'GO:0009405', ('167', '179'))	('E-cadherin', 'Gene', (22, 32))	('E-cadherin', 'Gene', '999', (22, 32))	('breast cancers', 'Phenotype', 'HP:0003002', (210, 224))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('loss of function', 'NegReg', (110, 126))	('described', 'Reg', (43, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('24', '32'))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('colorectal and breast cancers', 'Disease', 'MESH:D015179', (195, 224))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('gastric cancer', 'Disease', (90, 104))
3097	11305955	The role of E-cadherin mutation in development of hereditary gastric cancer has been shown, but its role in predisposing to breast cancer is still unproved.	('hereditary gastric cancer', 'Disease', 'MESH:D013274', (50, 75))	('E-cadherin', 'Gene', (12, 22))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('mutation', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('E-cadherin', 'Gene', '999', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('hereditary gastric cancer', 'Disease', (50, 75))	('breast cancer', 'Disease', (124, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))
3100	11305955	1a) (Salahshor S, et al, manuscript submitted), we identified an E-cadherin germline mutation that cosegregated with the disease.	('disease', 'Disease', (121, 128))	('mutation', 'Var', (85, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('67', '75'))	('cosegregated with', 'Reg', (99, 116))	('E-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (65, 75))
3101	11305955	This missense mutation in exon 12 (Ala592Thr) was also detected in the index patient's mother, who had ductal breast cancer.	('ductal breast cancer', 'Disease', (103, 123))	('ductal breast cancer', 'Disease', 'MESH:D001943', (103, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Ala592Thr', 'Chemical', '-', (35, 44))	('Ala592Thr', 'Var', (35, 44))	('patient', 'Species', '9606', (77, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
3102	11305955	In an attempt to clarify a possible role for the Ala592Thr alteration in predisposing to breast cancer, we screened for this specific alteration in different series of breast cancer patients and control individuals.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('patients', 'Species', '9606', (182, 190))	('Ala592Thr', 'Chemical', '-', (49, 58))	('Ala592Thr', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
3104	11305955	Nineteen probands with familial breast cancer who demonstrated LOH at chromosome 16q, and 12 patients from 10 families with breast, gastric and colorectal cancers were screened for germline mutations in the coding sequences of E-cadherin.	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('colorectal cancers', 'Disease', 'MESH:D015179', (144, 162))	('cadherin', 'molecular_function', 'GO:0008014', ('229', '237'))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('familial breast cancer', 'Disease', 'MESH:D001943', (23, 45))	('LOH', 'Var', (63, 66))	('colorectal cancers', 'Disease', (144, 162))	('familial breast cancer', 'Disease', (23, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('E-cadherin', 'Gene', (227, 237))	('E-cadherin', 'Gene', '999', (227, 237))	('patients', 'Species', '9606', (93, 101))
3106	11305955	The frequencies of the 1774G A variant (Ala592Thr) were determined in DNA extracted from the blood of 358 unrelated probands with familial breast cancer, 214 unrelated early-onset breast cancer patients (age of onset <41 years), 126 unrelated BRCA1 or BRCA2 carriers, and 604 unselected breast cancer patients and 497 control individuals, who were considered to represent the general population in Sweden and Norway.	('patients', 'Species', '9606', (301, 309))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('BRCA1', 'Gene', '672', (243, 248))	('Ala592Thr', 'Chemical', '-', (40, 49))	('BRCA1', 'Gene', (243, 248))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('familial breast cancer', 'Disease', 'MESH:D001943', (130, 152))	('breast cancer', 'Disease', (180, 193))	('familial breast cancer', 'Disease', (130, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('variant', 'Var', (31, 38))	('patients', 'Species', '9606', (194, 202))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('BRCA2', 'Gene', (252, 257))	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', 'MESH:D001943', (287, 300))	('BRCA2', 'Gene', '675', (252, 257))	('breast cancer', 'Disease', (287, 300))
3108	11305955	Single-stranded conformation polymorphism (SSCP) and denaturing high-performance liquid chromotography (DHPLC; Transgenomic, Santa Clara, CA, USA) were used to screen 16 exons of the E-cadherin gene for the presence of alterations (Table 1).	('E-cadherin', 'Gene', '999', (183, 193))	('DHPLC', 'Chemical', '-', (104, 109))	('alterations', 'Var', (219, 230))	('cadherin', 'molecular_function', 'GO:0008014', ('185', '193'))	('E-cadherin', 'Gene', (183, 193))
3112	11305955	We also searched for germline alterations in 19 individuals with familial breast cancer who showed LOH at the E-cadherin locus in their tumours.	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('LOH', 'Var', (99, 102))	('familial breast cancer', 'Disease', (65, 87))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('cadherin', 'molecular_function', 'GO:0008014', ('112', '120'))	('tumours', 'Disease', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('familial breast cancer', 'Disease', 'MESH:D001943', (65, 87))	('E-cadherin', 'Gene', (110, 120))	('E-cadherin', 'Gene', '999', (110, 120))
3117	11305955	1a) (Salahshor S, et al, manuscript submitted), we found a germline missense mutation in exon 12 (Ala592Thr) of E-cadherin.	('Ala592Thr', 'Chemical', '-', (98, 107))	('missense mutation in', 'Var', (68, 88))	('E-cadherin', 'Gene', (112, 122))	('E-cadherin', 'Gene', '999', (112, 122))	('cadherin', 'molecular_function', 'GO:0008014', ('114', '122'))
3120	11305955	In order to investigate whether this alteration was associated with an increased risk for breast cancer, we used a specific restriction enzyme digestion/PCR test to detect the variant, in an allelic association study in familial and sporadic breast cancer cases, as well as control samples that represented the general population.	('breast cancer', 'Phenotype', 'HP:0003002', (242, 255))	('variant', 'Var', (176, 183))	('associated', 'Reg', (52, 62))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('digestion', 'biological_process', 'GO:0007586', ('143', '152'))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('breast cancer', 'Disease', (242, 255))	('breast cancer', 'Disease', 'MESH:D001943', (242, 255))
3122	11305955	1b), one woman with ductal comedo-type breast cancer at age 75 years had the Ala592Thr variant.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('Ala592Thr variant', 'Var', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('comedo', 'Phenotype', 'HP:0025249', (27, 33))	('Ala592Thr', 'Chemical', '-', (77, 86))	('breast cancer', 'Disease', (39, 52))	('woman', 'Species', '9606', (9, 14))
3123	11305955	1c), one woman with a breast cancer of ductal comedo type at age 37 years showed the Ala592Thr variant.	('Ala592Thr', 'Chemical', '-', (85, 94))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('Ala592Thr', 'Var', (85, 94))	('comedo', 'Phenotype', 'HP:0025249', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('woman', 'Species', '9606', (9, 14))
3126	11305955	Because the variant did not segregate with the disease, it is not likely that this alteration predisposes to breast cancer in either of these two families.	('variant', 'Var', (12, 19))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
3127	11305955	We also screened 126 BRCA1 or BRCA2 carriers from different families, and found the mutation in one breast cancer patient (family 4056) with a BRCA1 germline mutation (delC2594).	('delC2594', 'Var', (168, 176))	('BRCA1', 'Gene', '672', (143, 148))	('BRCA1', 'Gene', '672', (21, 26))	('delC2594', 'Mutation', 'c.2594delC', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('one breast', 'Phenotype', 'HP:0012813', (96, 106))	('BRCA1', 'Gene', (143, 148))	('BRCA1', 'Gene', (21, 26))	('patient', 'Species', '9606', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('BRCA2', 'Gene', (30, 35))	('breast cancer', 'Disease', (100, 113))	('BRCA2', 'Gene', '675', (30, 35))
3128	11305955	It was possible to obtain a sample from her sister who also carried the BRCA1 mutation, and she was found to share the Ala592Thr variant (Fig.	('BRCA1', 'Gene', '672', (72, 77))	('mutation', 'Var', (78, 86))	('Ala592Thr', 'Chemical', '-', (119, 128))	('Ala592Thr', 'Var', (119, 128))	('BRCA1', 'Gene', (72, 77))
3130	11305955	Because both of these tumours were caused by a germline BRCA1 mutation, the E-cadherin variant was not likely to have predisposed to breast cancer.	('caused by', 'Reg', (35, 44))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('breast cancer', 'Disease', (133, 146))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('BRCA1', 'Gene', '672', (56, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('cadherin', 'molecular_function', 'GO:0008014', ('78', '86'))	('tumours', 'Disease', (22, 29))	('BRCA1', 'Gene', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('mutation', 'Var', (62, 70))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('E-cadherin', 'Gene', (76, 86))	('E-cadherin', 'Gene', '999', (76, 86))
3131	11305955	Among the 604 sporadic breast cancer cases, five were found to carry the Ala592Thr alteration (0.83%; Table 2).	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('Ala592Thr', 'Chemical', '-', (73, 82))	('Ala592Thr alteration', 'Var', (73, 93))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
3136	11305955	So far, E-cadherin germline mutations have been reported in 17 diffuse gastric cancer families.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('germline mutations', 'Var', (19, 37))	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('reported', 'Reg', (48, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))
3137	11305955	The frequency of E-cadherin germline mutations in breast cancer reported thus far is low.	('germline mutations', 'Var', (28, 46))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('E-cadherin', 'Gene', (17, 27))	('E-cadherin', 'Gene', '999', (17, 27))	('breast cancer', 'Disease', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
3138	11305955	Mutations reported in E-cadherin in lobular breast cancer patients are in most cases tumour restricted, and not germline alterations.	('lobular breast cancer', 'Disease', 'MESH:D013274', (36, 57))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('E-cadherin', 'Gene', (22, 32))	('E-cadherin', 'Gene', '999', (22, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (36, 57))	('tumour', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Mutations', 'Var', (0, 9))	('cadherin', 'molecular_function', 'GO:0008014', ('24', '32'))	('patients', 'Species', '9606', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('lobular breast cancer', 'Disease', (36, 57))
3140	11305955	We conclude that, although germline E-cadherin mutations are sometimes found in familial gastric and colon cancer, they are not frequently involved in families in which gastric cancer appears to segregate as a part of an inherited predisposition to primary breast cancer.	('gastric cancer', 'Disease', (169, 183))	('primary breast cancer', 'Disease', (249, 270))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('familial gastric and colon cancer', 'Disease', 'MESH:D013274', (80, 113))	('found', 'Reg', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('mutations', 'Var', (47, 56))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('primary breast cancer', 'Disease', 'MESH:D001943', (249, 270))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))
3141	11305955	The frequency of Ala592Thr alteration, which was first identified in one family with familial diffuse gastric cancer plus one case of colon and one case of breast cancer (Fig.	('Ala592Thr alteration', 'Var', (17, 37))	('familial diffuse gastric cancer', 'Disease', 'MESH:D013274', (85, 116))	('Ala592Thr', 'Chemical', '-', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('familial diffuse gastric cancer', 'Disease', (85, 116))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))
3143	11305955	Thus, available data indicate that germline E-cadherin mutations do not constitute a major risk factor for breast cancer.	('mutations', 'Var', (55, 64))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('cadherin', 'molecular_function', 'GO:0008014', ('46', '54'))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
3145	11305955	The fact that many tumours with the alteration (Ala592Thr) in the present study were of the ductal comedo type may indicate a genetic basis for the phenotypic divergence caused by this germline E-cadherin alteration.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('E-cadherin', 'Gene', '999', (194, 204))	('alteration', 'Var', (36, 46))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('Ala592Thr', 'Chemical', '-', (48, 57))	('tumours', 'Disease', (19, 26))	('comedo', 'Phenotype', 'HP:0025249', (99, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('196', '204'))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('E-cadherin', 'Gene', (194, 204))
3148	11305955	In summary, the present study, together with previously reported data, suggests that a germline mutation in E-cadherin is not a major risk factor for breast cancer.	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('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))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('germline mutation', 'Var', (87, 104))
3149	11305955	However, germline, and more often somatic mutations in this gene could have an impact on phenotypic divergence and prognosis, including growth pattern of the tumours, such as in lobular and perhaps ductal comedo-type breast cancer.	('lobular', 'Disease', (178, 185))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (217, 230))	('have', 'Reg', (71, 75))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('comedo', 'Phenotype', 'HP:0025249', (205, 211))	('growth pattern', 'biological_process', 'GO:0007150', ('136', '150'))	('mutations', 'Var', (42, 51))	('growth pattern', 'biological_process', 'GO:0040007', ('136', '150'))	('tumours', 'Disease', (158, 165))	('impact', 'Reg', (79, 85))
3150	11305955	In addition, other genetic alterations or epigenetic changes in the E-cadherin gene may have an impact on the metastatic behaviour of the cancer cells, and thereby on the clinical outcome.	('cancer', 'Disease', (138, 144))	('have', 'Reg', (88, 92))	('epigenetic changes', 'Var', (42, 60))	('genetic alterations', 'Var', (19, 38))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('impact', 'Reg', (96, 102))	('behaviour', 'biological_process', 'GO:0007610', ('121', '130'))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
3152	11305955	Mutations in E-cadherin, which encodes a transmembrane protein, have been described in cancers of the endometrium and ovary, signet ring cell carcinoma of the stomach, the diffuse sclerosing variant of papillary thyroid carcinoma, invasive lobular breast cancer, and diffuse and mixed gastric cancer.	('carcinoma of the stomach', 'Disease', (142, 166))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (212, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('gastric cancer', 'Disease', (285, 299))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('diffuse sclerosing variant', 'Disease', (172, 198))	('transmembrane', 'cellular_component', 'GO:0016021', ('41', '54'))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (231, 261))	('Mutations', 'Var', (0, 9))	('described', 'Reg', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('cancers', 'Disease', (87, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (285, 299))	('invasive lobular breast cancer', 'Disease', (231, 261))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('transmembrane', 'cellular_component', 'GO:0044214', ('41', '54'))	('carcinoma of the stomach', 'Disease', 'MESH:D013274', (142, 166))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('ovary', 'Disease', (118, 123))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (202, 229))	('gastric cancer', 'Phenotype', 'HP:0012126', (285, 299))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (240, 261))	('papillary thyroid carcinoma', 'Disease', (202, 229))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (202, 229))
3153	11305955	E-cadherin germline mutations have been found in early-onset hereditary diffuse gastric cancer, and such mutations have even been implicated as risk factors for early-onset breast and colon cancers.	('colon cancer', 'Phenotype', 'HP:0003003', (184, 196))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('colon cancers', 'Phenotype', 'HP:0003003', (184, 197))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('found', 'Reg', (40, 45))	('hereditary diffuse gastric cancer', 'Disease', (61, 94))	('mutations', 'Var', (105, 114))	('E-cadherin', 'Gene', (0, 10))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (61, 94))	('germline mutations', 'Var', (11, 29))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('E-cadherin', 'Gene', '999', (0, 10))	('breast and colon cancers', 'Disease', 'MESH:D001943', (173, 197))
3154	11305955	Inactivating mutations and decreased expression of E-cadherin have been reported in invasive lobular breast carcinomas, which demonstrate involvement of E-cadherin alteration in sporadic lobular breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast carcinoma', 'Phenotype', 'HP:0003002', (101, 117))	('cadherin', 'molecular_function', 'GO:0008014', ('155', '163'))	('decreased', 'NegReg', (27, 36))	('cadherin', 'molecular_function', 'GO:0008014', ('53', '61'))	('Inactivating mutations', 'Var', (0, 22))	('sporadic lobular breast cancer', 'Disease', 'MESH:D013274', (178, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('invasive lobular breast carcinomas', 'Disease', 'MESH:D018275', (84, 118))	('E-cadherin', 'Gene', (51, 61))	('E-cadherin', 'Gene', '999', (51, 61))	('E-cadherin', 'Gene', (153, 163))	('E-cadherin', 'Gene', '999', (153, 163))	('invasive lobular breast carcinomas', 'Disease', (84, 118))	('expression', 'MPA', (37, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (187, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('sporadic lobular breast cancer', 'Disease', (178, 208))	('breast carcinomas', 'Phenotype', 'HP:0003002', (101, 118))
3158	11305955	A role of E-cadherin mutation in development of hereditary gastric cancer has been shown, but its role in predisposing to breast cancer is still unproved.	('E-cadherin', 'Gene', '999', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('hereditary gastric cancer', 'Disease', (48, 73))	('mutation', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cadherin', 'molecular_function', 'GO:0008014', ('12', '20'))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('hereditary gastric cancer', 'Disease', 'MESH:D013274', (48, 73))	('E-cadherin', 'Gene', (10, 20))
3161	11305955	The remaining 19 familial breast cancer patients were identified as having LOH at 16q in their tumour.	('familial breast cancer', 'Disease', (17, 39))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('patients', 'Species', '9606', (40, 48))	('LOH at 16q', 'Var', (75, 85))	('tumour', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('familial breast cancer', 'Disease', 'MESH:D001943', (17, 39))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
3162	11305955	LOH at 16q occurs frequently in sporadic and in familial breast cancer.	('familial breast cancer', 'Disease', (48, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('LOH at 16q', 'Var', (0, 10))	('sporadic', 'Disease', (32, 40))	('familial breast cancer', 'Disease', 'MESH:D001943', (48, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
3163	11305955	In the familial breast cancer patients in whom LOH at 16q was identified, E-cadherin was suggested to be a candidate predisposing tumour suppressor gene, and the aim of the present study was to elucidate this relation.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('familial breast cancer', 'Disease', (7, 29))	('LOH', 'Var', (47, 50))	('E-cadherin', 'Gene', (74, 84))	('tumour', 'Disease', (130, 136))	('E-cadherin', 'Gene', '999', (74, 84))	('patients', 'Species', '9606', (30, 38))	('familial breast cancer', 'Disease', 'MESH:D001943', (7, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
3165	11305955	In an attempt to clarify a possible role of the Ala592Thr alteration in predisposing to breast cancer, we screened for this specific alteration in different series of breast cancer patients and control individuals.	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('Ala592Thr', 'Chemical', '-', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('patients', 'Species', '9606', (181, 189))	('Ala592Thr', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
3167	11305955	Nineteen women with breast cancer who exhibited LOH at 16q were included in the present study.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('women', 'Species', '9606', (9, 14))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('LOH', 'Var', (48, 51))
3170	11305955	In order to examine whether germline mutations in E-cadherin are involved in familial breast, gastric and colon cancer, 12 patients from 10 such families were also included in the present study.	('E-cadherin', 'Gene', (50, 60))	('colon cancer', 'Phenotype', 'HP:0003003', (106, 118))	('patients', 'Species', '9606', (123, 131))	('E-cadherin', 'Gene', '999', (50, 60))	('familial breast, gastric and colon cancer', 'Disease', 'MESH:D013274', (77, 118))	('involved', 'Reg', (65, 73))	('germline mutations', 'Var', (28, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cadherin', 'molecular_function', 'GO:0008014', ('52', '60'))
3173	11305955	The frequencies of Ala592Thr variant were determined in DNA extracted from blood of 358 probands with familial breast cancer, 214 unrelated early-onset breast cancer patients (age of onset <41 years), 126 unrelated BRCA1 or BRCA2 carriers, and 604 unselected breast cancer patients from consecutive series.	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('BRCA2', 'Gene', (224, 229))	('Ala592Thr', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('breast cancer', 'Disease', (259, 272))	('patients', 'Species', '9606', (273, 281))	('BRCA2', 'Gene', '675', (224, 229))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('BRCA1', 'Gene', '672', (215, 220))	('Ala592Thr', 'Chemical', '-', (19, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('BRCA1', 'Gene', (215, 220))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('familial breast cancer', 'Disease', 'MESH:D001943', (102, 124))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('familial breast cancer', 'Disease', (102, 124))	('patients', 'Species', '9606', (166, 174))
3177	11305955	All familial cases had already been tested for germline mutations in the BRCA1 and BRCA2 genes.	('BRCA2', 'Gene', '675', (83, 88))	('germline', 'Var', (47, 55))	('BRCA1', 'Gene', '672', (73, 78))	('BRCA1', 'Gene', (73, 78))	('BRCA2', 'Gene', (83, 88))
3178	11305955	In the previous study of allelic loss at 16q in familial tumours the two markers D16S7/p79-2-23 and APRT/HUAP15, which map to 16q24.3, were used.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('APRT', 'Gene', (100, 104))	('allelic loss', 'Var', (25, 37))	('familial tumours', 'Disease', (48, 64))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('familial tumours', 'Disease', 'MESH:D009386', (48, 64))	('APRT', 'Gene', '353', (100, 104))
3180	11305955	SSCP was used to screen 16 exons of the E-cadherin gene for the presence of alterations, as described by Berx et al and Salahshor et al (manuscript submitted), but with some modification.	('E-cadherin', 'Gene', (40, 50))	('alterations', 'Var', (76, 87))	('E-cadherin', 'Gene', '999', (40, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))
3186	11305955	In short, two pairs of primers, E-CAD12F (TGTCTGATGT-GAATGACAGC) and E-CAD12R (TGCTGTGAAGGGAGATGTAT) were used for amplification of nucleotides 1574-1884 of E-cadherin (based on GenBank accession number Z13009).	('E-CAD12F', 'CellLine', 'CVCL:0199', (32, 40))	('E-CAD12R', 'Var', (69, 77))	('E-cadherin', 'Gene', (157, 167))	('nucleotides 1574-1884', 'Var', (132, 153))	('cadherin', 'molecular_function', 'GO:0008014', ('159', '167'))	('E-cadherin', 'Gene', '999', (157, 167))
3189	11305955	Negative results were also obtained by screening for germline alterations in 19 individuals with familial breast cancer who exhibited LOH at the E-cadherin locus in their tumours.	('familial breast cancer', 'Disease', 'MESH:D001943', (97, 119))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('E-cadherin', 'Gene', '999', (145, 155))	('familial breast cancer', 'Disease', (97, 119))	('cadherin', 'molecular_function', 'GO:0008014', ('147', '155'))	('LOH', 'Var', (134, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('tumours', 'Disease', 'MESH:D009369', (171, 178))	('tumours', 'Disease', (171, 178))	('E-cadherin', 'Gene', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
3197	11305955	1a) (Salahshor S, et al, manuscript submitted), we identified a germline missense alteration in exon12 (Ala592Thr) of E-cadherin.	('E-cadherin', 'Gene', (118, 128))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('E-cadherin', 'Gene', '999', (118, 128))	('missense alteration', 'Var', (73, 92))	('Ala592Thr', 'Chemical', '-', (104, 113))
3199	11305955	In order to investigate whether this alteration was associated with an increased breast cancer risk we used a specific restriction enzyme digestion/PCR test to detect the variant, in an allelic association study of familial and sporadic breast cancer patients as well as control individuals who were considered to represent the general population.	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('digestion', 'biological_process', 'GO:0007586', ('138', '147'))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('variant', 'Var', (171, 178))	('breast cancer', 'Disease', (237, 250))	('patients', 'Species', '9606', (251, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
3200	11305955	1c), one woman with a breast cancer of ductal comedo type at age 37 years exhibited the Ala592Thr variant, whereas her two sisters with breast cancer at ages 45 and 51 years did not.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Disease', (22, 35))	('Ala592Thr', 'Var', (88, 97))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('comedo', 'Phenotype', 'HP:0025249', (46, 52))	('exhibited', 'Reg', (74, 83))	('Ala592Thr', 'Chemical', '-', (88, 97))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('woman', 'Species', '9606', (9, 14))
3202	11305955	We also screened 126 BRCA1 or BRCA2 carriers from different families, and identified the mutation in one patient with breast cancer (family 4056) with a BRCA1 germline mutation (2594delC).	('patient', 'Species', '9606', (105, 112))	('BRCA1', 'Gene', '672', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BRCA1', 'Gene', '672', (153, 158))	('BRCA1', 'Gene', (21, 26))	('2594delC', 'Var', (178, 186))	('BRCA2', 'Gene', (30, 35))	('BRCA1', 'Gene', (153, 158))	('2594delC', 'Mutation', 'c.2594delC', (178, 186))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('BRCA2', 'Gene', '675', (30, 35))
3203	11305955	It was possible to obtain a sample from her sister who also carried the BRCA1 mutation, and she was found to share the Ala592Thr variant also (Fig.	('BRCA1', 'Gene', '672', (72, 77))	('mutation', 'Var', (78, 86))	('Ala592Thr', 'Chemical', '-', (119, 128))	('Ala592Thr', 'Var', (119, 128))	('BRCA1', 'Gene', (72, 77))
3204	11305955	Among the 604 sporadic breast cancer patients, five were found to carry the Ala592Thr alteration (0.83%; Table 2).	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('patients', 'Species', '9606', (37, 45))	('Ala592Thr', 'Chemical', '-', (76, 85))	('Ala592Thr alteration', 'Var', (76, 96))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
3207	11305955	Thus far, E-cadherin germline mutations have been reported in 17 diffuse gastric cancer families.	('E-cadherin', 'Gene', '999', (10, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('germline mutations', 'Var', (21, 39))	('reported', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cadherin', 'molecular_function', 'GO:0008014', ('12', '20'))	('gastric cancer', 'Disease', (73, 87))	('E-cadherin', 'Gene', (10, 20))
3209	11305955	In other studies, a low frequency of E-cadherin germline mutations in familial gastric cancer has been reported.	('E-cadherin', 'Gene', (37, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('39', '47'))	('familial gastric cancer', 'Disease', (70, 93))	('E-cadherin', 'Gene', '999', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('familial gastric cancer', 'Disease', 'MESH:D013274', (70, 93))	('germline mutations', 'Var', (48, 66))
3210	11305955	Mutations in E-cadherin reported in lobular breast cancer cases are in most cases tumour restricted, and are not germline alterations.	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('lobular breast cancer', 'Disease', 'MESH:D013274', (36, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (36, 57))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Disease', (82, 88))	('E-cadherin', 'Gene', (13, 23))	('Mutations', 'Var', (0, 9))	('E-cadherin', 'Gene', '999', (13, 23))	('lobular breast cancer', 'Disease', (36, 57))
3211	11305955	In the 17 gastric cancer families with germline mutations, five members from three families were also affected by breast cancer.	('germline mutations', 'Var', (39, 57))	('gastric cancer', 'Phenotype', 'HP:0012126', (10, 24))	('affected', 'Reg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('gastric cancer', 'Disease', (10, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (10, 24))	('breast cancer', 'Disease', (114, 127))
3217	11305955	We conclude that, although germline E-cadherin mutations are sometimes found in familial gastric and colon cancer, they are not frequently involved in families in which breast cancer appears to segregate as a part of an inherited predisposition for gastric and colon cancer.	('gastric and colon cancer', 'Disease', 'MESH:D013274', (89, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('familial gastric and colon cancer', 'Disease', 'MESH:D013274', (80, 113))	('found', 'Reg', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('mutations', 'Var', (47, 56))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('colon cancer', 'Phenotype', 'HP:0003003', (261, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))	('gastric and colon cancer', 'Disease', 'MESH:D013274', (249, 273))	('breast cancer', 'Disease', (169, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
3220	11305955	Thus, available data thus far indicate that germline E-cadherin mutations do not constitute a major risk factor for breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('mutations', 'Var', (64, 73))	('cadherin', 'molecular_function', 'GO:0008014', ('55', '63'))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))
3222	11305955	The fact that many breast cancer cases with the alteration (Ala592Thr) in the present study were of the ductal comedo type may indicate a genetic basis for the phenotypic divergence caused by this germline E-cadherin alteration.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('cadherin', 'molecular_function', 'GO:0008014', ('208', '216'))	('Ala592Thr', 'Chemical', '-', (60, 69))	('comedo', 'Phenotype', 'HP:0025249', (111, 117))	('alteration', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('E-cadherin', 'Gene', (206, 216))	('E-cadherin', 'Gene', '999', (206, 216))	('breast cancer', 'Disease', (19, 32))
3227	11305955	If E-cadherin functions as a classical tumour suppressor gene, then loss or inactivation of the remaining normal E-cadherin allele would be an important event in tumourigenesis in individuals who carry a germline mutation.	('cadherin', 'molecular_function', 'GO:0008014', ('115', '123'))	('tumour', 'Disease', (162, 168))	('germline mutation', 'Var', (204, 221))	('tumour', 'Disease', (39, 45))	('cadherin', 'molecular_function', 'GO:0008014', ('5', '13'))	('E-cadherin', 'Gene', (113, 123))	('inactivation', 'NegReg', (76, 88))	('E-cadherin', 'Gene', '999', (113, 123))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('loss', 'NegReg', (68, 72))	('E-cadherin', 'Gene', (3, 13))	('E-cadherin', 'Gene', '999', (3, 13))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (162, 168))
3228	11305955	In tumours with somatic E-cadherin mutations, there is often evidence of deletion of the wild-type E-cadherin allele, whereas in cases with germline mutations in the E-cadherin gene this is not usually seen.	('E-cadherin', 'Gene', (166, 176))	('E-cadherin', 'Gene', '999', (166, 176))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('cadherin', 'molecular_function', 'GO:0008014', ('168', '176'))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('E-cadherin', 'Gene', '999', (24, 34))	('cadherin', 'molecular_function', 'GO:0008014', ('26', '34'))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', (24, 34))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('E-cadherin', 'Gene', '999', (99, 109))	('tumours', 'Disease', (3, 10))	('deletion', 'Var', (73, 81))	('mutations', 'Var', (35, 44))
3232	11305955	Furthermore, epigenetic changes such as promoter region hypermethylation, post-transcriptional alteration and aberrant phosphorylation of members of the cadherin-catenin complex can dysregulate E-cadherin function.	('post-transcriptional alteration', 'Var', (74, 105))	('E-cadherin', 'Gene', '999', (194, 204))	('phosphorylation', 'MPA', (119, 134))	('dysregulate', 'Reg', (182, 193))	('epigenetic changes', 'Var', (13, 31))	('cadherin', 'molecular_function', 'GO:0008014', ('196', '204'))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('promoter', 'MPA', (40, 48))	('aberrant', 'Var', (110, 118))	('function', 'MPA', (205, 213))	('cadherin', 'molecular_function', 'GO:0008014', ('153', '161'))	('catenin complex', 'cellular_component', 'GO:0016342', ('162', '177'))	('E-cadherin', 'Gene', (194, 204))
3234	11305955	This present study, together with previously reported data, suggests that a germline mutation in E-cadherin is not a major risk factor for breast cancer.	('germline mutation', 'Var', (76, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('99', '107'))	('E-cadherin', 'Gene', (97, 107))	('E-cadherin', 'Gene', '999', (97, 107))	('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))
3235	11305955	However, germline, and more often somatic mutations in this gene probably have an impact on phenotypic divergence and prognosis, including growth patterns of tumours, such as in lobular and perhaps ductal comedo breast cancers.	('lobular', 'Disease', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('breast cancers', 'Phenotype', 'HP:0003002', (212, 226))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('breast cancers', 'Disease', 'MESH:D001943', (212, 226))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('breast cancers', 'Disease', (212, 226))	('comedo', 'Phenotype', 'HP:0025249', (205, 211))	('impact', 'Reg', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('tumours', 'Disease', (158, 165))	('mutations', 'Var', (42, 51))
3236	11305955	In addition, other genetic alterations or epigenetic events at the E-cadherin gene may have an impact on the metastatic behaviour of the cancer cells, and thereby on the clinical outcome.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('impact', 'Reg', (95, 101))	('E-cadherin', 'Gene', (67, 77))	('E-cadherin', 'Gene', '999', (67, 77))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('genetic alterations', 'Var', (19, 38))	('cadherin', 'molecular_function', 'GO:0008014', ('69', '77'))	('behaviour', 'biological_process', 'GO:0007610', ('120', '129'))	('cancer', 'Disease', (137, 143))	('epigenetic events', 'Var', (42, 59))	('have', 'Reg', (87, 91))
3242	30935019	ZNF143 knockdown affected the stability of p53, which showed a dependence on MG132, a proteasome inhibitor.	('proteasome', 'molecular_function', 'GO:0004299', ('86', '96'))	('stability', 'MPA', (30, 39))	('affected', 'Reg', (17, 25))	('ZNF143', 'Gene', (0, 6))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('knockdown', 'Var', (7, 16))	('MG132', 'Chemical', 'MESH:C072553', (77, 82))	('proteasome', 'cellular_component', 'GO:0000502', ('86', '96'))
3243	30935019	Data from proteome profiling in breast cancer cells with less ZNF143 suggest a role of NAD(P)H quinone dehydrogenase 1(NQO1) for p53 stability.	('breast cancer', 'Disease', (32, 45))	('less', 'Var', (57, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('NQO1', 'molecular_function', 'GO:0003955', ('119', '123'))	('ZNF143', 'Gene', (62, 68))	('NQO1', 'Gene', (119, 123))	('NAD(P)H', 'Disease', 'MESH:C000656865', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('NQO1', 'Gene', '1728', (119, 123))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))
3254	30935019	Pharmacological or genetic inhibition of autophagy in dormant breast cancer cells has recently been shown to result in decreased cell survival and metastatic burden in mice and human three-dimensional in vitro and in vivo preclinical models of dormancy, implying that targeting autophagy stimulation might be beneficial for breast cancer recurrence or metastasis.	('autophagy', 'CPA', (41, 50))	('autophagy', 'biological_process', 'GO:0016236', ('41', '50'))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('inhibition', 'Var', (27, 37))	('cell survival', 'CPA', (129, 142))	('human', 'Species', '9606', (177, 182))	('autophagy', 'biological_process', 'GO:0006914', ('278', '287'))	('breast cancer', 'Phenotype', 'HP:0003002', (324, 337))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Disease', (62, 75))	('breast cancer', 'Disease', 'MESH:D001943', (324, 337))	('autophagy', 'biological_process', 'GO:0006914', ('41', '50'))	('breast cancer', 'Disease', (324, 337))	('decreased', 'NegReg', (119, 128))	('dormancy', 'biological_process', 'GO:0030431', ('244', '252'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mice', 'Species', '10090', (168, 172))	('autophagy', 'biological_process', 'GO:0016236', ('278', '287'))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
3259	30935019	ZNF143 knockdown has also been shown to increase cell motility in colon cancer cells and breast cancer cells; however, it remains unclear whether ZNF143 expression affects tumor malignancy by regulating cell biology more than motility, such as cell viability.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('colon cancer', 'Disease', (66, 78))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('increase', 'PosReg', (40, 48))	('regulating', 'Reg', (192, 202))	('tumor malignancy', 'Disease', 'MESH:D018198', (172, 188))	('affects', 'Reg', (164, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cell motility', 'CPA', (49, 62))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('ZNF143', 'Gene', (146, 152))	('knockdown', 'Var', (7, 16))	('cell motility', 'biological_process', 'GO:0048870', ('49', '62'))	('tumor malignancy', 'Disease', (172, 188))
3265	30935019	For transient transfection of ZNF143 (pFLAG-CMV-ZNF143), growing cells were transfected with pFLAG-CMV or pFLAG-CMV-ZNF143FL plasmid using lipofectamine2000 according to the manufacturer's instructions.	('pFLAG-CMV-ZNF143', 'Gene', (38, 54))	('pFLAG-CMV', 'Var', (93, 102))	('pFLAG-CMV-ZNF143', 'Gene', '7702', (106, 122))	('pFLAG-CMV-ZNF143', 'Gene', '7702', (38, 54))	('lipofectamine2000', 'Chemical', 'MESH:C086724', (139, 156))	('pFLAG-CMV-ZNF143', 'Gene', (106, 122))
3273	30935019	Lysates were resolved by SDS-polyacrylamide gel electrophoresis (SDS-PAGE), transferred to Amersham Hybond  sequencing 0.2 mum PVDF membranes (GE Healthcare, Little Chalfont, UK), and blotted with antibodies against ZNF143 (sc-100983; Santa Cruz Biotechnology, Santa Cruz, CA, USA), Beclin1 (#3738; Cell Signaling Technology, Danvers, MA, USA), ATG5 (#2630; Cell Signaling Technology), ATG12-ATG5 (#2630; Cell Signaling Technology), free ATG12 (#2010; Cell Signaling Technology), LC3B (#2775; Cell Signaling Technology), p62 (610832; BD Biosciences), p53 (sc-126; Santa Cruz Biotechnology), p14ARF (sc-8613; Santa Cruz Biotechnology), p-AKTSer473 (#4060; Cell Signaling Technology), p-AKTThr308 (#2965; Cell Signaling Technology), AKT (#9272; Cell Signaling Technology), and beta-actin (sc-69879; Santa Cruz Biotechnology).	('#2965', 'Var', (696, 701))	('p53', 'Gene', (551, 554))	('AKT', 'Gene', '207', (637, 640))	('p14ARF', 'Gene', '1029', (591, 597))	('AKT', 'Gene', '207', (685, 688))	('Signaling', 'biological_process', 'GO:0023052', ('457', '466'))	('Signaling', 'biological_process', 'GO:0023052', ('498', '507'))	('ATG5', 'Gene', (392, 396))	('beta-actin', 'Gene', (775, 785))	('ATG5', 'Gene', (345, 349))	('ATG12', 'Gene', '9140', (438, 443))	('LC3B', 'Gene', (480, 484))	('Signaling', 'biological_process', 'GO:0023052', ('363', '372'))	('Signaling', 'biological_process', 'GO:0023052', ('660', '669'))	('Beclin1', 'Gene', '8678', (283, 290))	('LC3B', 'Gene', '81631', (480, 484))	('AKT', 'Gene', '207', (731, 734))	('p14ARF', 'Gene', (591, 597))	('SDS', 'Chemical', 'MESH:D012967', (25, 28))	('SDS', 'Chemical', 'MESH:D012967', (65, 68))	('Signaling', 'biological_process', 'GO:0023052', ('748', '757'))	('p62', 'Gene', '23636', (521, 524))	('Signaling', 'biological_process', 'GO:0023052', ('708', '717'))	('p62', 'Gene', (521, 524))	('ATG12', 'Gene', (386, 391))	('Signaling', 'biological_process', 'GO:0023052', ('410', '419'))	('beta-actin', 'Gene', '728378', (775, 785))	('AKT', 'Gene', (637, 640))	('AKT', 'Gene', (685, 688))	('Beclin1', 'Gene', (283, 290))	('ATG12', 'Gene', (438, 443))	('p53', 'Gene', '7157', (551, 554))	('ATG5', 'Gene', '9474', (392, 396))	('ATG5', 'Gene', '9474', (345, 349))	('ATG12', 'Gene', '9140', (386, 391))	('AKT', 'Gene', (731, 734))	('Signaling', 'biological_process', 'GO:0023052', ('304', '313'))
3286	30935019	Among 10,000 events, the number of PI positive, dying cells was much lower in MCF7 sh-ZNF143 cells than in MCF7 sh-Control cells when the cells were exposed to glucose-free or FBS-free media for 48 h. To confirm the ZNF143 knockdown effect on cell survival under metabolic stress, cells were grown on 96-well plates for 24 h, then were exposed to nutrient-deprived media, and were monitored using the IncuCyte ZOOM  System.	('MCF7', 'CellLine', 'CVCL:0031', (107, 111))	('MCF7 sh-ZNF143', 'Gene', '7702', (78, 92))	('glucose-free or FBS-free', 'Disease', 'MESH:D000072662', (160, 184))	('ZNF143', 'Gene', (216, 222))	('MCF7 sh-ZNF143', 'Gene', (78, 92))	('MCF7', 'CellLine', 'CVCL:0031', (78, 82))	('knockdown', 'Var', (223, 232))	('glucose-free or FBS-free', 'Disease', (160, 184))
3288	30935019	The ZNF143 knockdown effect on cell survival reached a maximum in FBS-free and glucose-free media, which was reversed by chloroquine, an autophagic flux inhibitor (Figure 1D), but not by Wortmannin, an inhibitor for phosphoinositide 3-kinase (PI3-kinase) (Figure 1E).	('cell survival', 'CPA', (31, 44))	('ZNF143', 'Gene', (4, 10))	('chloroquine', 'Chemical', 'MESH:D002738', (121, 132))	('FBS-free and glucose-free', 'Disease', 'MESH:D000072662', (66, 91))	('Wortmannin', 'Chemical', 'MESH:D000077191', (187, 197))	('knockdown', 'Var', (11, 20))
3294	30935019	Notably, more foci were observed in sh-ZNF143 cells than in sh-Control cells, similar to the TEM data, implying a relationship between ZNF143 and the autophagic process in breast cancer cells.	('relationship', 'Interaction', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('sh-ZNF143', 'Var', (36, 45))	('breast cancer', 'Disease', (172, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('TEM', 'cellular_component', 'GO:0097197', ('93', '96'))	('autophagic process', 'CPA', (150, 168))
3295	30935019	To understand the molecular mechanism involved in how ZNF143 knockdown might be related to autophagy, we examined and compared the expression levels of a few autophagy-related genes, such as beclin1, autophagy-related 5 (ATG5), autophagy-related 12 (ATG12), and microtubule-associated protein light chain 3 (MAP1LC3B, LC3B).	('autophagy', 'biological_process', 'GO:0006914', ('228', '237'))	('MAP', 'molecular_function', 'GO:0004239', ('308', '311'))	('autophagy-related 12', 'Gene', (228, 248))	('protein', 'cellular_component', 'GO:0003675', ('285', '292'))	('beclin1', 'Gene', '8678', (191, 198))	('knockdown', 'Var', (61, 70))	('autophagy-related 12', 'Gene', '9140', (228, 248))	('autophagy', 'biological_process', 'GO:0006914', ('91', '100'))	('beclin1', 'Gene', (191, 198))	('LC3B', 'Gene', (312, 316))	('autophagy-related 5', 'Gene', (200, 219))	('ATG5', 'Gene', '9474', (221, 225))	('LC3B', 'Gene', '81631', (312, 316))	('autophagy', 'biological_process', 'GO:0016236', ('200', '209'))	('MAP1LC3B', 'Gene', '81631', (308, 316))	('LC3B', 'Gene', (318, 322))	('autophagy-related 5', 'Gene', '9474', (200, 219))	('autophagy', 'biological_process', 'GO:0016236', ('158', '167'))	('LC3B', 'Gene', '81631', (318, 322))	('ATG12', 'Gene', (250, 255))	('ATG5', 'Gene', (221, 225))	('MAP1LC3B', 'Gene', (308, 316))	('autophagy', 'biological_process', 'GO:0006914', ('200', '209'))	('autophagy', 'biological_process', 'GO:0016236', ('228', '237'))	('autophagy', 'biological_process', 'GO:0006914', ('158', '167'))	('autophagy', 'biological_process', 'GO:0016236', ('91', '100'))	('microtubule', 'cellular_component', 'GO:0005874', ('262', '273'))	('ATG12', 'Gene', '9140', (250, 255))	('ZNF143', 'Gene', (54, 60))
3305	30935019	Almost 5000 proteins were profiled, and 177 proteins were selected based on altered ZNF143 expression (more than 1.2-fold or less than 0.83-fold in sh-ZNF143 cells compared to that in sh-Control controls, with a significant p-value), and were used for pathway analysis in breast cancer cells (Figure 5A and Supplementary Table S2).	('sh-ZNF143', 'Var', (148, 157))	('expression', 'MPA', (91, 101))	('breast cancer', 'Disease', 'MESH:D001943', (272, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('altered', 'Reg', (76, 83))	('breast cancer', 'Disease', (272, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('ZNF143', 'Gene', (84, 90))	('less', 'NegReg', (125, 129))
3312	30935019	NQO1 was downregulated by ZNF143 knockdown, and recovered when ZNF143 expression recovered, implying a role for ZNF143 in NQO1 expression (Figure 5C).	('NQO1', 'molecular_function', 'GO:0003955', ('0', '4'))	('knockdown', 'Var', (33, 42))	('NQO1', 'Gene', (122, 126))	('NQO1', 'Gene', (0, 4))	('NQO1', 'Gene', '1728', (122, 126))	('NQO1', 'molecular_function', 'GO:0003955', ('122', '126'))	('downregulated', 'NegReg', (9, 22))	('NQO1', 'Gene', '1728', (0, 4))	('ZNF143', 'Gene', (26, 32))
3313	30935019	In addition, ZNF143 knockdown significantly increased cellular ROS levels (Figure 5D), showing an altered equilibrium for ROS during ZNF143 knockdown.	('increased cellular ROS levels', 'Phenotype', 'HP:0025464', (44, 73))	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('ZNF143', 'Gene', (13, 19))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('increased', 'PosReg', (44, 53))	('cellular ROS levels', 'MPA', (54, 73))	('knockdown', 'Var', (20, 29))	('altered', 'Reg', (98, 105))
3315	30935019	In terms of breast cancer, the dataset released in 2012 (n = 1098) confers overall survival and disease-free survival based on most types of gene alterations, including copy number alteration, mutations, mRNAs, and proteins.	('breast cancer', 'Disease', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('disease-free survival', 'CPA', (96, 117))	('alterations', 'Var', (146, 157))	('copy number alteration', 'Var', (169, 191))	('mRNAs', 'Var', (204, 209))	('mutations', 'Var', (193, 202))	('proteins', 'Protein', (215, 223))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('overall survival', 'CPA', (75, 91))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))
3316	30935019	To determine if ZNF143 expression contributes to tumor malignancy, such as recurrence and metastasis in breast cancer patients, we compared disease-free survival between selected patients with altered ZNF143 expression and the remaining patients in the whole data set (Figure 6A,B).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('contributes', 'Reg', (34, 45))	('compared', 'Reg', (131, 139))	('tumor malignancy', 'Disease', 'MESH:D018198', (49, 65))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', (104, 117))	('altered', 'Var', (193, 200))	('expression', 'MPA', (208, 218))	('patients', 'Species', '9606', (179, 187))	('ZNF143', 'Gene', (201, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('patients', 'Species', '9606', (237, 245))	('patients', 'Species', '9606', (118, 126))	('tumor malignancy', 'Disease', (49, 65))
3319	30935019	The major findings of this study were as follows: (1) ZNF143 knockdown protected cancer cells from cell death under metabolic stress in breast cancer; (2) cell survival by ZNF143 knockdown under metabolic stress was dependent on chloroquine, an inhibitor of the autophagic process; (3) ZNF143 knockdown altered proteins related to the autophagic process; (4) the p53-NQO1 axis was related to ZNF143 expression; and (5) according to the TCGA cohort, ZNF143 mRNA expression was related to disease-free survival of breast cancer patients.	('cancer', 'Disease', (519, 525))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('altered', 'Reg', (303, 310))	('cancer', 'Disease', (81, 87))	('knockdown', 'Var', (293, 302))	('cancer', 'Phenotype', 'HP:0002664', (519, 525))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ZNF143', 'Gene', (449, 455))	('NQO1', 'molecular_function', 'GO:0003955', ('367', '371'))	('breast cancer', 'Phenotype', 'HP:0003002', (512, 525))	('cancer', 'Disease', (143, 149))	('p53', 'Gene', '7157', (363, 366))	('NQO1', 'Gene', '1728', (367, 371))	('cancer', 'Disease', 'MESH:D009369', (519, 525))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('NQO1', 'Gene', (367, 371))	('breast cancer', 'Disease', 'MESH:D001943', (512, 525))	('p53', 'Gene', (363, 366))	('breast cancer', 'Disease', (512, 525))	('cell death', 'biological_process', 'GO:0008219', ('99', '109'))	('chloroquine', 'Chemical', 'MESH:D002738', (229, 240))	('proteins', 'Protein', (311, 319))	('patients', 'Species', '9606', (526, 534))	('related', 'Reg', (476, 483))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('related', 'Reg', (381, 388))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
3328	30935019	Importantly, we explained how ZNF143 expression might be responsible for cell survival by showing the effect of ZNF143 knockdown on the Beclin1-p53-NQO1-linked cascade during autophagy.	('Beclin1', 'Gene', (136, 143))	('ZNF143', 'Gene', (112, 118))	('NQO1', 'Gene', '1728', (148, 152))	('p53', 'Gene', '7157', (144, 147))	('autophagy', 'biological_process', 'GO:0016236', ('175', '184'))	('autophagy', 'biological_process', 'GO:0006914', ('175', '184'))	('Beclin1', 'Gene', '8678', (136, 143))	('knockdown', 'Var', (119, 128))	('NQO1', 'Gene', (148, 152))	('NQO1', 'molecular_function', 'GO:0003955', ('148', '152'))	('p53', 'Gene', (144, 147))	('autophagy', 'CPA', (175, 184))
3340	30935019	Although further confirmation should be conducted in the future, we currently suggest that breast cancer patients without TP53 mutations and less ZNF143 and NQO1 might be more sensitive when treated with various autophagic regulators as therapeutic treatments.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('TP53', 'Gene', (122, 126))	('patients', 'Species', '9606', (105, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('NQO1', 'Gene', '1728', (157, 161))	('NQO1', 'Gene', (157, 161))	('NQO1', 'molecular_function', 'GO:0003955', ('157', '161'))	('ZNF143', 'Gene', (146, 152))	('TP53', 'Gene', '7157', (122, 126))	('mutations', 'Var', (127, 136))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
3341	30935019	The following are available online at , Figure S1: The effect of ZNF143 knockdown on cell survival in T47D cells; Table S1: Primers for RT-PCR; Table S2: Altered proteins by ZNF143 knockdown in MCF7 cells.	('ZNF143', 'Gene', (174, 180))	('proteins', 'MPA', (162, 170))	('MCF7', 'CellLine', 'CVCL:0031', (194, 198))	('Altered', 'Reg', (154, 161))	('knockdown', 'Var', (181, 190))	('T47D', 'CellLine', 'CVCL:0553', (102, 106))
3399	30131246	The receptor status distribution were: ER+/PR+/HER2- (n=54), ER+/PR+/HER2+ (n=1), ER+/PR-/HER2- (n=9), ER-/PR-/HER2+ (n=1), and triple-negative (n=1).	('HER2', 'Gene', (111, 115))	('HER2', 'Gene', (90, 94))	('HER2', 'Gene', '2064', (111, 115))	('HER2', 'Gene', '2064', (90, 94))	('HER2', 'Gene', (47, 51))	('HER2', 'Gene', '2064', (47, 51))	('triple-negative', 'Var', (128, 143))	('HER2', 'Gene', (69, 73))	('HER2', 'Gene', '2064', (69, 73))
3462	22080244	Cadherin-Catenin Complex Dissociation in Lobular Neoplasia of the Breast E-cadherin (E-CD) inactivation with loss of E-CD-mediated cell adhesion is the hallmark of lesions of the lobular phenotype.	('Catenin Complex', 'cellular_component', 'GO:0016342', ('9', '24'))	('E-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', '999', (73, 83))	('E-CD', 'Gene', '999', (117, 121))	('E-CD', 'Gene', (85, 89))	('Neoplasia', 'Phenotype', 'HP:0002664', (49, 58))	('cell adhesion', 'biological_process', 'GO:0007155', ('131', '144'))	('loss', 'NegReg', (109, 113))	('Lobular Neoplasia', 'Disease', (41, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('Lobular Neoplasia', 'Phenotype', 'HP:0030076', (41, 58))	('E-CD', 'Gene', '999', (85, 89))	('Neoplasia of the Breast', 'Phenotype', 'HP:0100013', (49, 72))	('inactivation', 'Var', (91, 103))	('Lobular Neoplasia', 'Disease', 'MESH:D009369', (41, 58))	('E-CD', 'Gene', (117, 121))	('Cadherin', 'molecular_function', 'GO:0008014', ('0', '8'))
3475	22080244	Epidemiological data supporting its role as a marker of increased risk for the future development of breast cancer rely largely on the finding that patients with LCIS are equally likely to develop both ductal and lobular cancers, and that cancers in the contralateral breast occur at similar rates.	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('lobular cancers', 'Disease', (213, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('patients', 'Species', '9606', (148, 156))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('cancers', 'Disease', (239, 246))	('LCIS', 'Phenotype', 'HP:0030076', (162, 166))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('LCIS', 'Var', (162, 166))	('breast cancer', 'Disease', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('develop', 'PosReg', (189, 196))	('cancers', 'Disease', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('lobular cancers', 'Disease', 'MESH:D013274', (213, 228))	('ductal', 'Disease', (202, 208))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))
3484	22080244	Recent studies have suggested that phosphorylation of beta-catenin results in its translocation to the nucleus where it binds the transcription factor Tcf/Lef, thereby promoting cell proliferation and activation of the Wnt pathway.	('activation', 'PosReg', (201, 211))	('promoting', 'PosReg', (168, 177))	('Tcf/Lef', 'Gene', '3172', (151, 158))	('translocation to the nucleus', 'MPA', (82, 110))	('cell proliferation', 'CPA', (178, 196))	('Wnt pathway', 'Pathway', (219, 230))	('transcription', 'biological_process', 'GO:0006351', ('130', '143'))	('transcription factor', 'molecular_function', 'GO:0000981', ('130', '150'))	('beta-catenin', 'Gene', (54, 66))	('nucleus', 'cellular_component', 'GO:0005634', ('103', '110'))	('beta-catenin', 'Gene', '1499', (54, 66))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('cell proliferation', 'biological_process', 'GO:0008283', ('178', '196'))	('binds', 'Interaction', (120, 125))	('phosphorylation', 'Var', (35, 50))	('Tcf/Lef', 'Gene', (151, 158))
3487	22080244	Mutational inactivation of the E-CD gene leads to loss of function of the extracellular component of the CCC in lobular breast cancer and occurs early the neoplastic process, as it is evident in LCIS.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('E-CD', 'Gene', '999', (31, 35))	('lobular breast cancer', 'Disease', (112, 133))	('LCIS', 'Phenotype', 'HP:0030076', (195, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('neoplastic process', 'Phenotype', 'HP:0002664', (155, 173))	('lobular breast cancer', 'Disease', 'MESH:D013274', (112, 133))	('Mutational inactivation', 'Var', (0, 23))	('CCC', 'cellular_component', 'GO:0030896', ('105', '108'))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (112, 133))	('extracellular', 'cellular_component', 'GO:0005576', ('74', '87'))	('loss of function', 'NegReg', (50, 66))	('E-CD', 'Gene', (31, 35))
3558	22080244	According to genomic models of breast carcinogenesis, LOH at 16q is a common finding among low-grade lesions of both the lobular and ductal phenotype, and further CDH1 inactivation in the retained allele is unique to lobular carcinomas.	('LOH at 16q', 'Var', (54, 64))	('inactivation', 'Var', (168, 180))	('lobular carcinomas', 'Disease', 'MESH:D018275', (217, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('CDH1', 'Gene', (163, 167))	('breast carcinogenesis', 'Disease', (31, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (217, 235))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (217, 234))	('lobular carcinomas', 'Disease', (217, 235))	('CDH1', 'Gene', '999', (163, 167))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (31, 52))
3559	22080244	Mutations, deletions, promoter hypermethylation, transcriptional repression and, more recently, miRNA modulation, have all been proposed as potential mechanisms of E-CD inactivation.	('transcriptional', 'MPA', (49, 64))	('promoter', 'CPA', (22, 30))	('deletions', 'Var', (11, 20))	('Mutations', 'Var', (0, 9))	('E-CD', 'Gene', (164, 168))	('E-CD', 'Gene', '999', (164, 168))
3561	22080244	In the same series, a CDH1 mutation was identified in 10 (22%) of ILCs; loss of heterozygosity (LOH) was observed in 30/41 (73%) ILCs, and CDH1 promoter hypermethylation was identified in 19/46 (41%) cases.	('CDH1', 'Gene', '999', (22, 26))	('ILCs', 'Disease', (129, 133))	('mutation', 'Var', (27, 35))	('CDH1', 'Gene', (139, 143))	('identified', 'Reg', (40, 50))	('CDH1', 'Gene', '999', (139, 143))	('CDH1', 'Gene', (22, 26))	('ILCs', 'Disease', (66, 70))
3563	22080244	LOH was strongly associated with negative staining of E-CD, but this relationship was not present in all cases.	('E-CD', 'Gene', (54, 58))	('LOH', 'Var', (0, 3))	('E-CD', 'Gene', '999', (54, 58))	('staining', 'MPA', (42, 50))	('negative', 'NegReg', (33, 41))
3585	24567879	All grade 1 tumours and ER-positive (ER+) grade 2 tumours with Ki67 <= 30% were classified as low-KiGE and all the others as high-KiGE.	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('ER', 'Gene', '2099', (24, 26))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('tumours', 'Disease', (12, 19))	('tumours', 'Disease', (50, 57))	('Ki67', 'Var', (63, 67))	('ER', 'Gene', '2099', (37, 39))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
3588	24567879	Age, tumour size, axillary lymph node status (nodal status), histological grade, Ki67 and KiGE were significant prognostic factors for breast cancer mortality (BCM) in univariable analysis.	('BC', 'Phenotype', 'HP:0003002', (160, 162))	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('Ki67', 'Var', (81, 85))	('axillary lymph node status', 'Phenotype', 'HP:0025289', (18, 44))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('BCM', 'Chemical', '-', (160, 163))	('tumour', 'Disease', (5, 11))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
3596	24567879	ILC is, compared to IDC, more often associated with higher age at diagnosis, larger tumour size, multicentricity, multifocality, bilaterality, histological grade 2, hormone receptor positivity, HER2 negativity, different metastatic pattern, lower cell proliferation rate and less responsiveness to chemotherapy (Arpino et al.	('tumour', 'Disease', (84, 90))	('cell proliferation rate', 'CPA', (247, 270))	('cell proliferation', 'biological_process', 'GO:0008283', ('247', '265'))	('HER2', 'Gene', '2064', (194, 198))	('HER2', 'Gene', (194, 198))	('hormone receptor', 'CPA', (165, 181))	('lower', 'NegReg', (241, 246))	('negativity', 'Var', (199, 209))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('ILC', 'Disease', (0, 3))	('associated', 'Reg', (36, 46))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
3600	24567879	Recent studies by our group have shown the strong prognostic impact of an index (KiGE) combining Ki67, histological grade and ER in primary breast cancer, including all histological subtypes (Klintman et al.	('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))	('Ki67', 'Var', (97, 101))	('ER', 'Gene', '2099', (126, 128))
3621	24567879	Ki67 (Mib-1, Immunotech, 1:100) was categorized into three groups depending on the percentage of stained nuclei: low (0-10%), intermediate (11-30%) and high (>30%).	('Mib-1', 'Gene', (6, 11))	('11-30', 'Var', (140, 145))	('Mib-1', 'Gene', '57534', (6, 11))
3623	24567879	A value of IHC 3+ was considered as HER2 positive (Barnes et al.).	('HER2', 'Gene', '2064', (36, 40))	('IHC 3+', 'Var', (11, 17))	('HER2', 'Gene', (36, 40))
3628	24567879	The ER positive (ER+) grade 2 tumours with Ki67 <=30% are defined as low-KiGE whereas all other grade 2 tumours are defined as high-KiGE (Figure 2).	('Ki67 <=30%', 'Var', (43, 53))	('ER', 'Gene', '2099', (17, 19))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('ER', 'Gene', '2099', (4, 6))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumours', 'Disease', (30, 37))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('tumours', 'Disease', 'MESH:D009369', (104, 111))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('tumours', 'Disease', (104, 111))
3629	24567879	In these analyses, the ordinal variables Ki67 and histological grade were linearly coded 1/2/3 whereas the continuous values were used for age and tumour size.	('tumour', 'Disease', (147, 153))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('Ki67', 'Var', (41, 45))
3636	24567879	The expression of Ki67 in the tumour was low in 115 patients (60%), intermediate in 62 (32%) and high in 15 (8%).	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('tumour', 'Disease', (30, 36))	('expression', 'MPA', (4, 14))	('low', 'NegReg', (41, 44))	('Ki67', 'Var', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('patients', 'Species', '9606', (52, 60))
3641	24567879	A significant positive correlation (r = 0.26) was seen between Ki67 and histological grade (p < 0.001), but not between Ki67 and other prognostic factors (nodal status, ER, PgR, age and tumour size).	('tumour', 'Disease', (186, 192))	('PgR', 'Gene', '5241', (173, 176))	('PgR', 'Gene', (173, 176))	('ER', 'Gene', '2099', (169, 171))	('Ki67', 'Var', (63, 67))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('histological grade', 'CPA', (72, 90))
3644	24567879	Furthermore, a Cox-regression analysis showed, that the BCM was significantly higher in the high Ki67-group compared to the low Ki67-group (hazard ratio (HR) = 2.6, 95% confidence interval (95% CI): 1.2-5.8, p = 0.01), whereas the difference between the intermediate Ki67-group and the low Ki67-group was non-significant (HR = 1.4, 95% CI: 0.84-2.5, p = 0.19) (Figure 3).	('high Ki67-group', 'Var', (92, 107))	('BCM', 'Chemical', '-', (56, 59))	('BCM', 'CPA', (56, 59))	('higher', 'PosReg', (78, 84))	('BC', 'Phenotype', 'HP:0003002', (56, 58))
3651	24567879	We found also that in ILC, KiGE was a strong prognostic factor for BCM (Cox-regression, HR = 2.8, 95% CI: 1.6-5.0, p < 0.001) (Figure 5).	('BCM', 'Chemical', '-', (67, 70))	('BC', 'Phenotype', 'HP:0003002', (67, 69))	('ILC', 'Disease', (22, 25))	('KiGE', 'Var', (27, 31))	('BCM', 'Disease', (67, 70))
3668	24567879	The combination of Ki67, histological grade and ER into KiGE however, gives useful independent long-term prognostic information in ILC.	('ILC', 'Disease', (131, 134))	('ER', 'Gene', '2099', (48, 50))	('Ki67', 'Var', (19, 23))
3670	24567879	Patients with high-KiGE ILC's in this cohort represent an under-treated group, with poor prognostic tumours, and today the majority would have been recommended adjuvant chemotherapy to improve outcome.	('ILC', 'Disease', (24, 27))	('high-KiGE', 'Var', (14, 23))	('tumours', 'Disease', (100, 107))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('Patients', 'Species', '9606', (0, 8))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))
3671	24567879	Patients with low-KiGE ILC's, on the other hand, represent the greater part of this cohort, containg tumours with a more diversified prognosis, causing difficulties in adjuvant treatment decision-making.	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('tumours', 'Disease', (101, 108))	('ILC', 'Disease', (23, 26))	('low-KiGE', 'Var', (14, 22))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))
3695	21326853	Pre-invasive breast tumors with aberrant expression of tumor suppressors in the myoepithelial cell layers had a significantly higher proliferation, genetic and biochemical abnormalities than their morphologically similar counterparts with normal expression of these tumor suppressors (Fig 3).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('myoepithelial', 'Disease', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('higher', 'PosReg', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('breast tumors', 'Phenotype', 'HP:0100013', (13, 26))	('tumor', 'Disease', (55, 60))	('breast tumors', 'Disease', 'MESH:D001943', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('myoepithelial', 'Disease', 'MESH:D009208', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('breast tumors', 'Disease', (13, 26))	('aberrant', 'Var', (32, 40))	('tumor', 'Disease', (266, 271))	('tumor', 'Disease', (20, 25))
3701	21326853	Similarly, aberrant expression of tumor suppressors and focal disruptions on the basal cell layer have the same impact on the associated prostate tumor cells.	('prostate tumor', 'Disease', 'MESH:D011471', (137, 151))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('impact', 'Reg', (112, 118))	('aberrant expression', 'Var', (11, 30))	('tumor', 'Disease', (146, 151))	('prostate tumor', 'Disease', (137, 151))	('prostate tumor', 'Phenotype', 'HP:0100787', (137, 151))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
3704	21326853	Alterations in the myoepithelial cell layer may directly impact the clinical outcomes of ILC and IDC by controlling the genetic property and biological behavior of the precursors of invasive lesions, and by dictating the lobular and ductal tumors to follow different pathways for invasion and/or metastasis.	('impact', 'Reg', (57, 63))	('invasion', 'CPA', (280, 288))	('follow', 'Reg', (250, 256))	('Alterations', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('ILC', 'Disease', (89, 92))	('ductal tumors', 'Disease', 'MESH:D044584', (233, 246))	('dictating', 'Reg', (207, 216))	('myoepithelial', 'Disease', (19, 32))	('controlling', 'Reg', (104, 115))	('IDC', 'Gene', '4000', (97, 100))	('myoepithelial', 'Disease', 'MESH:D009208', (19, 32))	('IDC', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('ductal tumors', 'Disease', (233, 246))
3707	21326853	In addition, as aberrant expression of tumor suppressors with malignancy-associated changes are exclusively seen in some acinar clusters or lobules, degradation of the myoepithelial cell layers could potentially lead to in situ malignant transformation of the entire tumor cell population within a given lobule to invasive lesions.	('aberrant', 'Var', (16, 24))	('degradation', 'biological_process', 'GO:0009056', ('149', '160'))	('myoepithelial', 'Disease', (168, 181))	('malignancy', 'Disease', 'MESH:D009369', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('myoepithelial', 'Disease', 'MESH:D009208', (168, 181))	('malignancy', 'Disease', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('lead to', 'Reg', (212, 219))	('in situ malignant transformation', 'CPA', (220, 252))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', (39, 44))
3712	21326853	Together, these alterations could selectively favor monoclonal proliferation of the overlying tumor progenitors or a biologically more aggressive cell clone.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('favor', 'PosReg', (46, 51))	('alterations', 'Var', (16, 27))	('tumor', 'Disease', (94, 99))	('monoclonal proliferation', 'CPA', (52, 76))
3754	29181072	Moreover, the size of the tumor of type T1a, T3, and T4b was found in fewer than 2% of patients with IDC-NST (Table I).	('IDC', 'Gene', (101, 104))	('T4b', 'Var', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('IDC', 'Gene', '4000', (101, 104))	('patients', 'Species', '9606', (87, 95))
3762	29181072	Our study demonstrated a statistically significant relationship between histological grade G1, G1/2, and G2/3, and tumor size T1-T4 (G1/T1-T4 p < 0.001; G1/2/T1-T4 p < 0.001; G2/3/T1-T4 p < 0.0267) (Table IV).	('T1-T4', 'Var', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('G1/2, and G2/3', 'Gene', '5544;7916;7917', (95, 109))	('tumor', 'Disease', (115, 120))	('significant', 'Reg', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
3808	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.	('LCIS', 'Disease', (158, 162))	('c-src', 'Gene', (123, 128))	('LCIS', 'Phenotype', 'HP:0030076', (158, 162))	('PIK3CA', 'Gene', '5290', (112, 118))	('c-src', 'Gene', '6714', (123, 128))	('E-cadherin', 'Gene', '999', (18, 28))	('altered', 'Reg', (147, 154))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('PIK3CA', 'Gene', (112, 118))	('E-cadherin', 'Gene', (18, 28))	('Disruption', 'Var', (0, 10))
3828	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))	('pre', 'molecular_function', 'GO:0003904', ('100', '103'))	('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))
3831	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))
3835	26041550	Andrade and colleagues also reached this conclusion comparing single nucleotide polymorphism (SNP) DNA microarrays of matched LCIS and synchronous lesions.	('LCIS', 'Phenotype', 'HP:0030076', (126, 130))	('synchronous lesions', 'Disease', (135, 154))	('single nucleotide polymorphism', 'Var', (62, 92))	('synchronous lesions', 'Disease', 'MESH:D009378', (135, 154))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))
3857	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))
3863	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))
3881	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))	('ER', 'Gene', '2099', (68, 70))	('invasive ductal cancers', 'Disease', 'MESH:D018270', (263, 286))	('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))
3890	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))	('HER2', 'Gene', '2064', (27, 31))	('HER2', 'Gene', (27, 31))	('IBC', 'Chemical', '-', (80, 83))	('patients', 'Species', '9606', (66, 74))
3899	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.	('protein stabilization', 'biological_process', 'GO:0050821', ('40', '61'))	('LCIS', 'Phenotype', 'HP:0030076', (3, 7))	('mutation', 'Var', (75, 83))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))	('overexpression', 'PosReg', (13, 27))
3910	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))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('CDH1', 'Gene', '999', (224, 228))	('methylation', 'biological_process', 'GO:0032259', ('173', '184'))	('Loss', 'NegReg', (0, 4))	('biallelic', 'MPA', (198, 207))	('mutations', 'Var', (38, 47))	('lead to', 'Reg', (190, 197))
3912	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', 'molecular_function', 'GO:0016538', ('45', '51'))	('cyclin D1', 'Gene', '595', (45, 54))	('LCIS', 'Phenotype', 'HP:0030076', (113, 117))	('LCIS', 'Phenotype', 'HP:0030076', (133, 137))	('cyclin D1', 'Gene', (45, 54))
3913	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))	('HER2', 'Gene', '2064', (80, 84))	('17q', 'Protein', (48, 51))	('HER2', 'Gene', (80, 84))	('LCIS', 'Phenotype', 'HP:0030076', (19, 23))	('FLCIS', 'Disease', (18, 23))	('CLCIS', 'Chemical', '-', (119, 124))	('amplification', 'Var', (31, 44))
3914	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))
3916	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.	('cadherin', 'molecular_function', 'GO:0008014', ('66', '74'))	('hereditary diffuse gastric cancer syndrome', 'Disease', (161, 203))	('predispose', 'Reg', (76, 86))	('patients', 'Species', '9606', (134, 142))	('CDH1', 'Gene', '999', (148, 152))	('women', 'Species', '9606', (87, 92))	('CDH1', 'Gene', '999', (53, 57))	('LCIS', 'Disease', (96, 100))	('CDH1', 'Gene', (148, 152))	('found', 'Reg', (120, 125))	('CDH1', 'Gene', (53, 57))	('LCIS', 'Phenotype', 'HP:0030076', (106, 110))	('germline', 'Var', (23, 31))	('LCIS', 'Phenotype', 'HP:0030076', (96, 100))	('hereditary diffuse gastric cancer syndrome', 'Disease', 'MESH:D013274', (161, 203))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('E-cadherin', 'Gene', (64, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (180, 194))	('E-cadherin', 'Gene', '999', (64, 74))
3922	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))
3923	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))
3924	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))	('MAP3K', 'molecular_function', 'GO:0004709', ('121', '126'))	('FGFR2', 'Gene', (111, 116))	('FGFR2', 'Gene', '2263', (111, 116))	('associated', 'Reg', (45, 55))	('MAP3K1', 'Gene', (121, 127))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('ILC', 'Disease', (61, 64))	('variants', 'Var', (95, 103))	('MAP3K1', 'Gene', '4214', (121, 127))
3929	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).	('cadherin', 'molecular_function', 'GO:0008014', ('74', '82'))	('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))
3933	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))	('hypermethylation', 'Var', (99, 115))	('overexpression', 'PosReg', (147, 161))	('TWIST', 'Gene', '7291', (58, 63))	('TWIST', 'Gene', (58, 63))
3942	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))
3943	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))
3944	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))
3945	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))
3964	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))	('LIN', 'Disease', 'None', (393, 396))	('lobular carcinoma', 'Disease', 'MESH:D018275', (93, 110))	('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))	('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))	('progesterone receptor', 'Gene', '5241', (500, 521))	('CLCIS', 'Chemical', '-', (77, 82))	('lobular carcinoma', 'Disease', 'MESH:D018275', (343, 360))	('breast cancer', 'Phenotype', 'HP:0003002', (289, 302))	('EMT', 'biological_process', 'GO:0001837', ('174', '177'))	('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))	('TDLU', 'Chemical', '-', (557, 561))	('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))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('178', '214'))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (93, 110))	('IBC', 'Chemical', '-', (276, 279))	('LCIS', 'Phenotype', 'HP:0030076', (78, 82))	('ductal carcinoma in situ', 'Disease', (148, 172))	('estrogen receptor', 'Gene', '2099', (218, 235))
3979	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))
3997	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))
4041	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))
4047	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))	('cadherin', 'molecular_function', 'GO:0008014', ('141', '149'))
4049	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))
4050	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))
4055	18046629	Hereditary diffuse gastric cancer: association with lobular breast cancer Hereditary diffuse gastric cancer (HDGC) has been shown to be caused by germline mutations in the gene CDH1 located at 16q22.1, which encodes the cell-cell adhesion molecule, E-cadherin.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('cell-cell adhesion molecule', 'molecular_function', 'GO:0098632', ('220', '247'))	('caused', 'Reg', (136, 142))	('cadherin', 'molecular_function', 'GO:0008014', ('251', '259'))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('GC', 'Phenotype', 'HP:0012126', (111, 113))	('lobular breast cancer', 'Disease', (52, 73))	('gastric cancer', 'Disease', (93, 107))	('gastric cancer', 'Disease', (19, 33))	('E-cadherin', 'Gene', (249, 259))	('association', 'Interaction', (35, 46))	('E-cadherin', 'Gene', '999', (249, 259))	('lobular breast cancer', 'Disease', 'MESH:D013274', (52, 73))	('CDH1', 'Gene', '999', (177, 181))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (52, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('mutations', 'Var', (155, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CDH1', 'Gene', (177, 181))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('220', '238'))
4056	18046629	Not only does loss of expression of E-cadherin account for the morphologic differences between intestinal and diffuse gastric cancer (DGC) variants, but it also appears to lead to distinct cellular features which appear to be common amongst related cancers that have been seen in the syndrome.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastric cancer', 'Disease', (118, 132))	('intestinal', 'Disease', (95, 105))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('E-cadherin', 'Gene', (36, 46))	('lead to', 'Reg', (172, 179))	('cancers', 'Disease', (249, 256))	('E-cadherin', 'Gene', '999', (36, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('GC', 'Phenotype', 'HP:0012126', (135, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('DGC', 'cellular_component', 'GO:0016010', ('134', '137'))	('variants', 'Var', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('expression', 'MPA', (22, 32))	('loss', 'NegReg', (14, 18))
4058	18046629	Given the complexity of HDGC, not only with regard to the management of the DGC risk, but also with regard to the risk for other related cancers, such as LBC, a multi-disciplinary approach is needed for the management of individuals with known CDH1 mutations.	('LBC', 'Phenotype', 'HP:0006625', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CDH1', 'Gene', (244, 248))	('GC', 'Phenotype', 'HP:0012126', (26, 28))	('CDH1', 'Gene', '999', (244, 248))	('mutations', 'Var', (249, 258))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('DGC', 'cellular_component', 'GO:0016010', ('76', '79'))	('cancers', 'Disease', (137, 144))	('men', 'Species', '9606', (64, 67))	('GC', 'Phenotype', 'HP:0012126', (77, 79))	('men', 'Species', '9606', (213, 216))
4060	18046629	Within the past ten years, germline mutations in CDH1, which encodes E-cadherin, have been found in over 50% of hereditary diffuse gastric cancer (HDGC) families with at least two cases of GC, with one diagnosed as DGC before the age of 50 years.	('E-cadherin', 'Gene', '999', (69, 79))	('CDH1', 'Gene', (49, 53))	('GC', 'Phenotype', 'HP:0012126', (216, 218))	('GC', 'Phenotype', 'HP:0012126', (189, 191))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('found', 'Reg', (91, 96))	('CDH1', 'Gene', '999', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (112, 145))	('GC', 'Phenotype', 'HP:0012126', (149, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('71', '79'))	('DGC', 'cellular_component', 'GO:0016010', ('215', '218'))	('hereditary diffuse gastric cancer', 'Disease', (112, 145))	('E-cadherin', 'Gene', (69, 79))	('germline mutations', 'Var', (27, 45))
4063	18046629	Recently our group has reported a novel germline CDH1 truncating mutation (517insA) in an LBC family with no known history of GC.	('CDH1', 'Gene', (49, 53))	('CDH1', 'Gene', '999', (49, 53))	('517insA', 'Mutation', 'c.517insA', (75, 82))	('517insA', 'Var', (75, 82))	('LBC', 'Phenotype', 'HP:0006625', (90, 93))	('GC', 'Phenotype', 'HP:0012126', (126, 128))
4064	18046629	Within this review we report a germline CDH1 mutation in a second family in which breast cancer is the predominant cancer diagnosis.	('breast cancer', 'Disease', (82, 95))	('cancer', 'Disease', (115, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('CDH1', 'Gene', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (89, 95))	('mutation', 'Var', (45, 53))	('CDH1', 'Gene', '999', (40, 44))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
4065	18046629	The management of HDGC in all patients with a particular focus on the management of the breast cancer risk associated with germline CDH1 mutations will be discussed.	('men', 'Species', '9606', (10, 13))	('GC', 'Phenotype', 'HP:0012126', (20, 22))	('CDH1', 'Gene', (132, 136))	('men', 'Species', '9606', (76, 79))	('mutations', 'Var', (137, 146))	('patients', 'Species', '9606', (30, 38))	('CDH1', 'Gene', '999', (132, 136))	('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))
4068	18046629	Our laboratory carried out the molecular genetic testing for the CDH1 mutation on a research basis.	('mutation', 'Var', (70, 78))	('CDH1', 'Gene', '999', (65, 69))	('CDH1', 'Gene', (65, 69))
4074	18046629	For exon 10 of CDH1, the initial amplicon failed and was therefore analyzed by direct sequencing and thus revealed a donor splice site mutation, 1565 + 1G > A (Fig.	('1565 + 1G > A', 'Var', (145, 158))	('1565 + 1G > A', 'Mutation', 'rs587780113', (145, 158))	('CDH1', 'Gene', (15, 19))	('CDH1', 'Gene', '999', (15, 19))	('donor', 'Species', '9606', (117, 122))
4076	18046629	They were appropriately concerned about their risk of breast cancer, but had not thought much about the possibility of getting gastric cancer until the CDH1 mutation was found.	('breast cancer', 'Disease', (54, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('mutation', 'Var', (157, 165))	('CDH1', 'Gene', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CDH1', 'Gene', '999', (152, 156))	('gastric cancer', 'Disease', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
4077	18046629	IV-2 and IV-6 had predictive genetic testing for the CDH1 mutation testing and both were found to be negative.	('CDH1', 'Gene', (53, 57))	('CDH1', 'Gene', '999', (53, 57))	('mutation', 'Var', (58, 66))
4088	18046629	In support of the role of E-cadherin as a tumour suppressor is the observation of abnormal or absent E-cadherin expression in precursor lesions of DGC and LBC, where the phenomenon is seen in in situ signet ring cell carcinomas found in prophylactic gastrectomy specimens from germline CDH1 mutation carriers and the lobular carcinoma in situ lesions seen adjacent to invasive lobular breast cancers.	('carcinomas', 'Disease', 'MESH:D002277', (217, 227))	('mutation', 'Var', (291, 299))	('CDH1', 'Gene', (286, 290))	('lobular carcinoma', 'Disease', 'MESH:D018275', (317, 334))	('absent', 'NegReg', (94, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (217, 227))	('DGC', 'cellular_component', 'GO:0016010', ('147', '150'))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('lobular carcinoma', 'Disease', (317, 334))	('expression', 'MPA', (112, 122))	('E-cadherin', 'Gene', (101, 111))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('E-cadherin', 'Gene', '999', (101, 111))	('LBC', 'Phenotype', 'HP:0006625', (155, 158))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('men', 'Species', '9606', (175, 178))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))	('invasive lobular breast cancers', 'Disease', (368, 399))	('invasive lobular breast cancers', 'Disease', 'MESH:D013274', (368, 399))	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('breast cancers', 'Phenotype', 'HP:0003002', (385, 399))	('carcinomas', 'Disease', (217, 227))	('E-cadherin', 'Gene', (26, 36))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('E-cadherin', 'Gene', '999', (26, 36))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (317, 334))	('DGC', 'Gene', (147, 150))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (377, 398))	('breast cancer', 'Phenotype', 'HP:0003002', (385, 398))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (317, 342))	('CDH1', 'Gene', '999', (286, 290))	('LBC', 'Disease', (155, 158))	('men', 'Species', '9606', (267, 270))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (325, 342))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('cancers', 'Phenotype', 'HP:0002664', (392, 399))
4090	18046629	Inactivating CDH1 mutations are found in 50% of sporadic DGCs and cluster between exons seven and nine, in contrast with the low percentage of mutations seen in sporadic intestinal type GCs.	('CDH1', 'Gene', '999', (13, 17))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('DGCs', 'Disease', (57, 61))	('Inactivating', 'Var', (0, 12))	('GC', 'Phenotype', 'HP:0012126', (186, 188))	('CDH1', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
4093	18046629	In the cancers from individuals with CDH1 mutations, CDH1 acts as a classic tumour suppressor gene with loss of expression of the wildtype allele.	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('CDH1', 'Gene', '999', (53, 57))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('CDH1', 'Gene', (37, 41))	('cancers', 'Disease', (7, 14))	('CDH1', 'Gene', (53, 57))	('mutations', 'Var', (42, 51))	('tumour', 'Disease', (76, 82))	('CDH1', 'Gene', '999', (37, 41))	('expression', 'MPA', (112, 122))
4095	18046629	This finding warrants verification in a larger cohort as abnormal promoter methylation in early cancers could potentially form the basis of a screening test.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('promoter', 'MPA', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('abnormal', 'Var', (57, 65))	('cancers', 'Disease', (96, 103))
4096	18046629	Currently germline mutations in single genes account for approximately 5-10% of breast cancer.	('germline', 'Var', (10, 18))	('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))
4101	18046629	LBCs compose only 3% and 9% of the breast cancer tumour types seen in germline BRCA 1 and 2 mutation carriers, respectively, illustrating that the genetic risk factors for the majority of cases are unaccounted for by these genes.	('mutation', 'Var', (92, 100))	('breast cancer tumour', 'Phenotype', 'HP:0100013', (35, 55))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('LBC', 'Phenotype', 'HP:0006625', (0, 3))	('breast cancer tumour', 'Disease', (35, 55))	('BRCA 1 and 2', 'Gene', '672;675', (79, 91))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer tumour', 'Disease', 'MESH:D009369', (35, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
4103	18046629	This is not unexpected as E-cadherin staining is absent in 85% of sporadic invasive LBC and somatic CDH1 mutations have been identified in 56% of sporadic LBCs.	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))	('CDH1', 'Gene', (100, 104))	('CDH1', 'Gene', '999', (100, 104))	('E-cadherin', 'Gene', (26, 36))	('identified', 'Reg', (125, 135))	('LBC', 'Phenotype', 'HP:0006625', (155, 158))	('E-cadherin', 'Gene', '999', (26, 36))	('mutations', 'Var', (105, 114))	('invasive LBC', 'Disease', (75, 87))	('LBC', 'Phenotype', 'HP:0006625', (84, 87))
4106	18046629	In sporadic LBC, mutations in CDH1 are spread throughout the gene compared with the mutations seen in sporadic DGC which tend to cluster.	('LBC', 'Disease', (12, 15))	('CDH1', 'Gene', '999', (30, 34))	('DGC', 'cellular_component', 'GO:0016010', ('111', '114'))	('GC', 'Phenotype', 'HP:0012126', (112, 114))	('LBC', 'Phenotype', 'HP:0006625', (12, 15))	('mutations', 'Var', (17, 26))	('CDH1', 'Gene', (30, 34))
4107	18046629	Germline CDH1 mutations associated with DGC and/or LBC occur throughout the gene (Fig.	('associated', 'Reg', (24, 34))	('GC', 'Phenotype', 'HP:0012126', (41, 43))	('CDH1', 'Gene', (9, 13))	('LBC', 'Phenotype', 'HP:0006625', (51, 54))	('DGC', 'cellular_component', 'GO:0016010', ('40', '43'))	('CDH1', 'Gene', '999', (9, 13))	('DGC', 'Disease', (40, 43))	('LBC', 'Disease', (51, 54))	('mutations', 'Var', (14, 23))
4108	18046629	However, when the DGC and LBC associated CDH1 mutations are tabulated and compared based on their 3' or 5' positions relative to the halfway point of the CDH1 coding sequence (1324 or the start of exon 10), LBC associated mutations show a statistically significant trend towards clustering at the 3' end (Fisher's exact test, two-tailed P-value equals 0.0467) (Fig.	('CDH1', 'Gene', (154, 158))	('LBC', 'Disease', (207, 210))	('LBC', 'Phenotype', 'HP:0006625', (26, 29))	('CDH1', 'Gene', '999', (154, 158))	('mutations', 'Var', (46, 55))	('CDH1', 'Gene', '999', (41, 45))	('mutations', 'Var', (222, 231))	('DGC', 'cellular_component', 'GO:0016010', ('18', '21'))	('LBC', 'Phenotype', 'HP:0006625', (207, 210))	('GC', 'Phenotype', 'HP:0012126', (19, 21))	('CDH1', 'Gene', (41, 45))
4109	18046629	Future analyses of novel germline LBC-associated CDH1 mutations should help to confirm this observation.	('CDH1', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('LBC', 'Phenotype', 'HP:0006625', (34, 37))	('CDH1', 'Gene', '999', (49, 53))
4110	18046629	Another difference between the molecular genetics of the two types of cancers, is that in sporadic LBC, silencing of E-cadherin expression is generally accomplished by a mutation in one allele in combination with loss of heterozygosity (LOH) or promoter hypermethylation in the remaining allele.	('LBC', 'Phenotype', 'HP:0006625', (99, 102))	('loss of heterozygosity', 'Var', (213, 235))	('silencing', 'NegReg', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('LBC', 'Disease', (99, 102))	('promoter hypermethylation', 'Var', (245, 270))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('expression', 'MPA', (128, 138))	('cadherin', 'molecular_function', 'GO:0008014', ('119', '127'))	('cancers', 'Disease', (70, 77))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))	('mutation', 'Var', (170, 178))
4111	18046629	We have recently identified a truncating germline CDH1 mutation in an LBC family where analysis of the tumour was suggestive of partial LOH in the WT allele.	('germline', 'Var', (41, 49))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('CDH1', 'Gene', (50, 54))	('CDH1', 'Gene', '999', (50, 54))	('mutation', 'Var', (55, 63))	('LBC', 'Phenotype', 'HP:0006625', (70, 73))	('tumour', 'Disease', (103, 109))
4112	18046629	Our current case demonstrates a germline CDH1 mutation (1565 + 1G > A) in a predominantly breast cancer family, which is predicted to disrupt splicing.	('CDH1', 'Gene', '999', (41, 45))	('1565 + 1G > A', 'Var', (56, 69))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('splicing', 'biological_process', 'GO:0045292', ('142', '150'))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('1565 + 1G > A', 'Mutation', 'rs587780113', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('splicing', 'MPA', (142, 150))	('CDH1', 'Gene', (41, 45))
4113	18046629	The mutation is in the same conserved position as a previously reported mutation (1565 + 1G > T) which was found in an Arabian HDGC family with no recorded history of breast cancer.	('GC', 'Phenotype', 'HP:0012126', (129, 131))	('breast cancer', 'Disease', (167, 180))	('1565 + 1G > T', 'Var', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('1565 + 1G > T', 'Mutation', 'rs587780113', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
4114	18046629	Breast cancer has been observed in HDGC kindreds to the extent where clustering of LBCs within HDGC families has led to the misclassification of families as breast cancer kindreds who test negative for BRCA1/2 mutations.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('GC', 'Phenotype', 'HP:0012126', (37, 39))	('mutations', 'Var', (210, 219))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('breast cancer', 'Disease', (157, 170))	('BRCA1/2', 'Gene', '672;675', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('LBC', 'Phenotype', 'HP:0006625', (83, 86))	('BRCA1/2', 'Gene', (202, 209))	('Breast cancer', 'Disease', (0, 13))
4118	18046629	Salashor examined 19 breast cancer tumours exhibiting LOH at the CDH1 locus, however of those, only 3 were confirmed to be pure LBC or mixed LBC/IDC pathology.	('breast cancer tumours', 'Disease', (21, 42))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('CDH1', 'Gene', (65, 69))	('CDH1', 'Gene', '999', (65, 69))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('LBC', 'Phenotype', 'HP:0006625', (141, 144))	('LBC', 'Phenotype', 'HP:0006625', (128, 131))	('breast cancer tumours', 'Disease', 'MESH:D009369', (21, 42))	('pure', 'molecular_function', 'GO:0034023', ('123', '127'))	('LOH', 'Var', (54, 57))	('breast cancer tumour', 'Phenotype', 'HP:0100013', (21, 41))
4119	18046629	More recently we have published an estimated cumulative risk for breast cancer for females by the age of 75 years as being 52% (95% CI, 29-94%) from analysis of 4 predominantly gastric cancer pedigrees from Newfoundland with the 2398delC CDH1 founder mutation.	('gastric cancer', 'Disease', (177, 191))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('gastric cancer', 'Disease', 'MESH:D013274', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('2398delC', 'Var', (229, 237))	('2398delC', 'Mutation', 'rs587783048', (229, 237))	('CDH1', 'Gene', (238, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (177, 191))	('CDH1', 'Gene', '999', (238, 242))
4120	18046629	This is with the caveat that LBC risk for CDH1 mutation carriers has been assessed within high risk HDGC families, leading to a potential ascertainment bias and underestimation of the role of CDH1 mutations in LBC development.	('GC', 'Phenotype', 'HP:0012126', (102, 104))	('LBC', 'Phenotype', 'HP:0006625', (29, 32))	('CDH1', 'Gene', '999', (192, 196))	('CDH1', 'Gene', (42, 46))	('CDH1', 'Gene', '999', (42, 46))	('mutation', 'Var', (47, 55))	('mutations', 'Var', (197, 206))	('men', 'Species', '9606', (221, 224))	('LBC', 'Phenotype', 'HP:0006625', (210, 213))	('men', 'Species', '9606', (147, 150))	('CDH1', 'Gene', (192, 196))
4121	18046629	To accommodate for this we have begun analysis of CDH1 mutations within familial lobular breast cancer families or those families ascertained through a relatively young index case with confirmed LBC and have found germline CDH1 mutations in these kindreds.	('CDH1', 'Gene', (223, 227))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CDH1', 'Gene', '999', (223, 227))	('LBC', 'Phenotype', 'HP:0006625', (195, 198))	('familial lobular breast cancer', 'Disease', (72, 102))	('mutations', 'Var', (228, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (81, 102))	('CDH1', 'Gene', (50, 54))	('CDH1', 'Gene', '999', (50, 54))	('familial lobular breast cancer', 'Disease', 'MESH:D013274', (72, 102))
4122	18046629	At this time, it seems reasonable to conclude that at least four groups of women are at increased risk for LBC: women with LBC and a family history of breast cancer, women with a known CDH1 mutation, women from families with diffuse gastric cancer in whom no CDH1 mutation has yet been identified; and women with a germline BRCA2 mutation.	('women', 'Species', '9606', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('women', 'Species', '9606', (112, 117))	('LBC', 'Disease', (123, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('CDH1', 'Gene', '999', (259, 263))	('LBC', 'Disease', (107, 110))	('women', 'Species', '9606', (302, 307))	('women', 'Species', '9606', (166, 171))	('gastric cancer', 'Phenotype', 'HP:0012126', (233, 247))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('CDH1', 'Gene', (259, 263))	('breast cancer', 'Disease', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('BRCA2', 'Gene', (324, 329))	('LBC', 'Phenotype', 'HP:0006625', (123, 126))	('CDH1', 'Gene', '999', (185, 189))	('gastric cancer', 'Disease', (233, 247))	('LBC', 'Phenotype', 'HP:0006625', (107, 110))	('mutation', 'Var', (190, 198))	('CDH1', 'Gene', (185, 189))	('women', 'Species', '9606', (75, 80))	('mutation', 'Var', (330, 338))	('BRCA2', 'Gene', '675', (324, 329))	('gastric cancer', 'Disease', 'MESH:D013274', (233, 247))
4123	18046629	Since there has not yet been a large population based study of the prevalence of CDH1 mutations among women with lobular breast cancer, it is premature to recommend genetic evaluation to women with a family history of breast cancer unless, at the very least, one of the breast cancers can be shown to have been lobular.	('breast cancer', 'Phenotype', 'HP:0003002', (270, 283))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (270, 283))	('men', 'Species', '9606', (104, 107))	('women', 'Species', '9606', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('men', 'Species', '9606', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('mutations', 'Var', (86, 95))	('lobular breast cancer', 'Disease', (113, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('breast cancers', 'Disease', 'MESH:D001943', (270, 284))	('breast cancers', 'Disease', (270, 284))	('breast cancer', 'Disease', (218, 231))	('women', 'Species', '9606', (187, 192))	('CDH1', 'Gene', '999', (81, 85))	('men', 'Species', '9606', (189, 192))	('breast cancers', 'Phenotype', 'HP:0003002', (270, 284))	('lobular breast cancer', 'Disease', 'MESH:D013274', (113, 134))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (113, 134))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('CDH1', 'Gene', (81, 85))
4124	18046629	Although there are not yet definitive data available on surveillance or risk reduction programs for women with known CDH1 mutations or untested women from CDH1-positive families, the high lifetime risk of LBC (39-52%) that these women face mandates their careful management.	('men', 'Species', '9606', (269, 272))	('LBC', 'Disease', (205, 208))	('women', 'Species', '9606', (229, 234))	('CDH1', 'Gene', (155, 159))	('CDH1', 'Gene', (117, 121))	('men', 'Species', '9606', (146, 149))	('CDH1', 'Gene', '999', (117, 121))	('men', 'Species', '9606', (231, 234))	('CDH1', 'Gene', '999', (155, 159))	('mutations', 'Var', (122, 131))	('women', 'Species', '9606', (144, 149))	('LBC', 'Phenotype', 'HP:0006625', (205, 208))	('women', 'Species', '9606', (100, 105))	('men', 'Species', '9606', (102, 105))
4130	18046629	Several studies have reported a 90% reduction in breast cancer incidence with prophylactic mastectomy among women with a strong family history or with a germline BRCA1 or BRCA2 mutation.	('women', 'Species', '9606', (108, 113))	('mutation', 'Var', (177, 185))	('BRCA1', 'Gene', '672', (162, 167))	('reduction', 'NegReg', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('BRCA2', 'Gene', (171, 176))	('BRCA1', 'Gene', (162, 167))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('BRCA2', 'Gene', '675', (171, 176))
4133	18046629	Although identification of germline CDH1 mutations has enabled a significant proportion of HDGC families to utilise predictive testing to determine their individual risks of GC within CDH1 mutation positive pedigrees, unfortunately screening for DGC is ineffective and the current recommendation is for consideration of prophylactic gastrectomy in mutation positive individuals.	('mutations', 'Var', (41, 50))	('GC', 'Phenotype', 'HP:0012126', (247, 249))	('men', 'Species', '9606', (286, 289))	('CDH1', 'Gene', (184, 188))	('DGC', 'cellular_component', 'GO:0016010', ('246', '249'))	('CDH1', 'Gene', (36, 40))	('GC', 'Phenotype', 'HP:0012126', (93, 95))	('CDH1', 'Gene', '999', (36, 40))	('CDH1', 'Gene', '999', (184, 188))	('GC', 'Phenotype', 'HP:0012126', (174, 176))
4134	18046629	Positron emission tomography and chromoendoscopic-directed biopsies have been proposed over basic endoscopy as more sensitive means of screening carriers, however screening methods have been consistently undermined by the recurrent discovery of multifocal DGC lesions underlying normal mucosa in prophylactic gastrectomy specimens of individuals with recent negative screening.	('DGC', 'Gene', (256, 259))	('DGC', 'cellular_component', 'GO:0016010', ('256', '259'))	('GC', 'Phenotype', 'HP:0012126', (257, 259))	('men', 'Species', '9606', (326, 329))	('lesions', 'Var', (260, 267))
4140	18046629	This likely reflects underlying differences in the biology of these diseases, however also highlights the unique nature of germline mutations in the CDH1 gene which are strongly associated with specific histologically defined subtypes of breast and GI cancer, namely LBC and DGC which are both part of the HDGC syndrome.	('GC', 'Phenotype', 'HP:0012126', (308, 310))	('HDGC syndrome', 'Disease', 'MESH:D013274', (306, 319))	('LBC', 'Phenotype', 'HP:0006625', (267, 270))	('associated', 'Reg', (178, 188))	('DGC', 'Disease', (275, 278))	('GI cancer', 'Phenotype', 'HP:0007378', (249, 258))	('LBC', 'Disease', (267, 270))	('mutations', 'Var', (132, 141))	('CDH1', 'Gene', (149, 153))	('HDGC syndrome', 'Disease', (306, 319))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('GC', 'Phenotype', 'HP:0012126', (276, 278))	('DGC', 'cellular_component', 'GO:0016010', ('275', '278'))	('CDH1', 'Gene', '999', (149, 153))	('breast and GI cancer', 'Disease', 'MESH:D001943', (238, 258))
4141	18046629	With the recent demonstration of a CDH1 mutation in a family ascertained through an index case of LBC and in view of the additional new mutation in a predominantly breast cancer family that we have described here, the evidence for establishing LBC as part of the HDGC syndrome is strong.	('mutation', 'Var', (40, 48))	('LBC', 'Phenotype', 'HP:0006625', (98, 101))	('GC', 'Phenotype', 'HP:0012126', (265, 267))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('HDGC syndrome', 'Disease', 'MESH:D013274', (263, 276))	('CDH1', 'Gene', (35, 39))	('breast cancer', 'Disease', (164, 177))	('CDH1', 'Gene', '999', (35, 39))	('LBC', 'Phenotype', 'HP:0006625', (244, 247))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('LBC', 'Disease', (244, 247))	('HDGC syndrome', 'Disease', (263, 276))
4142	18046629	There now is a need for establishing the prevalence of CDH1 mutations in LBC families to avoid the ascertainment bias generated from only looking at cases from families identified because of their family history of GC.	('CDH1', 'Gene', (55, 59))	('men', 'Species', '9606', (108, 111))	('CDH1', 'Gene', '999', (55, 59))	('LBC', 'Phenotype', 'HP:0006625', (73, 76))	('GC', 'Phenotype', 'HP:0012126', (215, 217))	('mutations', 'Var', (60, 69))
4145	18046629	Here we have discussed germline CDH1 mutations and the risks with regard to DGC and LBC, however as the recognised spectrum of related cancers broadens, more affected families will be identified and successfully managed with regard to avoidance of specific cancer risks.	('cancer', 'Disease', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('LBC', 'Disease', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancers', 'Disease', (135, 142))	('DGC', 'Disease', (76, 79))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('CDH1', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('DGC', 'cellular_component', 'GO:0016010', ('76', '79'))	('CDH1', 'Gene', '999', (32, 36))	('GC', 'Phenotype', 'HP:0012126', (77, 79))	('cancer', 'Disease', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('LBC', 'Phenotype', 'HP:0006625', (84, 87))
4155	33413533	The multistep model of breast cancer progression contends that although lobular carcinomas arise along the low-grade, ER-positive arm of the pathway (with low-grade, ER-positive ductal lesions), de-differentiation to higher grade lesions can occur through acquisition of alterations in oncogenes such as ERBB2 and TP53, producing a spectrum of heterogenous proliferations (Fig.	('ERBB2', 'Gene', '2064', (304, 309))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('lobular carcinomas', 'Disease', 'MESH:D018275', (72, 90))	('ER', 'Gene', '2069', (304, 306))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('breast cancer', 'Disease', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('TP53', 'Gene', (314, 318))	('alterations', 'Var', (271, 282))	('ER', 'Gene', '2069', (118, 120))	('lobular carcinomas', 'Disease', (72, 90))	('ER', 'Gene', '2069', (166, 168))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (72, 90))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('ERBB2', 'Gene', (304, 309))	('heterogenous proliferations', 'MPA', (344, 371))	('TP53', 'Gene', '7157', (314, 318))	('producing', 'Reg', (320, 329))
4160	33413533	gene mutation combined with gene deletion) of the CDH1 gene encoding E-cadherin, although other mechanisms of expression loss also feature.	('CDH1', 'Gene', (50, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('71', '79'))	('CDH1', 'Gene', '999', (50, 54))	('gene mutation', 'Var', (0, 13))
4171	33413533	There is a striking similarity in the genomic profiles of CLCIS, PLCIS, and FLCIS (and invasive tumours), with recurrent gains of 1q and losses on 16q and CDH1 mutations suggesting they arise from a common aetiology (Fig.	('gains', 'PosReg', (121, 126))	('FLCIS', 'Disease', (76, 81))	('mutations', 'Var', (160, 169))	('LCIS', 'Phenotype', 'HP:0030076', (59, 63))	('CDH1', 'Gene', (155, 159))	('LCIS', 'Phenotype', 'HP:0030076', (66, 70))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('invasive tumours', 'Disease', (87, 103))	('CDH1', 'Gene', '999', (155, 159))	('CLCIS', 'Disease', (58, 63))	('losses', 'NegReg', (137, 143))	('16q', 'Gene', (147, 150))	('LCIS', 'Phenotype', 'HP:0030076', (77, 81))	('invasive tumours', 'Disease', 'MESH:D009361', (87, 103))
4172	33413533	An increased frequency of ERBB2/HER2 mutations or amplifications has been reported in PLCIS compared to classic LCIS.	('LCIS', 'Phenotype', 'HP:0030076', (112, 116))	('HER2', 'Gene', (32, 36))	('PLCIS', 'Disease', (86, 91))	('ERBB2', 'Gene', (26, 31))	('HER2', 'Gene', '2064', (32, 36))	('ERBB2', 'Gene', '2064', (26, 31))	('LCIS', 'Phenotype', 'HP:0030076', (87, 91))	('mutations', 'Var', (37, 46))	('amplifications', 'Var', (50, 64))
4173	33413533	Exome sequencing of a small cohort of PLCIS and two cases of FLCIS demonstrated frequent alterations similar to those seen in classic LCIS and ILC, including 16q loss, 1q gain, and mutations in CDH1, PIK3CA, RUNX1, and CBFB (Table 1).	('LCIS', 'Phenotype', 'HP:0030076', (39, 43))	('gain', 'PosReg', (171, 175))	('16q', 'CPA', (158, 161))	('CBFB', 'Gene', (219, 223))	('loss', 'NegReg', (162, 166))	('LCIS', 'Phenotype', 'HP:0030076', (134, 138))	('RUNX1', 'Gene', (208, 213))	('LCIS', 'Phenotype', 'HP:0030076', (62, 66))	('CDH1', 'Gene', (194, 198))	('CDH1', 'Gene', '999', (194, 198))	('RUNX1', 'Gene', '861', (208, 213))	('PIK3CA', 'Gene', (200, 206))	('mutations', 'Var', (181, 190))	('PIK3CA', 'Gene', '5290', (200, 206))	('CBFB', 'Gene', '865', (219, 223))
4174	33413533	However, there was a striking difference within the special variants of LCIS, with highly recurrent ERBB2 and ERBB3 alterations (mutations or amplifications) present in 94.7% of cases studied.	('LCIS', 'Phenotype', 'HP:0030076', (72, 76))	('ERBB3', 'Gene', (110, 115))	('ERBB3', 'Gene', '2065', (110, 115))	('ERBB2', 'Gene', '2064', (100, 105))	('alterations', 'Var', (116, 127))	('ERBB2', 'Gene', (100, 105))
4175	33413533	This important finding is supported by another study that also demonstrated an enrichment of ERBB2 and ERBB3 mutations in 50% of PLCIS and FLCIS variants relative to co-occurring CLCIS.	('LCIS', 'Phenotype', 'HP:0030076', (140, 144))	('PLCIS', 'Gene', (129, 134))	('ERBB3', 'Gene', '2065', (103, 108))	('FLCIS', 'Gene', (139, 144))	('variants', 'Var', (145, 153))	('ERBB3', 'Gene', (103, 108))	('LCIS', 'Phenotype', 'HP:0030076', (180, 184))	('ERBB2', 'Gene', (93, 98))	('mutations', 'Var', (109, 118))	('ERBB2', 'Gene', '2064', (93, 98))	('LCIS', 'Phenotype', 'HP:0030076', (130, 134))
4176	33413533	Thus, between 50 and 94% of PLCIS and FLCIS harbour ERBB2 or ERBB3 mutations (Table 2).	('LCIS', 'Phenotype', 'HP:0030076', (39, 43))	('ERBB3', 'Gene', (61, 66))	('mutations', 'Var', (67, 76))	('ERBB2', 'Gene', '2064', (52, 57))	('LCIS', 'Phenotype', 'HP:0030076', (29, 33))	('ERBB2', 'Gene', (52, 57))	('ERBB3', 'Gene', '2065', (61, 66))
4177	33413533	The presence of common mutations shared between lesions within an individual case inferred that PLCIS or FLCIS had a common clonal ancestry to classic LCIS, but that the additional acquisition of mutations in ERBB2 and ERBB3 (as well as in TP53, CCND1 and increased copy number aberrations) suggests these alterations are likely drivers of the enhanced cytological atypia and proliferative state seen in these variants.	('LCIS', 'Phenotype', 'HP:0030076', (106, 110))	('TP53', 'Gene', '7157', (240, 244))	('TP53', 'Gene', (240, 244))	('ERBB3', 'Gene', '2065', (219, 224))	('LCIS', 'Phenotype', 'HP:0030076', (151, 155))	('CCND1', 'Gene', (246, 251))	('ERBB2', 'Gene', (209, 214))	('ERBB3', 'Gene', (219, 224))	('ERBB2', 'Gene', '2064', (209, 214))	('LCIS', 'Phenotype', 'HP:0030076', (97, 101))	('CCND1', 'Gene', '595', (246, 251))	('mutations', 'Var', (196, 205))
4182	33413533	The authors showed the overall survival in both triple-negative ILC and HER2+ ILC was significantly worse compared to their IBC-NST counterparts raising the possibility that within ILC, HER2+ status or triple-negative status identifies clinically important subtypes of ILC.	('ILC', 'Disease', (269, 272))	('HER2', 'Gene', (72, 76))	('HER2', 'Gene', '2064', (72, 76))	('HER2', 'Gene', (186, 190))	('HER2', 'Gene', '2064', (186, 190))	('worse', 'NegReg', (100, 105))	('triple-negative', 'Var', (48, 63))
4204	33413533	Recent evidence suggests that PIK3CA mutation status may impact the tumour immune microenvironment in ER-positive breast cancer, and this is therefore likely to be important in ILC.	('PIK3CA', 'Gene', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('impact', 'Reg', (57, 63))	('ILC', 'Disease', (177, 180))	('mutation', 'Var', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('PIK3CA', 'Gene', '5290', (30, 36))	('tumour', 'Disease', (68, 74))	('ER', 'Gene', '2069', (102, 104))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
4205	33413533	Despite increasing numbers of samples profiled across a number of high impact studies including from TCGA and RATHER cohorts, the frequency of CDH1 (and other gene) mutations in ILC is variably reported (e.g.	('ER', 'Gene', '2069', (114, 116))	('ILC', 'Gene', (178, 181))	('mutations', 'Var', (165, 174))	('CDH1', 'Gene', (143, 147))	('CDH1', 'Gene', '999', (143, 147))
4206	33413533	It is interesting to note that in studies examining LCIS, in which microdissection was employed to enrich for neoplastic cells, the frequency of CDH1 mutation is 81-94%, suggesting that some of this variability may be related to the sensitivity of sequencing platforms used when analysing a tumour type with a diffuse growth pattern and hence samples of potentially low tumour cellularity.	('tumour', 'Disease', 'MESH:D009369', (291, 297))	('tumour', 'Disease', 'MESH:D009369', (370, 376))	('mutation', 'Var', (150, 158))	('CDH1', 'Gene', (145, 149))	('tumour', 'Disease', (291, 297))	('tumour', 'Disease', (370, 376))	('LCIS', 'Phenotype', 'HP:0030076', (52, 56))	('growth pattern', 'biological_process', 'GO:0007150', ('318', '332'))	('growth pattern', 'biological_process', 'GO:0040007', ('318', '332'))	('CDH1', 'Gene', '999', (145, 149))	('tumour', 'Phenotype', 'HP:0002664', (291, 297))	('tumour', 'Phenotype', 'HP:0002664', (370, 376))
4207	33413533	In addition to the well-characterised alterations in CDH1, and the copy number alterations involving gain of chromosome 1q, loss of 16q, and amplifications of 8p12 (FGRF1 locus) and 11q13 (CCND1 locus), the importance of mutations in driver genes PIK3CA, PTEN, AKT1, TBX3, FOXA1, and ERBB2/3 is repeatedly observed (Table 1).	('loss', 'NegReg', (124, 128))	('TBX3', 'Gene', (267, 271))	('AKT1', 'Gene', '207', (261, 265))	('PIK3CA', 'Gene', '5290', (247, 253))	('CDH1', 'Gene', '999', (53, 57))	('ERBB2/3', 'Gene', '2064;2065', (284, 291))	('mutations', 'Var', (221, 230))	('AKT1', 'Gene', (261, 265))	('PTEN', 'Gene', (255, 259))	('CDH1', 'Gene', (53, 57))	('CCND1', 'Gene', '595', (189, 194))	('PIK3CA', 'Gene', (247, 253))	('FOXA1', 'Gene', '3169', (273, 278))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('CCND1', 'Gene', (189, 194))	('ERBB2/3', 'Gene', (284, 291))	('FOXA1', 'Gene', (273, 278))	('16q', 'Protein', (132, 135))	('TBX3', 'Gene', '6926', (267, 271))	('gain', 'PosReg', (101, 105))
4208	33413533	Whilst CDH1 mutations are pathognomonic for ILC and the morphological variants, there are other genes which are altered to different frequencies in ILC compared to IBC-NST.	('CDH1', 'Gene', (7, 11))	('ILC', 'Disease', (148, 151))	('mutations', 'Var', (12, 21))	('CDH1', 'Gene', '999', (7, 11))	('ILC', 'Disease', (44, 47))	('pathognomonic', 'Reg', (26, 39))
4209	33413533	One notable finding is that FOXA1 and GATA3 mutations are reciprocally more common in ILC or IBC-NST, respectively.	('common', 'Reg', (76, 82))	('IBC-NST', 'Disease', (93, 100))	('GATA3', 'Gene', '2625', (38, 43))	('FOXA1', 'Gene', (28, 33))	('mutations', 'Var', (44, 53))	('FOXA1', 'Gene', '3169', (28, 33))	('GATA3', 'Gene', (38, 43))	('ILC', 'Disease', (86, 89))
4210	33413533	Further, PIK3CA, PTEN, and AKT1 are collectively mutated in over half of all ILC and at a higher frequency to molecular subtype-matched (luminal A) IBC-NST, thus leading to an enriched Akt pathway activation in ILC.	('AKT1', 'Gene', '207', (27, 31))	('mutated', 'Var', (49, 56))	('luminal', 'Chemical', 'MESH:D010634', (137, 144))	('AKT1', 'Gene', (27, 31))	('activation', 'PosReg', (197, 207))	('ILC', 'Disease', (77, 80))	('PIK3CA', 'Gene', '5290', (9, 15))	('PTEN', 'Gene', (17, 21))	('PIK3CA', 'Gene', (9, 15))	('Akt pathway', 'Pathway', (185, 196))
4211	33413533	Also of note, the frequency of mutations in, for example, TP53, ESR1, and ERBB2 increases with increasing severity of disease, for example CLCIS vs. FLCIS/PLCIS (as noted above), CILC vs. PILC, or primary vs. metastatic ILC (Table 1, and see below), attesting to the importance of these gene alterations in driving a more aggressive tumour biology which, importantly, are linked to endocrine therapy resistance.	('tumour', 'Phenotype', 'HP:0002664', (333, 339))	('CLCIS', 'Disease', (139, 144))	('mutations', 'Var', (31, 40))	('ERBB2', 'Gene', (74, 79))	('LCIS', 'Phenotype', 'HP:0030076', (150, 154))	('TP53', 'Gene', '7157', (58, 62))	('LCIS', 'Phenotype', 'HP:0030076', (140, 144))	('TP53', 'Gene', (58, 62))	('aggressive tumour', 'Disease', 'MESH:D009369', (322, 339))	('CILC', 'Disease', (179, 183))	('ESR1', 'Gene', '2099', (64, 68))	('increases', 'PosReg', (80, 89))	('LCIS', 'Phenotype', 'HP:0030076', (156, 160))	('aggressive tumour', 'Disease', (322, 339))	('ESR1', 'Gene', (64, 68))	('ERBB2', 'Gene', '2064', (74, 79))	('alterations', 'Var', (292, 303))
4212	33413533	As discussed above, ERBB2 and ERBB3 mutations are more commonly identified in PLCIS than classic LCIS, and this holds true for their invasive counterparts classic and pleomorphic ILC.	('identified', 'Reg', (64, 74))	('ERBB3', 'Gene', (30, 35))	('classic', 'Disease', (155, 162))	('ERBB2', 'Gene', '2064', (20, 25))	('LCIS', 'Phenotype', 'HP:0030076', (79, 83))	('ERBB2', 'Gene', (20, 25))	('mutations', 'Var', (36, 45))	('pleomorphic ILC', 'Disease', (167, 182))	('LCIS', 'Phenotype', 'HP:0030076', (97, 101))	('PLCIS', 'Disease', (78, 83))	('ERBB3', 'Gene', '2065', (30, 35))
4213	33413533	An enrichment of IRS2 mutations has also been reported in approximately 30% of PILC tumours, with in vitro studies suggesting a role in enhanced invasion.	('enhanced', 'PosReg', (136, 144))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('PILC tumours', 'Disease', 'MESH:D009369', (79, 91))	('IRS2', 'Gene', '8660', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('reported', 'Reg', (46, 54))	('mutations', 'Var', (22, 31))	('PILC tumours', 'Disease', (79, 91))	('invasion', 'CPA', (145, 153))	('IRS2', 'Gene', (17, 21))
4214	33413533	defined interesting mutation and copy number alterations with different ILC variant morphology: solid ILC variants were shown to be enriched for ERBB2, TP53, and ARID1A mutations; 11p and 6q25.1 (ESR1) gains; and 1p36.22 (ARID1A) deletions, whilst the alveolar variant harboured 11q13.3 (CCND1) and 11q14 (PAK1) gains (see Fig.	('mutations', 'Var', (169, 178))	('TP53', 'Gene', '7157', (152, 156))	('ARID1A', 'Gene', (162, 168))	('PAK1', 'Gene', '5058', (306, 310))	('ERBB2', 'Gene', '2064', (145, 150))	('CCND1', 'Gene', '595', (288, 293))	('variants', 'Var', (106, 114))	('CCND1', 'Gene', (288, 293))	('ARID1A', 'Gene', '8289', (162, 168))	('ARID1A', 'Gene', (222, 228))	('ILC', 'Gene', (102, 105))	('deletions', 'Var', (230, 239))	('gains', 'PosReg', (312, 317))	('TP53', 'Gene', (152, 156))	('ARID1A', 'Gene', '8289', (222, 228))	('gains', 'PosReg', (202, 207))	('1p36.22', 'Var', (213, 220))	('ESR1', 'Gene', '2099', (196, 200))	('ERBB2', 'Gene', (145, 150))	('PAK1', 'Gene', (306, 310))	('ESR1', 'Gene', (196, 200))
4215	33413533	1); mixed, non-classic types had mutations in TP53 and ERBB2.	('TP53', 'Gene', '7157', (46, 50))	('mutations', 'Var', (33, 42))	('TP53', 'Gene', (46, 50))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))
4216	33413533	ESR1 mutations are known to occur in the hormone therapy resistance setting, and the prevalence and type of ESR1 mutation in ILC are comparable to IBC-NST.	('ESR1', 'Gene', '2099', (108, 112))	('mutation', 'Var', (113, 121))	('ESR1', 'Gene', (0, 4))	('ILC', 'Disease', (125, 128))	('ESR1', 'Gene', (108, 112))	('ESR1', 'Gene', '2099', (0, 4))
4217	33413533	The increasing importance of ESR1 copy number gains is emerging, with gains and amplifications reported in 14% and 10% of ILC cases, respectively; this was significantly associated with disease recurrence.	('copy number gains', 'Var', (34, 51))	('amplifications', 'MPA', (80, 94))	('ESR1', 'Gene', '2099', (29, 33))	('ILC', 'Disease', (122, 125))	('ESR1', 'Gene', (29, 33))	('associated with', 'Reg', (170, 185))	('gains', 'PosReg', (70, 75))
4218	33413533	ESR1 copy number gains in metastatic ILC were significantly enriched in bone metastatic deposits.	('ESR1', 'Gene', (0, 4))	('enriched', 'Reg', (60, 68))	('bone metastatic deposits', 'CPA', (72, 96))	('ESR1', 'Gene', '2099', (0, 4))	('copy number gains', 'Var', (5, 22))
4220	33413533	The authors used the MSK-IMPACT targeted gene panel sequencing assay, and they confirmed interesting histo-specific changes enriched in ILC (relative to IBC-NST) including TBX3 (N297) and particular mutations in the forkhead domain of FOXA1, with an enrichment of ERBB2 and NF1 mutations in metastatic clones.	('mutations', 'Var', (278, 287))	('FOXA1', 'Gene', '3169', (235, 240))	('NF1', 'Gene', (274, 277))	('TBX3', 'Gene', '6926', (172, 176))	('ERBB2', 'Gene', (264, 269))	('NF1', 'Gene', '4763', (274, 277))	('ERBB2', 'Gene', '2064', (264, 269))	('ILC', 'Disease', (136, 139))	('mutations in', 'Var', (199, 211))	('TBX3', 'Gene', (172, 176))	('FOXA1', 'Gene', (235, 240))
4221	33413533	These findings are independently supported by others, with both NF1 and ERBB2 mutations being enriched in metastatic ILC; indeed, both gene mutations are also found to be mutually exclusive with ESR1 mutations, suggesting they play important roles in mediating endocrine therapy resistance in both ER-positive breast cancer overall and specifically in ILC.	('roles', 'Reg', (242, 247))	('mutations', 'Var', (200, 209))	('NF1', 'Gene', (64, 67))	('breast cancer', 'Disease', 'MESH:D001943', (310, 323))	('ESR1', 'Gene', '2099', (195, 199))	('ERBB2', 'Gene', (72, 77))	('breast cancer', 'Disease', (310, 323))	('ER', 'Gene', '2069', (72, 74))	('ESR1', 'Gene', (195, 199))	('mutations', 'Var', (78, 87))	('ERBB2', 'Gene', '2064', (72, 77))	('mediating', 'Reg', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('mutations', 'Var', (140, 149))	('play', 'Reg', (227, 231))	('ILC', 'Disease', (352, 355))	('ER', 'Gene', '2069', (298, 300))	('NF1', 'Gene', '4763', (64, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (310, 323))
4222	33413533	The acquisition of ERBB2 and ERBB3 mutations in ILC has been shown to be associated with an increased risk of relapse and poorer outcomes, likely representing an escape mechanism to endocrine therapy.	('relapse', 'CPA', (110, 117))	('ERBB2', 'Gene', '2064', (19, 24))	('ERBB2', 'Gene', (19, 24))	('ERBB3', 'Gene', '2065', (29, 34))	('ILC', 'Gene', (48, 51))	('ERBB3', 'Gene', (29, 34))	('mutations', 'Var', (35, 44))
4223	33413533	Indeed, a recent, large meta-analysis showed that ILCs account for 47% of all ERBB2 mutated (not amplified) cases, and that targetable ERBB2 mutations are an independent prognostic marker of poorer 10-year overall survival.	('ERBB2', 'Gene', '2064', (78, 83))	('ILCs', 'Disease', (50, 54))	('ERBB2', 'Gene', (78, 83))	('mutations', 'Var', (141, 150))	('mutated', 'Var', (84, 91))	('poorer', 'NegReg', (191, 197))	('ERBB2', 'Gene', '2064', (135, 140))	('ERBB2', 'Gene', (135, 140))
4224	33413533	This team then postulated that mutation of ERBB2/3 may initiate alternate downstream activity (as opposed to ERBB2/3 amplification) and derived a gene expression signature to measure this.	('initiate', 'Reg', (55, 63))	('ERBB2/3', 'Gene', (43, 50))	('ERBB2/3', 'Gene', '2064;2065', (43, 50))	('gene expression', 'biological_process', 'GO:0010467', ('146', '161'))	('mutation', 'Var', (31, 39))	('ERBB2/3', 'Gene', (109, 116))	('alternate downstream activity', 'MPA', (64, 93))	('ERBB2/3', 'Gene', '2064;2065', (109, 116))
4225	33413533	This signature measured the impact and actionability of the ERBB2 alterations, and exhibited potential clinical value by being predictive of neratinib response in breast cancer cell line data.	('ERBB2', 'Gene', '2064', (60, 65))	('ERBB2', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('neratinib', 'Chemical', 'MESH:C487932', (141, 150))	('breast cancer', 'Disease', (163, 176))	('alterations', 'Var', (66, 77))
4226	33413533	As most of the mutations in ERBB2 and ERBB3 cause activation of the HER2 pathway, they may be amenable to treatment with HER2 inhibitors (e.g.	('HER2', 'Gene', '2064', (121, 125))	('ERBB3', 'Gene', '2065', (38, 43))	('HER2', 'Gene', (68, 72))	('mutations', 'Var', (15, 24))	('activation', 'PosReg', (50, 60))	('ERBB3', 'Gene', (38, 43))	('ERBB2', 'Gene', '2064', (28, 33))	('HER2', 'Gene', '2064', (68, 72))	('ERBB2', 'Gene', (28, 33))	('HER2', 'Gene', (121, 125))
4228	33413533	However, it should be noted one of the most common recurrent ERBB2 mutations, p.L755S, confers resistance to lapatinib.	('p.L755S', 'Var', (78, 85))	('ERBB2', 'Gene', (61, 66))	('ERBB2', 'Gene', '2064', (61, 66))	('resistance to lapatinib', 'MPA', (95, 118))	('p.L755S', 'Mutation', 'rs121913470', (78, 85))	('lapatinib', 'Chemical', 'MESH:D000077341', (109, 118))
4229	33413533	The frequency of alterations in ERBB2 in lesions with lobular morphology is summarised in Table 2.	('alterations', 'Var', (17, 28))	('ERBB2', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (32, 37))
4232	33413533	Further, alterations private to the metastasis compared to the paired primary ILC (of 32 patients) were seen in such genes, including mutations in CDH1, ARID1A, ERBB2, ESR1, AKT1, GATA3, and NF1; copy number deletions for MAP2K4, NCOR1, TP53, PTEN, and AKT1; and amplifications of CCND1 and CCNE1.	('ERBB2', 'Gene', '2064', (161, 166))	('NF1', 'Gene', (191, 194))	('TP53', 'Gene', (237, 241))	('CCND1', 'Gene', (281, 286))	('MAP2K4', 'Gene', '6416', (222, 228))	('PTEN', 'Gene', (243, 247))	('MAP2K4', 'Gene', (222, 228))	('ARID1A', 'Gene', (153, 159))	('CCND1', 'Gene', '595', (281, 286))	('AKT1', 'Gene', (253, 257))	('CCNE1', 'Gene', (291, 296))	('CDH1', 'Gene', '999', (147, 151))	('AKT1', 'Gene', (174, 178))	('GATA3', 'Gene', '2625', (180, 185))	('ARID1A', 'Gene', '8289', (153, 159))	('mutations', 'Var', (134, 143))	('NCOR1', 'Gene', (230, 235))	('CDH1', 'Gene', (147, 151))	('GATA3', 'Gene', (180, 185))	('CCNE1', 'Gene', '898', (291, 296))	('TP53', 'Gene', '7157', (237, 241))	('NCOR1', 'Gene', '9611', (230, 235))	('metastasis', 'CPA', (36, 46))	('ESR1', 'Gene', '2099', (168, 172))	('ERBB2', 'Gene', (161, 166))	('ESR1', 'Gene', (168, 172))	('NF1', 'Gene', '4763', (191, 194))	('MAP2K', 'molecular_function', 'GO:0004708', ('222', '227'))	('alterations', 'Reg', (9, 20))	('copy number deletions', 'Var', (196, 217))	('patients', 'Species', '9606', (89, 97))	('amplifications', 'Var', (263, 277))	('AKT1', 'Gene', '207', (253, 257))	('AKT1', 'Gene', '207', (174, 178))
4233	33413533	ILCs from EuroILC and MSK-IMPACT were in general similar, whilst there was an increase in CDH1, ERBB2, FOXA1, and TBX3 mutations and fewer TP53 mutations between ILC and IBC-NST metastases.	('FOXA1', 'Gene', '3169', (103, 108))	('TBX3', 'Gene', (114, 118))	('IBC-NST metastases', 'Disease', (170, 188))	('FOXA1', 'Gene', (103, 108))	('CDH1', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (139, 143))	('fewer', 'NegReg', (133, 138))	('CDH1', 'Gene', '999', (90, 94))	('ERBB2', 'Gene', '2064', (96, 101))	('IBC-NST metastases', 'Disease', 'MESH:D009362', (170, 188))	('ERBB2', 'Gene', (96, 101))	('TP53', 'Gene', (139, 143))	('mutations', 'Var', (119, 128))	('mutations', 'Var', (144, 153))	('TBX3', 'Gene', '6926', (114, 118))
4234	33413533	Interestingly, an increase in IGFR1 mutations was specifically noted for the EuroILC ILC metastasis cohort compared to the MSK-IMPACT IBC-NST cohort, and previous findings of increased NF1 alterations in ILC metastases were not replicated.	('increase', 'PosReg', (18, 26))	('mutations', 'Var', (36, 45))	('IGFR1', 'Gene', (30, 35))	('ILC', 'Disease', (85, 88))	('NF1', 'Gene', (185, 188))	('ILC metastases', 'Disease', (204, 218))	('ILC metastases', 'Disease', 'MESH:D009362', (204, 218))	('NF1', 'Gene', '4763', (185, 188))	('IGFR1', 'Gene', '100132417', (30, 35))
4236	33413533	Whether these alterations are already present in minor subclones of the primary tumour or arise during treatment exposure, the enrichment of this plethora of targetable and potentially mutations in metastatic deposits of ILC is of high clinical importance.	('tumour', 'Disease', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('mutations', 'Var', (185, 194))	('plethora', 'Phenotype', 'HP:0001050', (146, 154))	('ILC', 'Gene', (221, 224))
4246	33413533	Prosigna  is the commercial diagnostic test based on the PAM50 'intrinsic' subtyping (long established as being prognostic in breast cancers).	('breast cancers', 'Disease', 'MESH:D001943', (126, 140))	("PAM50 'intrinsic", 'Var', (57, 73))	('breast cancers', 'Disease', (126, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('breast cancers', 'Phenotype', 'HP:0003002', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
4247	33413533	The Prosigna  test generates a Risk of Recurrence score (ROR), and the latest research demonstrates that ROR provides additional prognostic value in ILC, with an increased 10-year distant recurrence rate significantly associated with luminal B status (see for a detailed summary of the transcriptomics of ILC).	('ROR', 'Gene', '100885779', (57, 60))	('luminal', 'Chemical', 'MESH:D010634', (234, 241))	('luminal B status', 'Var', (234, 250))	('distant recurrence', 'CPA', (180, 198))	('ROR', 'Gene', (105, 108))	('associated', 'Reg', (218, 228))	('ROR', 'Gene', (57, 60))	('ROR', 'Gene', '100885779', (105, 108))	('ILC', 'Disease', (149, 152))
4251	33413533	We reported that ILCs associated with a high-risk score were enriched for mutations in ERBB2, ERBB3, TP53, AKT1, and ROS1, highlighting the potential application of targeted therapies in the high-risk ILC patients.	('patients', 'Species', '9606', (205, 213))	('TP53', 'Gene', '7157', (101, 105))	('AKT1', 'Gene', '207', (107, 111))	('mutations', 'Var', (74, 83))	('ERBB3', 'Gene', '2065', (94, 99))	('TP53', 'Gene', (101, 105))	('ERBB2', 'Gene', (87, 92))	('ROS1', 'Gene', (117, 121))	('AKT1', 'Gene', (107, 111))	('ILCs', 'Disease', (17, 21))	('ERBB3', 'Gene', (94, 99))	('ROS1', 'Gene', '6098', (117, 121))	('ERBB2', 'Gene', '2064', (87, 92))
4254	33413533	SUM44PE was shown to have acquired a naturally occurring ESR1 mutation following long-term oestrogen deprivation, and this represents an excellent model with which to further address issues surrounding endocrine therapy resistance, which is an increasing clinical problem.	('ESR1', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('SUM44PE', 'Chemical', '-', (0, 7))	('ESR1', 'Gene', '2099', (57, 61))
4258	33413533	The presence of oestrogen has also been shown to activate distinct signalling pathways in ILC (compared to IDC), including PI3K/Akt/mTOR signalling, in part through the actions of WNT4.	('oestrogen', 'Protein', (16, 25))	('signalling', 'biological_process', 'GO:0023052', ('67', '77'))	('activate', 'PosReg', (49, 57))	('WNT4', 'Gene', (180, 184))	('WNT4', 'Gene', '54361', (180, 184))	('signalling pathways', 'Pathway', (67, 86))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))	('PI3K/Akt/mTOR signalling', 'Pathway', (123, 147))	('presence', 'Var', (4, 12))	('signalling', 'biological_process', 'GO:0023052', ('137', '147'))	('ILC', 'Disease', (90, 93))
4259	33413533	Similarly, and further to the idea that FGFR1 might be a driver of ILC, FGFR4 was identified as a candidate molecule involved in ER resistance in vitro, with clinical relevance to this finding being revealed through FGFR4 upregulation and mutations being subsequently found in metastatic ILC.	('FGFR4', 'Gene', '2264', (72, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('FGFR4', 'Gene', (72, 77))	('ILC', 'Disease', (67, 70))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('ER', 'Gene', '2069', (129, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('216', '220'))	('mutations', 'Var', (239, 248))	('upregulation', 'PosReg', (222, 234))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('involved', 'Reg', (117, 125))	('FGFR4', 'Gene', '2264', (216, 221))	('FGFR4', 'Gene', (216, 221))
4261	33413533	These resistant tumours showed the acquisition of secondary mutations in FGFR2, overexpression of MET, increased drug efflux activity, and inactivation of negative regulators of RAS signalling.	('overexpression', 'PosReg', (80, 94))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('increased', 'PosReg', (103, 112))	('tumours', 'Disease', (16, 23))	('MET', 'Gene', (98, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('FGFR2', 'Gene', (73, 78))	('FGFR2', 'Gene', '14183', (73, 78))	('drug efflux activity', 'MPA', (113, 133))	('signalling', 'biological_process', 'GO:0023052', ('182', '192'))	('inactivation', 'NegReg', (139, 151))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('efflux', 'biological_process', 'GO:0140352', ('118', '124'))	('mutations', 'Var', (60, 69))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('efflux', 'biological_process', 'GO:0140115', ('118', '124'))	('MET', 'Gene', '79811', (98, 101))
4263	33413533	It is now clear from the work of Nagle et al  that a loss of E-cadherin (a canonical feature of ILC) hyperactivates the IGF1R pathway, whilst also sensitising to anti-IGF1R small-molecular inhibitor therapies OSI-906 and BMS-754807.	('cadherin', 'molecular_function', 'GO:0008014', ('63', '71'))	('IGF1R', 'Gene', (167, 172))	('IGF1R', 'Gene', (120, 125))	('E-cadherin', 'Protein', (61, 71))	('IGF1R', 'Gene', '3480', (167, 172))	('IGF1R', 'Gene', '3480', (120, 125))	('loss', 'Var', (53, 57))	('hyperactivates', 'PosReg', (101, 115))	('sensitising', 'Reg', (147, 158))
4264	33413533	Pre-clinical evidence to support a role for IRS2 mutations in driving PILC invasion has recently been presented, further implicating the insulin receptor (IR)/IGF1R/IRS2 signalling pathway in PILC biology.	('IRS2', 'Gene', (165, 169))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('IR', 'Gene', '3643', (44, 46))	('mutations', 'Var', (49, 58))	('IGF1R', 'Gene', '3480', (159, 164))	('insulin receptor', 'Gene', '3643', (137, 153))	('IRS2', 'Gene', '8660', (44, 48))	('insulin', 'molecular_function', 'GO:0016088', ('137', '144'))	('signalling pathway', 'biological_process', 'GO:0007165', ('170', '188'))	('IR', 'Gene', '3643', (165, 167))	('IR', 'Gene', '3643', (155, 157))	('IRS2', 'Gene', '8660', (165, 169))	('IRS2', 'Gene', (44, 48))	('IGF1R', 'Gene', (159, 164))	('insulin receptor', 'Gene', (137, 153))	('driving PILC', 'Disease', (62, 74))
4270	33413533	In an effort to identify clinically actionable pathways downstream of E-cadherin loss, Derksen and colleagues used CRISPR/Cas9 knockouts to show increased growth factor receptor (GFR)-dependent activation of PI3K/Akt signalling; treatment with Akt inhibitors resulted in robust inhibition of tumour growth in their murine ILC models.	('PR', 'Gene', '5241', (119, 121))	('PI3K', 'molecular_function', 'GO:0016303', ('208', '212'))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('tumour', 'Phenotype', 'HP:0002664', (292, 298))	('Cas', 'cellular_component', 'GO:0005650', ('122', '125'))	('tumour', 'Disease', 'MESH:D009369', (292, 298))	('murine', 'Species', '10090', (315, 321))	('PI3K/Akt signalling', 'Pathway', (208, 227))	('growth factor receptor', 'Gene', (155, 177))	('inhibition', 'NegReg', (278, 288))	('knockouts', 'Var', (127, 136))	('GFR', 'Gene', (179, 182))	('tumour', 'Disease', (292, 298))	('signalling', 'biological_process', 'GO:0023052', ('217', '227'))	('GFR', 'Gene', '20187', (179, 182))	('growth factor receptor', 'Gene', '20187', (155, 177))
4285	33413533	The prevalence of ERBB2 mutations in ILC and their responsiveness to neratinib has been confirmed in the MutHER (NCT01670877) trial, with this study expanding to include fulvestrant in future phases.	('responsiveness', 'MPA', (51, 65))	('ER', 'Gene', '2069', (109, 111))	('ERBB2', 'Gene', '2064', (18, 23))	('neratinib', 'Chemical', 'MESH:C487932', (69, 78))	('ERBB2', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))	('ER', 'Gene', '2069', (18, 20))
4287	33413533	Eligible patients with advanced E-cadherin defective ILC are treated with crizotinib, a readily available ROS1 inhibitor, in combination with fulvestrant.	('cadherin', 'molecular_function', 'GO:0008014', ('34', '42'))	('ROS1', 'Gene', (106, 110))	('patients', 'Species', '9606', (9, 17))	('ROS1', 'Gene', '6098', (106, 110))	('crizotinib', 'Chemical', 'MESH:D000077547', (74, 84))	('E-cadherin', 'Protein', (32, 42))	('ILC', 'Disease', (53, 56))	('defective', 'Var', (43, 52))
4345	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))
4386	25733146	Conversely, disruption of adhesion and polarity is thought to drive cancer progression.	('adhesion', 'MPA', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('disruption', 'Var', (12, 22))	('polarity', 'MPA', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))
4411	25733146	Classic work in kidney epithelial cells in culture revealed that antibody-based disruption of E-cadherin coordinately inhibits the formation of adherens junctions, tight junctions, and desmosomes.	('antibody', 'cellular_component', 'GO:0042571', ('65', '73'))	('desmosomes', 'CPA', (185, 195))	('epithelia', 'Disease', 'None', (23, 32))	('E-cadherin', 'Protein', (94, 104))	('epithelia', 'Disease', (23, 32))	('tight junctions', 'CPA', (164, 179))	('antibody', 'cellular_component', 'GO:0019815', ('65', '73'))	('inhibits', 'NegReg', (118, 126))	('formation', 'MPA', (131, 140))	('antibody', 'cellular_component', 'GO:0019814', ('65', '73'))	('antibody', 'molecular_function', 'GO:0003823', ('65', '73'))	('formation', 'biological_process', 'GO:0009058', ('131', '140'))	('disruption', 'Var', (80, 90))	('cadherin', 'molecular_function', 'GO:0008014', ('96', '104'))
4412	25733146	This approach revealed that disruption of E-cadherin specifically affects the luminal epithelium, while disruption of P-cadherin specifically affects the myoepithelium.	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('disruption', 'Var', (28, 38))	('affects', 'Reg', (66, 73))	('P-cadherin', 'Gene', '12560', (118, 128))	('P-cadherin', 'Gene', (118, 128))	('affects', 'Reg', (142, 149))	('E-cadherin', 'Protein', (42, 52))
4427	25733146	MMTV-Cre-mediated recombination in E-cadherin fl/fl mice induces E-cadherin deletion in differentiating alveolar epithelium, which impairs terminal differentiation during late pregnancy.	('deletion', 'Var', (76, 84))	('E-cadherin', 'Protein', (65, 75))	('terminal differentiation', 'biological_process', 'GO:0048468', ('139', '163'))	('terminal differentiation', 'CPA', (139, 163))	('mice', 'Species', '10090', (52, 56))	('late pregnancy', 'Phenotype', 'HP:0001622', (171, 185))	('cadherin', 'molecular_function', 'GO:0008014', ('37', '45'))	('cadherin', 'molecular_function', 'GO:0008014', ('67', '75'))	('impairs', 'NegReg', (131, 138))	('MMTV', 'Species', '11757', (0, 4))
4431	25733146	In two subsequent studies, conditional E-cadherin deletion was driven by K14-Cre expression, which has low, stochastic activity in the mammary epithelium, and by WAP-Cre expression, which has patchy activity in the virgin gland in addition to high activity in the lactating gland.	('deletion', 'Var', (50, 58))	('K14', 'Gene', (73, 76))	('E-cadherin', 'Protein', (39, 49))	('WAP', 'Gene', (162, 165))	('K14', 'Gene', '3861', (73, 76))	('WAP', 'Gene', '22373', (162, 165))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))
4435	25733146	E-cadherin deletion in transplanted donor tissue results in failure of E-cadherin- cells to contribute to ductal outgrowths, which are elaborated by E-cadherin+ cells (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('cadherin', 'molecular_function', 'GO:0008014', ('151', '159'))	('failure', 'NegReg', (60, 67))	('donor', 'Species', '9606', (36, 41))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('deletion', 'Var', (11, 19))	('ductal outgrowths', 'CPA', (106, 123))	('E-cadherin', 'Protein', (0, 10))
4436	25733146	E-cadherin deletion in polarized epithelial ducts results in the extrusion of E-cadherin- cells apically, into the ductal lumen, and basally, onto the ductal surface (Fig.	('epithelia', 'Disease', 'None', (33, 42))	('extrusion', 'MPA', (65, 74))	('epithelia', 'Disease', (33, 42))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('deletion', 'Var', (11, 19))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('E-cadherin', 'Protein', (0, 10))
4449	25733146	Importantly, these data demonstrate that loss of a myoepithelium-specific protein can induce a phenotype in the luminal epithelial cells, revealing a functional cross talk between epithelial lineages.	('epithelia', 'Disease', 'None', (180, 189))	('epithelia', 'Disease', (180, 189))	('loss', 'Var', (41, 45))	('epithelia', 'Disease', 'None', (120, 129))	('induce', 'Reg', (86, 92))	('epithelia', 'Disease', (120, 129))	('phenotype', 'MPA', (95, 104))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))
4455	25733146	Loss of alpha-catenin impaired functional differentiation and polarization in alveolar epithelial cells.	('functional differentiation', 'biological_process', 'GO:0048469', ('31', '57'))	('polarization', 'CPA', (62, 74))	('alpha-catenin', 'Protein', (8, 21))	('impaired', 'NegReg', (22, 30))	('epithelia', 'Disease', 'None', (87, 96))	('epithelia', 'Disease', (87, 96))	('Loss', 'Var', (0, 4))	('functional differentiation', 'CPA', (31, 57))
4458	25733146	Moreover, as with E-cadherin, deletion of alpha-catenin does not result in hyper-proliferation or tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('deletion', 'Var', (30, 38))	('hyper-proliferation or tumor', 'Disease', (75, 103))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('hyper-proliferation or tumor', 'Disease', 'MESH:D065703', (75, 103))	('alpha-catenin', 'Protein', (42, 55))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))
4459	25733146	Importantly, alpha-catenin deletion induced by MMTV-Cre has no detectable effect on branching morphogenesis.	('branching morphogenesis', 'biological_process', 'GO:0001763', ('84', '107'))	('deletion', 'Var', (27, 35))	('MMTV', 'Species', '11757', (47, 51))	('branching morphogenesis', 'CPA', (84, 107))	('alpha-catenin', 'Protein', (13, 26))
4463	25733146	For example, a stabilized, constitutively active form of beta-catenin expressed in luminal epithelial cells (MMTV::Delta N89-beta-catenin mice) induces precocious lobuloalveolar development and differentiation in male and female virgin mice, incomplete involution following cessation of lactation, and development of adenocarcinomas in all female mice early in life.	('mice', 'Species', '10090', (236, 240))	('induces', 'PosReg', (144, 151))	('incomplete involution', 'CPA', (242, 263))	(':Delta N89-beta-catenin', 'Var', (114, 137))	('epithelia', 'Disease', 'None', (91, 100))	('epithelia', 'Disease', (91, 100))	('adenocarcinomas', 'Disease', 'MESH:D000230', (317, 332))	('MMTV', 'Species', '11757', (109, 113))	('precocious lobuloalveolar development', 'CPA', (152, 189))	('differentiation', 'CPA', (194, 209))	('mice', 'Species', '10090', (138, 142))	('mice', 'Species', '10090', (347, 351))	('lactation', 'Disease', (287, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('carcinomas', 'Phenotype', 'HP:0030731', (322, 332))	('adenocarcinomas', 'Disease', (317, 332))	('lactation', 'biological_process', 'GO:0007595', ('287', '296'))	('lactation', 'Disease', 'MESH:D007775', (287, 296))
4465	25733146	We are not aware of any studies that have specifically tested the consequences of beta-catenin deletion on mammary epithelial development.	('beta-catenin', 'Protein', (82, 94))	('epithelia', 'Disease', 'None', (115, 124))	('deletion', 'Var', (95, 103))	('epithelia', 'Disease', (115, 124))
4466	25733146	Disruption of the adherens junction in otherwise normal mammary epithelial cells therefore does not necessarily activate beta-catenin signaling.	('adherens junction', 'cellular_component', 'GO:0005912', ('18', '35'))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('epithelia', 'Disease', 'None', (64, 73))	('epithelia', 'Disease', (64, 73))	('beta-catenin signaling', 'MPA', (121, 143))	('Disruption', 'Var', (0, 10))
4467	25733146	p120-catenin (p120) regulates cadherin levels at the cell surface by physically blocking cadherin endocytosis and subsequent degradation.	('degradation', 'biological_process', 'GO:0009056', ('125', '136'))	('degradation', 'MPA', (125, 136))	('cadherin', 'Gene', '114424;999;12550;1009;1000;12558;1001;12560;1004;1006', (30, 38))	('cadherin', 'Gene', '114424;999;12550;1009;1000;12558;1001;12560;1004;1006', (89, 97))	('p120-catenin', 'Gene', (0, 12))	('blocking', 'NegReg', (80, 88))	('endocytosis', 'biological_process', 'GO:0006897', ('98', '109'))	('cell surface', 'cellular_component', 'GO:0009986', ('53', '65'))	('cadherin', 'Gene', (30, 38))	('cadherin', 'Gene', (89, 97))	('cadherin', 'molecular_function', 'GO:0008014', ('30', '38'))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('p120', 'Var', (14, 18))	('p120-catenin', 'Gene', '1500', (0, 12))
4469	25733146	Sorting of both luminal and myoepithelial p120- cells is observed in nascent TEBs, with shedding of K8+p120- cells into the lumen and accumulation of SMA+p120- cells in the subcapsular space.	('K8+p120- cells', 'Var', (100, 114))	('epithelia', 'Disease', (31, 40))	('epithelia', 'Disease', 'None', (31, 40))
4471	25733146	Moreover, as loss of p120 induces concurrent depletion of E-cadherin, the absence of cadherin stability may serve as the ultimate driver of the phenotype.	('depletion', 'MPA', (45, 54))	('cadherin', 'Gene', '114424;999;12550;1009;1000;12558;1001;12560;1004;1006', (60, 68))	('cadherin', 'molecular_function', 'GO:0008014', ('60', '68'))	('cadherin', 'Gene', '114424;999;12550;1009;1000;12558;1001;12560;1004;1006', (85, 93))	('cadherin', 'Gene', (60, 68))	('cadherin', 'Gene', (85, 93))	('p120', 'Var', (21, 25))	('loss', 'Var', (13, 17))	('cadherin', 'molecular_function', 'GO:0008014', ('85', '93'))
4476	25733146	The function of desmosomal adhesion in cell positioning was tested in vitro by treating human mammary epithelial cells with blocking peptides against cell adhesion recognition (CAR) sites on the desmosomal cadherins.	('peptides', 'Var', (133, 141))	('cadherin', 'Gene', '114424;999;12550;1009;1000;12558;1001;12560;1004;1006', (206, 214))	('epithelia', 'Disease', 'None', (102, 111))	('epithelia', 'Disease', (102, 111))	('CAR', 'cellular_component', 'GO:0005826', ('177', '180'))	('cadherin', 'Gene', (206, 214))	('human', 'Species', '9606', (88, 93))	('cell adhesion', 'biological_process', 'GO:0007155', ('150', '163'))
4482	25733146	In the mouse, loss of E-cadherin synergizes with loss of p53 to accelerate tumor formation and metastasis.	('loss', 'Var', (14, 18))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('loss', 'Var', (49, 53))	('accelerate', 'PosReg', (64, 74))	('mouse', 'Species', '10090', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('E-cadherin', 'Protein', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('p53', 'Gene', (57, 60))	('cadherin', 'molecular_function', 'GO:0008014', ('24', '32'))	('tumor', 'Disease', (75, 80))
4486	25733146	Interestingly, germline E-cadherin mutations are rarely observed in patients with invasive lobular breast cancer but are implicated in hereditary diffuse gastric cancer.	('implicated in', 'Reg', (121, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (135, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (91, 112))	('hereditary diffuse gastric cancer', 'Disease', (135, 168))	('patients', 'Species', '9606', (68, 76))	('cadherin', 'molecular_function', 'GO:0008014', ('26', '34'))	('invasive lobular breast cancer', 'Disease', (82, 112))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (82, 112))	('E-cadherin', 'Protein', (24, 34))	('mutations', 'Var', (35, 44))
4499	25733146	Based on these observations, the expectation was that ectopic N-cadherin expression in mammary epithelial cells would promote invasion in vivo, regardless of E-cadherin expression.	('cadherin', 'molecular_function', 'GO:0008014', ('160', '168'))	('ectopic', 'Var', (54, 61))	('epithelia', 'Disease', 'None', (95, 104))	('cadherin', 'molecular_function', 'GO:0008014', ('64', '72'))	('N-cadherin', 'Gene', (62, 72))	('invasion', 'CPA', (126, 134))	('epithelia', 'Disease', (95, 104))	('N-cadherin', 'Gene', '1000', (62, 72))	('promote', 'PosReg', (118, 125))
4503	25733146	A knock-in of N-cadherin at the E-cadherin locus, combined with conditional deletion of the second E-cadherin allele during late pregnancy, induces massive apoptosis of alveolar cells and a lactation defect more severe than E-cadherin loss alone.	('cadherin', 'molecular_function', 'GO:0008014', ('34', '42'))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('late pregnancy', 'Phenotype', 'HP:0001622', (124, 138))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('induces', 'Reg', (140, 147))	('lactation defect', 'Disease', (190, 206))	('lactation defect', 'Disease', 'MESH:D007775', (190, 206))	('cadherin', 'molecular_function', 'GO:0008014', ('226', '234'))	('knock-in', 'Var', (2, 10))	('N-cadherin', 'Gene', (14, 24))	('lactation', 'biological_process', 'GO:0007595', ('190', '199'))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('N-cadherin', 'Gene', '1000', (14, 24))	('apoptosis', 'CPA', (156, 165))
4504	25733146	After multiple lactation cycles, mammary glands develop fibrocystic change that frequently progresses to tumor formation in combination with conditional deletion of one p53 allele.	('fibrocystic change', 'Disease', (56, 74))	('conditional deletion', 'Var', (141, 161))	('p53', 'Gene', (169, 172))	('fibrocystic change', 'Phenotype', 'HP:0006552', (56, 74))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('lactation', 'biological_process', 'GO:0007595', ('15', '24'))	('lactation', 'Disease', (15, 24))	('fibrocystic change', 'Disease', 'MESH:D005348', (56, 74))	('lactation', 'Disease', 'MESH:D007775', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('progresses', 'PosReg', (91, 101))	('tumor', 'Disease', (105, 110))
4510	25733146	Mammary glands with ectopic P-cadherin expression maintain membrane-localized E-cadherin and beta-catenin; have no apparent defects in branching morphogenesis, ductal architecture, lactation, or involution; and do not develop mammary tumors.	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('membrane-localized', 'MPA', (59, 77))	('beta-catenin', 'Protein', (93, 105))	('lactation', 'Disease', (181, 190))	('lactation', 'biological_process', 'GO:0007595', ('181', '190'))	('lactation', 'Disease', 'MESH:D007775', (181, 190))	('P-cadherin', 'Gene', '12560', (28, 38))	('P-cadherin', 'Gene', (28, 38))	('membrane', 'cellular_component', 'GO:0016020', ('59', '67'))	('cadherin', 'molecular_function', 'GO:0008014', ('30', '38'))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('branching morphogenesis', 'biological_process', 'GO:0001763', ('135', '158'))	('E-cadherin', 'Protein', (78, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('ductal architecture', 'CPA', (160, 179))	('branching morphogenesis', 'CPA', (135, 158))	('tumors', 'Disease', (234, 240))	('ectopic', 'Var', (20, 27))
4511	25733146	Taken together, misexpression of either N-cadherin or P-cadherin in normal mammary epithelium, without loss of E-cadherin, is not sufficient to disrupt mammary gland function or induce tumor formation.	('tumor', 'Disease', (185, 190))	('P-cadherin', 'Gene', (54, 64))	('N-cadherin', 'Gene', (40, 50))	('disrupt', 'NegReg', (144, 151))	('induce', 'Reg', (178, 184))	('formation', 'biological_process', 'GO:0009058', ('191', '200'))	('N-cadherin', 'Gene', '1000', (40, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('cadherin', 'molecular_function', 'GO:0008014', ('56', '64'))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('misexpression', 'Var', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('113', '121'))	('mammary gland function', 'CPA', (152, 174))	('P-cadherin', 'Gene', '12560', (54, 64))
4514	25733146	Alternately, the capacity of inappropriate cadherin expression to promote invasion and metastasis may require a decrease in E-cadherin levels and/or other as yet unknown molecular events.	('cadherin', 'Gene', '114424;999;12550;1009;1000;12558;1001;12560;1004;1006', (43, 51))	('cadherin', 'Gene', '114424;999;12550;1009;1000;12558;1001;12560;1004;1006', (126, 134))	('invasion', 'CPA', (74, 82))	('decrease', 'NegReg', (112, 120))	('cadherin', 'Gene', (43, 51))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('expression', 'MPA', (52, 62))	('promote', 'PosReg', (66, 73))	('cadherin', 'molecular_function', 'GO:0008014', ('126', '134'))	('inappropriate', 'Var', (29, 42))	('cadherin', 'Gene', (126, 134))
4535	25733146	Contrary to expectation, Twist1 did not result in a loss of epithelial-specific gene expression or significantly regulate any canonical EMT genes, such as E-cadherin, N-cadherin, and vimentin.	('E-cadherin', 'Protein', (155, 165))	('loss', 'NegReg', (52, 56))	('EMT', 'biological_process', 'GO:0001837', ('136', '139'))	('vimentin', 'Protein', (183, 191))	('N-cadherin', 'Gene', '1000', (167, 177))	('regulate', 'Reg', (113, 121))	('epithelia', 'Disease', 'None', (60, 69))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('cadherin', 'molecular_function', 'GO:0008014', ('169', '177'))	('epithelia', 'Disease', (60, 69))	('Twist1', 'Var', (25, 31))	('vimentin', 'cellular_component', 'GO:0045099', ('183', '191'))	('vimentin', 'cellular_component', 'GO:0045098', ('183', '191'))	('N-cadherin', 'Gene', (167, 177))
4539	25733146	In the developing zebrafish embryo, E-cadherin-mediated traction forces are required for single cell migration of chemokine-guided germ cells, and interfering with E-cadherin disrupts F-actin dynamics and organization at the cellular front and inhibits cell motility.	('cell migration', 'biological_process', 'GO:0016477', ('96', '110'))	('F-actin', 'cellular_component', 'GO:0031941', ('184', '191'))	('organization at the cellular front', 'CPA', (205, 239))	('disrupts', 'NegReg', (175, 183))	('interfering', 'Var', (147, 158))	('zebrafish', 'Species', '7955', (18, 27))	('inhibits', 'NegReg', (244, 252))	('cadherin', 'molecular_function', 'GO:0008014', ('166', '174'))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('F-actin', 'MPA', (184, 191))	('cell motility', 'biological_process', 'GO:0048870', ('253', '266'))	('E-cadherin', 'Protein', (164, 174))	('cell motility', 'CPA', (253, 266))
4552	25733146	In particular, there is not a simple relationship between loss of E-cadherin and invasive or disseminative behavior in normal or tumor mammary epithelium.	('E-cadherin', 'Protein', (66, 76))	('loss', 'Var', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('invasive', 'CPA', (81, 89))	('tumor', 'Disease', (129, 134))	('cadherin', 'molecular_function', 'GO:0008014', ('68', '76'))
4568	25733146	For example, loss of P-cadherin induces hyperbranching of mammary epithelium cultured in a basement membrane-rich ECM but promotes excess, sustained myoepithelial dissemination when the same epithelium is cultured in collagen I.	('collagen', 'molecular_function', 'GO:0005202', ('217', '225'))	('P-cadherin', 'Gene', (21, 31))	('promotes', 'PosReg', (122, 130))	('P-cadherin', 'Gene', '12560', (21, 31))	('hyperbranching', 'MPA', (40, 54))	('basement membrane', 'cellular_component', 'GO:0005604', ('91', '108'))	('myoepithelial dissemination', 'Disease', 'MESH:D009208', (149, 176))	('myoepithelial dissemination', 'Disease', (149, 176))	('loss', 'Var', (13, 17))	('cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))
4591	22117567	It has been shown that increased parity reduced the risk for all subtypes with the exception of medullary breast cancer.	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('parity', 'Var', (33, 39))	('reduced', 'NegReg', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
4599	22117567	The familial association of lobular breast cancer could mainly be due to patients with BRCA2 mutation or the occurrence of hereditary diffuse gastric cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('gastric cancer', 'Disease', (142, 156))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('BRCA2', 'Gene', '675', (87, 92))	('patients', 'Species', '9606', (73, 81))	('lobular breast cancer', 'Disease', 'MESH:D013274', (28, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('lobular breast cancer', 'Disease', (28, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (28, 49))	('mutation', 'Var', (93, 101))	('BRCA2', 'Gene', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
4673	22117567	In that case it could mean that the gene or polymorphism was maternally imprinted and therefore only the father's allele would be expressed, and predispose for cancer in men and breast cancer in their daughters.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (160, 166))	('predispose for', 'Reg', (145, 159))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('breast cancer', 'Disease', (178, 191))	('men', 'Species', '9606', (170, 173))	('polymorphism', 'Var', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
4675	22117567	Another possibility could be copy number variation which, when placed in a gene beneficial for cancer development could predispose for cancer in men and breast cancer in women.	('men', 'Species', '9606', (172, 175))	('copy number variation', 'Var', (29, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('cancer', 'Disease', (135, 141))	('women', 'Species', '9606', (170, 175))	('men', 'Species', '9606', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('predispose', 'Reg', (120, 130))	('men', 'Species', '9606', (109, 112))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('breast cancer', 'Disease', (153, 166))
4738	28693516	GATA3 positivity has been reported in 73-96% cases of metastatic breast carcinoma (MBC).	('reported', 'Reg', (26, 34))	('GATA3', 'Gene', '2625', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('MBC', 'Disease', (83, 86))	('positivity', 'Var', (6, 16))	('breast carcinoma', 'Disease', 'MESH:D001943', (65, 81))	('breast carcinoma', 'Disease', (65, 81))	('GATA3', 'Gene', (0, 5))	('MBC', 'Disease', 'MESH:D001943', (83, 86))	('breast carcinoma', 'Phenotype', 'HP:0003002', (65, 81))
4969	29344267	The evolution of breast cancer appears to be driven by the aberrant gene expression leading to gain of function or activation of downstream signal pathways (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('gain of function', 'PosReg', (95, 111))	('aberrant gene expression', 'Var', (59, 83))	('breast cancer', 'Disease', (17, 30))	('downstream signal pathways', 'Pathway', (129, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('gene expression', 'biological_process', 'GO:0010467', ('68', '83'))
4977	29344267	Cas9-induced double-stranded breaks (DSBs) are subjected to the error-prone repair by nonhomologous end-joining, which introduces mutations to disrupt integrity and functions of the targeted genomic sites.	('Cas', 'Chemical', 'MESH:D002118', (0, 3))	('integrity', 'MPA', (151, 160))	('mutations', 'Var', (130, 139))	('functions', 'MPA', (165, 174))	('disrupt', 'NegReg', (143, 150))	('Cas', 'cellular_component', 'GO:0005650', ('0', '3'))
4986	29344267	Most human ILCs lose the cell-cell adhesion protein E-cadherin as a result of loss of heterozygosity, methylation of the CDH1 gene promoter or compromised integrity of the E-cadherin-catenin membrane complex.	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('compromised', 'NegReg', (143, 154))	('CDH1', 'Gene', (121, 125))	('methylation', 'Var', (102, 113))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('25', '43'))	('cadherin', 'molecular_function', 'GO:0008014', ('174', '182'))	('membrane', 'cellular_component', 'GO:0016020', ('191', '199'))	('heterozygosity', 'MPA', (86, 100))	('integrity', 'MPA', (155, 164))	('lose', 'NegReg', (16, 20))	('cell-cell adhesion', 'MPA', (25, 43))	('loss', 'NegReg', (78, 82))	('cadherin', 'molecular_function', 'GO:0008014', ('54', '62'))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('human', 'Species', '9606', (5, 10))
4997	29344267	Although the HER2 exons are targeted by CRISPR/Cas9, such induced mutations in one copy of the oncogene cannot disrupt the HER2 protein production from all other copies, indicative of incompleteness of the HER2 mutations.	('mutations', 'Var', (66, 75))	('Cas', 'Chemical', 'MESH:D002118', (47, 50))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('Cas', 'cellular_component', 'GO:0005650', ('47', '50'))	('HER2', 'Gene', (123, 127))	('HER2', 'Gene', (13, 17))	('disrupt', 'NegReg', (111, 118))	('HER2', 'Gene', (206, 210))	('HER2', 'Gene', '2064', (123, 127))	('HER2', 'Gene', '2064', (13, 17))	('HER2', 'Gene', '2064', (206, 210))
4998	29344267	However, a mutant HER2 protein generated by a frame-shift mutation in HER2 exon12 is associated with the wildtype HER2 proteins, leading to a dominant negative mutant phenotype (Fig.	('HER2', 'Gene', (70, 74))	('HER2', 'Gene', '2064', (18, 22))	('frame-shift mutation', 'Var', (46, 66))	('HER2', 'Gene', (114, 118))	('HER2', 'Gene', '2064', (70, 74))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('HER2', 'Gene', '2064', (114, 118))	('HER2', 'Gene', (18, 22))
4999	29344267	This alteration was also found to inhibit the MAPK/ERK axis of HER2 downstream signaling and cancer cell proliferation.	('cancer', 'Disease', (93, 99))	('ERK', 'Gene', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('100', '118'))	('alteration', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('ERK', 'molecular_function', 'GO:0004707', ('51', '54'))	('inhibit', 'NegReg', (34, 41))	('ERK', 'Gene', '2048', (51, 54))	('HER2', 'Gene', '2064', (63, 67))	('HER2', 'Gene', (63, 67))
5000	29344267	This inhibitory effect is enhanced by inhibitors of the poly ADP-ribose polymerase (PARP) that is involved in key cellular processes such as DNA repair and cell death, suggestive of synergistic anti-cancer effects of CRISPR/Cas9 in combination with DNA repair inhibition in the clinical setting.	('Cas', 'cellular_component', 'GO:0005650', ('224', '227'))	('enhanced', 'PosReg', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('DNA', 'cellular_component', 'GO:0005574', ('249', '252'))	('poly ADP-ribose polymerase', 'Gene', '142', (56, 82))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('DNA repair', 'biological_process', 'GO:0006281', ('141', '151'))	('DNA repair', 'biological_process', 'GO:0006281', ('249', '259'))	('Cas', 'Chemical', 'MESH:D002118', (224, 227))	('inhibitory', 'MPA', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('inhibitors', 'Var', (38, 48))	('PARP', 'Gene', '142', (84, 88))	('cell death', 'biological_process', 'GO:0008219', ('156', '166'))	('cancer', 'Disease', (199, 205))	('poly ADP-ribose polymerase', 'Gene', (56, 82))	('PARP', 'Gene', (84, 88))
5002	29344267	For example, germline mutations in the BRCA1 gene are bypassed by somatic alternative splicing that leads to resistance to the anticancer therapy, the finding that is verified by CRISPR/Cas9 (Fig.	('cancer', 'Disease', (131, 137))	('leads to', 'Reg', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cas', 'cellular_component', 'GO:0005650', ('186', '189'))	('BRCA1', 'Gene', '672', (39, 44))	('germline mutations', 'Var', (13, 31))	('splicing', 'biological_process', 'GO:0045292', ('86', '94'))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('BRCA1', 'Gene', (39, 44))	('Cas', 'Chemical', 'MESH:D002118', (186, 189))
5003	29344267	Germline mutations in the BRCA1 gene resulting in dysfunctional BRCA incur a high risk of breast and ovarian cancer development.	('Germline mutations', 'Var', (0, 18))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (90, 115))	('BRCA1', 'Gene', (26, 31))	('dysfunctional BRCA', 'Disease', (50, 68))	('dysfunctional BRCA', 'Disease', 'MESH:D006331', (50, 68))	('BRCA1', 'Gene', '672', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))
5004	29344267	BRCA1 mutations in exon 11 account for approximately 30% of the total mutation carriers who develop breast and ovarian cancer in the United States.	('BRCA1', 'Gene', (0, 5))	('BRCA1', 'Gene', '672', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('mutation', 'Var', (70, 78))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (100, 125))	('develop', 'PosReg', (92, 99))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
5007	29344267	While such therapies can improve survival of breast cancer patients, the treatment with PARPi is not effective on many patients who carry germline BRCA1 or BRCA2 mutations.	('survival', 'CPA', (33, 41))	('mutations', 'Var', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BRCA1', 'Gene', '672', (147, 152))	('patients', 'Species', '9606', (119, 127))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('PARP', 'Gene', '142', (88, 92))	('BRCA2', 'Gene', (156, 161))	('BRCA1', 'Gene', (147, 152))	('improve', 'PosReg', (25, 32))	('breast cancer', 'Disease', (45, 58))	('patients', 'Species', '9606', (59, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('BRCA2', 'Gene', '675', (156, 161))	('PARP', 'Gene', (88, 92))
5009	29344267	The resistance is developed through various somatic mechanisms, such as reversion BRCA2 mutations, 53BP1 pathway activity loss, hypomorphic BRCA1 expression, and drug efflux.	('efflux', 'biological_process', 'GO:0140115', ('167', '173'))	('efflux', 'biological_process', 'GO:0140352', ('167', '173'))	('BRCA1', 'Gene', (140, 145))	('53BP1', 'Gene', (99, 104))	('53BP1', 'Gene', '7158', (99, 104))	('drug efflux', 'MPA', (162, 173))	('BRCA2', 'Gene', (82, 87))	('mutations', 'Var', (88, 97))	('activity', 'MPA', (113, 121))	('loss', 'NegReg', (122, 126))	('BRCA2', 'Gene', '675', (82, 87))	('expression', 'MPA', (146, 156))	('BRCA1', 'Gene', '672', (140, 145))	('hypomorphic', 'Var', (128, 139))
5011	29344267	Alternative splicing generates BRCA1 mRNA isoforms.	('Alternative splicing', 'Var', (0, 20))	('BRCA1', 'Gene', (31, 36))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))	('BRCA1', 'Gene', '672', (31, 36))
5013	29344267	These various isoforms range from full-length BRCA1 containing all coding exons to BRCA1 Delta11 skipping of exon 11 and BRCA1 Delta11q partial skipping of exon 11.	('Delta11', 'Mutation', 'c.del11', (127, 134))	('BRCA1', 'Gene', '672', (83, 88))	('skipping', 'Var', (97, 105))	('BRCA1', 'Gene', '672', (121, 126))	('BRCA1', 'Gene', '672', (46, 51))	('BRCA1', 'Gene', (83, 88))	('BRCA1', 'Gene', (46, 51))	('BRCA1', 'Gene', (121, 126))	('Delta11q partial skipping', 'Var', (127, 152))	('Delta11 skipping', 'Var', (89, 105))	('Delta11', 'Mutation', 'c.del11', (89, 96))
5014	29344267	Since germline mutations of BRCA1 often lead to reading frameshifts and nonsense-mediated mRNA decay, such mutations plausibly affect splicing and expression of BRCA1-Delta11q.	('BRCA1', 'Gene', '672', (28, 33))	('BRCA1', 'Gene', (161, 166))	('Delta11', 'Mutation', 'c.del11', (167, 174))	('mutations', 'Var', (107, 116))	('lead to', 'Reg', (40, 47))	('expression', 'MPA', (147, 157))	('BRCA1', 'Gene', (28, 33))	('nonsense-mediated mRNA decay', 'MPA', (72, 100))	('nonsense-mediated mRNA decay', 'biological_process', 'GO:0000184', ('72', '100'))	('splicing', 'MPA', (134, 142))	('splicing', 'biological_process', 'GO:0045292', ('134', '142'))	('reading frameshifts', 'MPA', (48, 67))	('BRCA1', 'Gene', '672', (161, 166))	('affect', 'Reg', (127, 133))
5015	29344267	This premise is supported by the results showing that a BRCA1-Delta11q splice variant lacking most of exon 11 is produced from the cancer cell lines and tumors carrying mutations in exon 11 of BRCA1.	('cancer', 'Disease', (131, 137))	('mutations in exon', 'Var', (169, 186))	('Delta11', 'Mutation', 'c.del11', (62, 69))	('BRCA1', 'Gene', '672', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('BRCA1', 'Gene', (56, 61))	('tumors', 'Disease', (153, 159))	('BRCA1', 'Gene', '672', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('BRCA1', 'Gene', (193, 198))
5016	29344267	The nature of the mutations is likely the frameshift mutations to exon 11 that cause nonsense-mediated mRNA decay of full-length but not the BRCA1-Delta11q isoform.	('Delta11', 'Mutation', 'c.del11', (147, 154))	('nonsense-mediated mRNA decay', 'biological_process', 'GO:0000184', ('85', '113'))	('frameshift mutations', 'Var', (42, 62))	('BRCA1', 'Gene', '672', (141, 146))	('cause', 'Reg', (79, 84))	('BRCA1', 'Gene', (141, 146))	('nonsense-mediated mRNA decay', 'MPA', (85, 113))	('mutations', 'Var', (18, 27))
5017	29344267	This premise is verified with CRISPR/Cas9 by introducing the additional out-of-frame mutations or reversion mutations that restore the reading frame and avoid the nonsense-mediated mRNA decay.	('Cas', 'Chemical', 'MESH:D002118', (37, 40))	('avoid', 'NegReg', (153, 158))	('mutations', 'Var', (108, 117))	('restore', 'PosReg', (123, 130))	('nonsense-mediated mRNA decay', 'MPA', (163, 191))	('reading frame', 'MPA', (135, 148))	('mutations', 'Var', (85, 94))	('Cas', 'cellular_component', 'GO:0005650', ('37', '40'))	('nonsense-mediated mRNA decay', 'biological_process', 'GO:0000184', ('163', '191'))
5019	29344267	The mechanism of the resistance appears to be the aberrant splicing because spliceosome inhibitors that decrease the BRCA1-Delta11q level sensitize the cancer cells harboring the exon 11 mutations to the PARPi treatment.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Delta11', 'Mutation', 'c.del11', (123, 130))	('BRCA1', 'Gene', '672', (117, 122))	('PARP', 'Gene', '142', (204, 208))	('spliceosome', 'cellular_component', 'GO:0005681', ('76', '87'))	('mutations', 'Var', (187, 196))	('BRCA1', 'Gene', (117, 122))	('splicing', 'biological_process', 'GO:0045292', ('59', '67'))	('decrease', 'NegReg', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('PARP', 'Gene', (204, 208))	('sensitize', 'Reg', (138, 147))
5020	29344267	Therefore, selected by the anti-cancer treatments, the cell populations in breast cancer tend to evolve resistance by removal of disadvantageous germline BRCA1 mutations through somatic alternative mRNA splicing that generates isoforms coding for therapeutic resistance.	('evolve', 'PosReg', (97, 103))	('mRNA splicing', 'biological_process', 'GO:0000398', ('198', '211'))	('mutations', 'Var', (160, 169))	('cancer', 'Disease', (82, 88))	('BRCA1', 'Gene', '672', (154, 159))	('mRNA splicing', 'biological_process', 'GO:0006371', ('198', '211'))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('isoforms', 'MPA', (227, 235))	('BRCA1', 'Gene', (154, 159))	('mRNA splicing', 'biological_process', 'GO:0000394', ('198', '211'))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mRNA splicing', 'biological_process', 'GO:0000374', ('198', '211'))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('therapeutic resistance', 'MPA', (247, 269))	('mRNA splicing', 'biological_process', 'GO:0000373', ('198', '211'))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('breast cancer', 'Disease', (75, 88))	('resistance', 'MPA', (104, 114))	('mRNA splicing', 'biological_process', 'GO:0000372', ('198', '211'))
5029	29344267	Third, we present a recent finding that the tumor-specific transcription programs appear affected epigenetically by a certain hormone signaling (Fig.	('epigenetically', 'Var', (98, 112))	('transcription', 'biological_process', 'GO:0006351', ('59', '72'))	('affected', 'Reg', (89, 97))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
5037	29344267	Such cell-specific FOXA1 regulation is validated with CRSPR/Cas9, specifying the unique FOXA1 binding, genetic variations, and potential epigenetic regulation.	('FOXA1', 'Gene', '3169', (88, 93))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('FOXA1', 'Gene', '3169', (19, 24))	('regulation', 'biological_process', 'GO:0065007', ('25', '35'))	('binding', 'Interaction', (94, 101))	('Cas', 'cellular_component', 'GO:0005650', ('60', '63'))	('regulation', 'biological_process', 'GO:0065007', ('148', '158'))	('FOXA1', 'Gene', (19, 24))	('FOXA1', 'Gene', (88, 93))	('Cas', 'Chemical', 'MESH:D002118', (60, 63))	('genetic variations', 'Var', (103, 121))
5039	29344267	Inhibition of CDK7, a transcriptional cyclin-dependent kinase, selectively targets the cancer cells, leading to apoptotic cell death.	('cancer', 'Disease', (87, 93))	('CDK', 'molecular_function', 'GO:0004693', ('14', '17'))	('leading to', 'Reg', (101, 111))	('CDK7', 'Gene', '1022', (14, 18))	('apoptotic cell death', 'CPA', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cyclin', 'molecular_function', 'GO:0016538', ('38', '44'))	('Inhibition', 'Var', (0, 10))	('CDK7', 'Gene', (14, 18))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('112', '132'))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
5042	29344267	Of an "Achilles cluster" of genes specific to TNBC encoding super-enhancer-associated transcriptional regulators, the knockouts of EGFR, FOSL1, FOXC1, MYC and SOX9 by CRISPR/Cas9 impair the cancer cell proliferation.	('cancer', 'Disease', (190, 196))	('Cas', 'Chemical', 'MESH:D002118', (174, 177))	('FOSL1', 'Gene', (137, 142))	('MYC', 'Gene', (151, 154))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('knockouts', 'Var', (118, 127))	('impair', 'NegReg', (179, 185))	('EGFR', 'Gene', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('FOXC1', 'Gene', (144, 149))
5050	29344267	Situated far away from target loci on the same or different chromosomes, DEREs can induce intra- or inter-chromatin interactions, through which the ERalpha-DERE complex is brought to the target promoters for transcriptional modulation.	('DEREs', 'Var', (73, 78))	('induce', 'Reg', (83, 89))	('chromatin', 'cellular_component', 'GO:0000785', ('106', '115'))	('intra-', 'MPA', (90, 96))	('ERalpha', 'Gene', (148, 155))	('ERalpha', 'Gene', '2099', (148, 155))
5052	29344267	The DERE regulatory depots synchronize gene expression of target loci and direct long-range epigenetic repression of estrogen-responsive tumor-suppressor genes.	('tumor', 'Disease', (137, 142))	('epigenetic', 'Var', (92, 102))	('gene expression', 'biological_process', 'GO:0010467', ('39', '54'))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('137', '153'))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))
5053	29344267	The CRISPR/Cas9-edited deletion of 20q13 DEREs attenuates the transcriptional modulation of proliferation-associated signaling networks, leading to a decrease in cancer cell growth but an increase in overall survival of the patients.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('Cas', 'cellular_component', 'GO:0005650', ('11', '14'))	('cancer', 'Disease', (162, 168))	('deletion', 'Var', (23, 31))	('cell growth', 'biological_process', 'GO:0016049', ('169', '180'))	('decrease', 'NegReg', (150, 158))	('Cas', 'Chemical', 'MESH:D002118', (11, 14))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))	('transcriptional modulation', 'MPA', (62, 88))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('increase', 'PosReg', (188, 196))	('patients', 'Species', '9606', (224, 232))	('proliferation-associated signaling networks', 'Pathway', (92, 135))	('attenuates', 'NegReg', (47, 57))	('20q13', 'Gene', (35, 40))
5056	29344267	As ERalpha is the major driver of breast cancer development and progression, inhibition of ER activity decreases relapse and increases patient survival.	('patient', 'Species', '9606', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('inhibition', 'Var', (77, 87))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('ERalpha', 'Gene', '2099', (3, 10))	('ERalpha', 'Gene', (3, 10))	('decreases', 'NegReg', (103, 112))	('increases', 'PosReg', (125, 134))	('breast cancer', 'Disease', (34, 47))	('relapse', 'CPA', (113, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('activity', 'MPA', (94, 102))	('patient survival', 'CPA', (135, 151))
5060	29344267	The rise after the treatments suggests that the resistance evolution occurs under the treatment-selective pressures for ESR1 mutations.	('mutations', 'Var', (125, 134))	('ESR1', 'Gene', (120, 124))	('ESR1', 'Gene', '2099', (120, 124))
5061	29344267	This premise is tested with CRISPR/Cas9-mediated introduction of mutations in the ESR1 gene, which is a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line.	('ESR1', 'Gene', (82, 86))	('Cas', 'cellular_component', 'GO:0005650', ('35', '38'))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (217, 235))	('tyrosine', 'Chemical', 'MESH:D014443', (176, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('Cas', 'Chemical', 'MESH:D002118', (35, 38))	('ESR1', 'Gene', '2099', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('MCF7 breast cancer', 'Disease', (217, 235))	('mutations', 'Var', (65, 74))
5062	29344267	This mutation confers global constitutive ER activity, causing estrogen-independent cell growth, so that the tumor cells carrying the mutation become resistant to the anti-estrogen medications.	('cell growth', 'biological_process', 'GO:0016049', ('84', '95'))	('causing', 'Reg', (55, 62))	('mutation', 'Var', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('resistant', 'MPA', (150, 159))	('estrogen-independent cell growth', 'MPA', (63, 95))	('mutation', 'Var', (5, 13))	('tumor', 'Disease', (109, 114))
5064	29344267	The CDK7 inhibition that prevents the phosphorylation inhibits MCF7-Y537S cell growth.	('inhibition', 'NegReg', (9, 19))	('CDK', 'molecular_function', 'GO:0004693', ('4', '7'))	('CDK7', 'Gene', '1022', (4, 8))	('cell growth', 'biological_process', 'GO:0016049', ('74', '85'))	('inhibits', 'NegReg', (54, 62))	('Y537S', 'SUBSTITUTION', 'None', (68, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('CDK7', 'Gene', (4, 8))	('Y537S', 'Var', (68, 73))
5072	29344267	The program can be disrupted by inhibition of CDKs, such as CDK7, a potential therapy for the ER mutation-mediated endocrine-resistant breast cancer (Fig.	('inhibition', 'Var', (32, 42))	('CDKs', 'Gene', '1022;1024', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CDK7', 'Gene', (60, 64))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))	('CDK7', 'Gene', '1022', (60, 64))	('breast cancer', 'Disease', (135, 148))	('CDKs', 'Gene', (46, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
5074	29344267	7, inhibition of CDK7 not just selectively impairs the cell growth and tumorigenesis of TNBC (Fig.	('impairs', 'NegReg', (43, 50))	('CDK7', 'Gene', '1022', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('inhibition', 'Var', (3, 13))	('CDK7', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CDK', 'molecular_function', 'GO:0004693', ('17', '20'))	('tumor', 'Disease', (71, 76))	('cell growth', 'biological_process', 'GO:0016049', ('55', '66'))	('TNBC', 'Gene', (88, 92))	('cell growth', 'CPA', (55, 66))
5088	29344267	Both mutations disrupt tumorigenesis of the proteasome-addicted human breast cancer cells in mice.	('human', 'Species', '9606', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('proteasome', 'molecular_function', 'GO:0004299', ('44', '54'))	('mutations', 'Var', (5, 14))	('proteasome', 'cellular_component', 'GO:0000502', ('44', '54'))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('breast cancer', 'Disease', (70, 83))	('mice', 'Species', '10090', (93, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('disrupt', 'NegReg', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (23, 28))
5092	29344267	Under such a therapeutic selection, advanced metastatic breast cancer become resistant and outgrown as ERalpha mutations ERalphaY537S and ERalphaD538G occur frequently.	('mutations', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ERalpha', 'Gene', '2099', (138, 145))	('ERalpha', 'Gene', (138, 145))	('ERalpha', 'Gene', '2099', (103, 110))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('ERalpha', 'Gene', (103, 110))	('ERalpha', 'Gene', '2099', (121, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('ERalpha', 'Gene', (121, 128))	('breast cancer', 'Disease', (56, 69))
5093	29344267	These mutations were investigated in cell lines derived from circulating tumor cells, with some results to suggest the mutations responsible for resistance to aromatase inhibitors and the others to tamoxifen and fulvestrant/ICI.	('tamoxifen', 'Chemical', 'MESH:D013629', (198, 207))	('resistance', 'MPA', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('ICI', 'Chemical', '-', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('responsible', 'Reg', (129, 140))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (119, 128))	('fulvestrant', 'Chemical', 'MESH:D000077267', (212, 223))	('aromatase', 'Protein', (159, 168))
5094	29344267	The uncertainty about the mutations was further investigated in an ERalpha positive breast cancer cell model in which the cells expressing the mutated ERalpha and wild-type ERalpha were compared.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('ERalpha', 'Gene', '2099', (67, 74))	('ERalpha', 'Gene', (151, 158))	('ERalpha', 'Gene', '2099', (151, 158))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('ERalpha', 'Gene', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutated', 'Var', (143, 150))	('ERalpha', 'Gene', '2099', (173, 180))	('ERalpha', 'Gene', (67, 74))	('breast cancer', 'Disease', (84, 97))
5101	29344267	CRISPR/Cas9-mediated knockout of UBR5 impairs tumor growth and metastasis in vivo as shown in an experimental murine mammary carcinoma model of TNBC.	('carcinoma', 'Disease', 'MESH:D002277', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('impairs tumor', 'Disease', 'MESH:D015417', (38, 51))	('Cas', 'Chemical', 'MESH:D002118', (7, 10))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (117, 134))	('carcinoma', 'Disease', (125, 134))	('Cas', 'cellular_component', 'GO:0005650', ('7', '10'))	('UBR5', 'Gene', (33, 37))	('knockout', 'Var', (21, 29))	('impairs tumor', 'Disease', (38, 51))	('murine', 'Species', '10090', (110, 116))
5113	29344267	This technical problem has hampered development of the CRISPR/Cas9-based therapeutics because the off-target activities cause mutations that may be carcinogenic to the patients.	('Cas', 'cellular_component', 'GO:0005650', ('62', '65'))	('Cas', 'Chemical', 'MESH:D002118', (62, 65))	('carcinogenic', 'Disease', 'MESH:D063646', (148, 160))	('patients', 'Species', '9606', (168, 176))	('mutations', 'Var', (126, 135))	('carcinogenic', 'Disease', (148, 160))
5123	29344267	The engineered Cas9 can nick the opposite DNA strand of the heteroduplex between sgRNAs and target DNA leading to DSB that decreases the off-target activity.	('Cas', 'cellular_component', 'GO:0005650', ('15', '18'))	('off-target activity', 'MPA', (137, 156))	('decreases', 'NegReg', (123, 132))	('nick', 'Var', (24, 28))	('DSB', 'MPA', (114, 117))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('Cas', 'Chemical', 'MESH:D002118', (15, 18))
5124	29344267	Such engineering can further increase specificity of Cas9 variants, which decrease the off-target effects.	('decrease', 'NegReg', (74, 82))	('specificity', 'MPA', (38, 49))	('variants', 'Var', (58, 66))	('off-target effects', 'MPA', (87, 105))	('Cas9', 'Gene', (53, 57))	('Cas', 'cellular_component', 'GO:0005650', ('53', '56'))	('increase', 'PosReg', (29, 37))	('Cas', 'Chemical', 'MESH:D002118', (53, 56))
5131	29344267	The incessant proliferation of cancer cells is not only encoded by the diverse sets of the mutated genes but also affected by epigenetic factors in cancer cells.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('mutated genes', 'Var', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('affected', 'Reg', (114, 122))	('cancer', 'Disease', (31, 37))
5134	29344267	When encountering anticancer treatments, the cancer cells carrying such a genomic diversity are capable of evolving resistance by multiple mechanisms, such as mutations, aberrant transcription, splicing, protein folding and degradation.	('cancer', 'Disease', (45, 51))	('degradation', 'MPA', (224, 235))	('transcription', 'biological_process', 'GO:0006351', ('179', '192'))	('splicing', 'MPA', (194, 202))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutations', 'Var', (159, 168))	('aberrant transcription', 'Var', (170, 192))	('protein folding', 'biological_process', 'GO:0006457', ('204', '219'))	('cancer', 'Disease', (22, 28))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('degradation', 'biological_process', 'GO:0009056', ('224', '235'))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('protein folding', 'MPA', (204, 219))	('splicing', 'biological_process', 'GO:0045292', ('194', '202'))
5138	29344267	The CRISPR/Cas9-mediated knockout of UBR5 encoding a key regulator of the unfolded protein response in an experimental murine mammary carcinoma model of TNBC impairs tumor growth and metastasis in vivo .	('carcinoma', 'Disease', (134, 143))	('Cas', 'cellular_component', 'GO:0005650', ('11', '14'))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TNBC impairs tumor', 'Disease', 'MESH:D015417', (153, 171))	('Cas', 'Chemical', 'MESH:D002118', (11, 14))	('UBR5', 'Gene', (37, 41))	('carcinoma', 'Disease', 'MESH:D002277', (134, 143))	('murine', 'Species', '10090', (119, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('knockout', 'Var', (25, 33))	('TNBC impairs tumor', 'Disease', (153, 171))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (126, 143))
5155	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))
5197	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))
5272	29176653	Subsequent studies found that inhibition of c-Kit activity using imatinib mesylate (Gleevec ) blocked estrogen mediated stimulation of BCK4 tumors and BCK4 cells in vitro as effectively as the anti-estrogen fulvestrant (Faslodex ).	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('inhibition', 'Var', (30, 40))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (65, 82))	('BCK', 'Gene', '1152', (135, 138))	('BCK', 'Gene', (135, 138))	('BCK', 'molecular_function', 'GO:0047323', ('151', '154'))	('c-Kit activity', 'Protein', (44, 58))	('BCK', 'molecular_function', 'GO:0047323', ('135', '138'))	('blocked', 'NegReg', (94, 101))	('Faslodex', 'Chemical', 'MESH:D000077267', (220, 228))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('estrogen mediated stimulation', 'MPA', (102, 131))	('BCK', 'Gene', '1152', (151, 154))	('BCK', 'Gene', (151, 154))	('Gleevec', 'Chemical', 'MESH:D000068877', (84, 91))
5288	29176653	Mutations in c-Kit that increase the binding of the c-Kit inhibitor, imatinib mesylate, commonly occur in gastrointestinal stromal tumors.	('binding', 'molecular_function', 'GO:0005488', ('37', '44'))	('binding', 'Interaction', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (106, 137))	('c-Kit', 'Gene', (13, 18))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (69, 86))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (106, 137))	('occur', 'Reg', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Mutations', 'Var', (0, 9))	('gastrointestinal stromal tumors', 'Disease', (106, 137))
5293	29176653	Among 112 breast tumors of histological special types, c-Kit was not detected in MBC nor ILC while in a larger study of 1600 breast tumors examined on breast tumor microarrays, c-Kit was detected in 2% of MBC and 0.5% of ILC.	('detected', 'Reg', (187, 195))	('breast tumors', 'Phenotype', 'HP:0100013', (10, 23))	('breast tumor', 'Phenotype', 'HP:0100013', (10, 22))	('MBC', 'Disease', (81, 84))	('breast tumor', 'Disease', 'MESH:D001943', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('MBC', 'Disease', 'MESH:D001943', (81, 84))	('breast tumor', 'Phenotype', 'HP:0100013', (151, 163))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('breast tumors', 'Disease', 'MESH:D001943', (125, 138))	('breast tumor', 'Disease', (151, 163))	('breast tumor', 'Disease', 'MESH:D001943', (125, 137))	('breast tumors', 'Disease', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('MBC', 'Disease', (205, 208))	('breast tumors', 'Phenotype', 'HP:0100013', (125, 138))	('breast tumor', 'Phenotype', 'HP:0100013', (125, 137))	('MBC', 'Disease', 'MESH:D001943', (205, 208))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('c-Kit', 'Var', (177, 182))	('breast tumors', 'Disease', (10, 23))	('breast tumors', 'Disease', 'MESH:D001943', (10, 23))	('breast tumor', 'Disease', 'MESH:D001943', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
5376	29176653	Mutating Cx43 in mice decreased total Cx43 levels and a developmental delay in puberty with dysfunction milk ejection and also increased mammary tumor metastases to the lung, suggesting wild type Cx43 suppresses metastasis.	('Mutating', 'Var', (0, 8))	('tumor metastases', 'Disease', 'MESH:D009362', (145, 161))	('puberty with dysfunction milk', 'Disease', (79, 108))	('mice', 'Species', '10090', (17, 21))	('milk ejection', 'biological_process', 'GO:0060156', ('104', '117'))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Cx43', 'Gene', (9, 13))	('total Cx43 levels', 'MPA', (32, 49))	('puberty with dysfunction milk', 'Disease', 'MESH:D016269', (79, 108))	('developmental delay', 'CPA', (56, 75))	('developmental delay', 'Phenotype', 'HP:0001263', (56, 75))	('puberty', 'biological_process', 'GO:0003006', ('79', '86'))	('increased', 'PosReg', (127, 136))	('decreased', 'NegReg', (22, 31))	('tumor metastases', 'Disease', (145, 161))
5379	29176653	Because Cx43 allows transfer of small molecules (glucose) and ions (Ca2+, K+) and small signaling mediators (IP3, cAMP) between cells, in the absence of e-cadherin, Cx43 may facilitate the informational flow between lobular breast cancer cells.	('facilitate', 'PosReg', (174, 184))	('glucose', 'Chemical', 'MESH:D005947', (49, 56))	('cAMP', 'Chemical', '-', (114, 118))	('cadherin', 'molecular_function', 'GO:0008014', ('155', '163'))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('lobular breast cancer', 'Disease', (216, 237))	('Cx43', 'Var', (165, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('lobular breast cancer', 'Disease', 'MESH:D013274', (216, 237))	('transfer', 'MPA', (20, 28))	('e-cadherin', 'Gene', '999', (153, 163))	('IP3', 'Chemical', 'MESH:D015544', (109, 112))	('e-cadherin', 'Gene', (153, 163))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (216, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('informational flow', 'CPA', (189, 207))	('Ca2+', 'Chemical', 'MESH:D000069285', (68, 72))
5394	29176653	The number of ILC metastases containing c-Kit is unclear.	('metastases', 'Disease', 'MESH:D009362', (18, 28))	('c-Kit', 'Var', (40, 45))	('metastases', 'Disease', (18, 28))
5396	29176653	A third ongoing trial examines the efficacy of combining imatinib with an aromatase inhibitor in patients with ER+ or PR+ and PDGFR+ or c-Kit+ metastatic breast cancer (NCT00338728).	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('c-Kit+', 'Var', (136, 142))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('ER+', 'Var', (111, 114))	('imatinib', 'Chemical', 'MESH:D000068877', (57, 65))	('PDGFR', 'Gene', (126, 131))	('PDGFR', 'Gene', '5159', (126, 131))	('patients', 'Species', '9606', (97, 105))
5397	29176653	However, no clinical studies have examined efficacy of imatinib in treating patients with early breast tumors and/or patients with breast tumors that are ER+/c-Kit+.	('breast tumors', 'Disease', 'MESH:D001943', (131, 144))	('patients', 'Species', '9606', (76, 84))	('breast tumors', 'Disease', (96, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('breast tumors', 'Disease', (131, 144))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('ER+/c-Kit+', 'Var', (154, 164))	('breast tumor', 'Phenotype', 'HP:0100013', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('breast tumors', 'Phenotype', 'HP:0100013', (96, 109))	('breast tumor', 'Phenotype', 'HP:0100013', (131, 143))	('breast tumors', 'Phenotype', 'HP:0100013', (131, 144))	('patients', 'Species', '9606', (117, 125))	('breast tumors', 'Disease', 'MESH:D001943', (96, 109))	('imatinib', 'Chemical', 'MESH:D000068877', (55, 63))
5398	29176653	Our studies suggest patients with ER+/c-Kit+ ILC respond to treatment with imatinib.	('respond', 'Reg', (49, 56))	('imatinib', 'Chemical', 'MESH:D000068877', (75, 83))	('patients', 'Species', '9606', (20, 28))	('ER+/c-Kit+ ILC', 'Var', (34, 48))
5431	29176653	1a), the data from 105 published gene expression arrays (GSE50470), along with the BCK4 arrays, which were performed on the same platform with identical methods, were downloaded.	('BCK', 'molecular_function', 'GO:0047323', ('83', '86'))	('BCK', 'Gene', '1152', (83, 86))	('BCK', 'Gene', (83, 86))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))	('GSE50470', 'Var', (57, 65))
5594	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.	('protein localization', 'biological_process', 'GO:0008104', ('202', '222'))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('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))
5615	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))	('sera', 'molecular_function', 'GO:0004617', ('61', '65'))	('positive', 'Reg', (156, 164))	('sera', 'molecular_function', 'GO:0004617', ('135', '139'))	('patient', 'Species', '9606', (125, 132))
5616	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))
5621	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))
5622	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))
5631	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))	('antibody', 'cellular_component', 'GO:0042571', ('36', '44'))	('patients', 'Species', '9606', (173, 181))	('antibody', 'cellular_component', 'GO:0019815', ('36', '44'))	('antibody', 'cellular_component', 'GO:0019814', ('36', '44'))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('anti-AKAP4', 'Var', (25, 35))	('antibody', 'molecular_function', 'GO:0003823', ('36', '44'))
5663	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))
5667	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))
5670	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).	('CT-X', 'Gene', (37, 41))	('AKAP4', 'Var', (70, 75))	('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))
5675	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))
5691	32819432	They lack E-cadherin protein expression and commonly present with loss of PTEN, activation of AKT, and mutations in TBX3 and FOXA1.	('E-cadherin', 'Gene', '999', (10, 20))	('AKT', 'Gene', '207', (94, 97))	('mutations', 'Var', (103, 112))	('loss', 'NegReg', (66, 70))	('TBX3', 'Gene', '6926', (116, 120))	('AKT', 'Gene', (94, 97))	('FOXA1', 'Gene', (125, 130))	('TBX3', 'Gene', (116, 120))	('PTEN', 'Gene', (74, 78))	('cadherin', 'molecular_function', 'GO:0008014', ('12', '20'))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('PTEN', 'Gene', '5728', (74, 78))	('lack', 'NegReg', (5, 9))	('FOXA1', 'Gene', '3169', (125, 130))	('expression', 'MPA', (29, 39))	('E-cadherin', 'Gene', (10, 20))	('activation', 'PosReg', (80, 90))
5695	32819432	Multifocality is more frequently associated with ILCs (40.7%) than with IDCs (14.1%).	('Multifocality', 'Var', (0, 13))	('ILC', 'Gene', (49, 52))	('ILC', 'Gene', '10850', (49, 52))	('associated', 'Reg', (33, 43))
5729	32819432	demonstrated that the odds ratio of breast cancer in high-risk patients significantly increased with high BPE.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('increased', 'PosReg', (86, 95))	('high BPE', 'Var', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('patients', 'Species', '9606', (63, 71))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
5770	29744328	The family history of breast carcinoma, estrogen receptor negativity, and human epidermal growth factor receptor-2 positivity are risk factors for the development of contralateral breast malignancy.	('breast carcinoma', 'Disease', 'MESH:D001943', (22, 38))	('epidermal growth factor receptor-2', 'Gene', (80, 114))	('contralateral breast malignancy', 'Disease', 'MESH:D001943', (166, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('epidermal growth factor receptor-2', 'Gene', '2064', (80, 114))	('breast carcinoma', 'Phenotype', 'HP:0003002', (22, 38))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('80', '103'))	('positivity', 'Var', (115, 125))	('human', 'Species', '9606', (74, 79))	('estrogen receptor', 'Gene', '2099', (40, 57))	('breast carcinoma', 'Disease', (22, 38))	('contralateral breast malignancy', 'Disease', (166, 197))	('estrogen receptor', 'Gene', (40, 57))
5800	29744328	Its characteristics have been well described, including the average age of onset, its rate of hormone receptor and erbB2 positivity, the frequency of nodal involvement, rates of metastatic spread and overall survival.	('positivity', 'Var', (121, 131))	('hormone receptor', 'Gene', '3164', (94, 110))	('erbB2', 'Gene', '2064', (115, 120))	('nodal', 'Gene', (150, 155))	('erbB2', 'Gene', (115, 120))	('hormone receptor', 'Gene', (94, 110))	('nodal', 'Gene', '4838', (150, 155))	('metastatic spread', 'CPA', (178, 195))
5812	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))	('Lobular carcinoma', 'Disease', (97, 114))	('mutations', 'Var', (7, 16))	('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))
5820	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.	('pure LCIS', 'Disease', (172, 181))	('LCIS', 'Phenotype', 'HP:0030076', (86, 90))	('pure', 'molecular_function', 'GO:0034023', ('172', '176'))	('CDH1', 'Gene', '999', (68, 72))	('frequent', 'Reg', (160, 168))	('CDH1', 'Gene', (68, 72))	('PIK3CA', 'Gene', '5290', (31, 37))	('associated', 'Reg', (193, 203))	('mutations', 'Var', (38, 47))	('frequent', 'Reg', (56, 64))	('ILC', 'Gene', '10850', (209, 212))	('LCIS', 'Disease', (188, 192))	('LCIS', 'Phenotype', 'HP:0030076', (127, 131))	('LCIS', 'Phenotype', 'HP:0030076', (177, 181))	('ILC', 'Gene', (209, 212))	('LCIS', 'Disease', (86, 90))	('PIK3CA', 'Gene', (31, 37))	('LCIS', 'Phenotype', 'HP:0030076', (188, 192))	('mutations', 'Var', (73, 82))
5821	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))
5834	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))	('pure', 'molecular_function', 'GO:0034023', ('29', '33'))	('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))
5836	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).	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))	('common', 'Reg', (106, 112))	('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))	('CDH1', 'Gene', (85, 89))	('hyperplasia', 'Disease', (151, 162))	('LCIS', 'Phenotype', 'HP:0030076', (116, 120))	('lobular hyperplasia', 'Disease', (143, 162))
5844	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.	('increased', 'PosReg', (123, 132))	('expression', 'MPA', (133, 143))	('hsa-miR-375', 'Gene', (147, 158))	('expression', 'MPA', (103, 113))	('hsa-miR-375', 'Gene', '494324', (147, 158))	('invasive disease', 'Disease', 'MESH:D009362', (57, 73))	('contributes', 'Reg', (159, 170))	('Ki67', 'Protein', (98, 102))	('lobular neoplastic progression', 'CPA', (174, 204))	('high', 'Var', (93, 97))	('invasive disease', 'Disease', (57, 73))
5852	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))
5870	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))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('c1624G_A', 'Var', (98, 106))	('PIK3CA', 'Gene', (90, 96))	('c1633G_A', 'Var', (111, 119))	('c1633G_A', 'Mutation', 'rs104886003', (111, 119))
5879	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))	('pure', 'molecular_function', 'GO:0034023', ('88', '92'))	('gain', 'PosReg', (13, 17))	('inv', 'Gene', '27130', (121, 124))
5884	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', 'molecular_function', 'GO:0034023', ('63', '67'))	('pure-cLCIS', 'Disease', (63, 73))	('LCIS', 'Phenotype', 'HP:0030076', (69, 73))	('inv', 'Gene', '27130', (89, 92))	('inv', 'Gene', (89, 92))	('LCIS', 'Phenotype', 'HP:0030076', (94, 98))	('Amplifications', 'Var', (0, 14))	('cLCIS', 'Chemical', '-', (68, 73))
5885	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))	('pure', 'molecular_function', 'GO:0034023', ('161', '165'))	('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))	('pure', 'molecular_function', 'GO:0034023', ('76', '80'))	('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))
5886	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))	('pure', 'molecular_function', 'GO:0034023', ('57', '61'))	('RAB11FIP4', 'Gene', (225, 234))	('LCIS', 'Phenotype', 'HP:0030076', (135, 139))	('MACROD2', 'Gene', (203, 210))	('pure', 'molecular_function', 'GO:0034023', ('130', '134'))	('LCIS', 'Phenotype', 'HP:0030076', (77, 81))	('MACROD2', 'Gene', '140733', (203, 210))
5902	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))
5903	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))
5908	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))
5910	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))	('pre', 'molecular_function', 'GO:0003904', ('152', '155'))	('ILC', 'Gene', '10850', (73, 76))	('ILC', 'Gene', (73, 76))
5912	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.	('pure', 'molecular_function', 'GO:0034023', ('304', '308'))	('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))
5914	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))
5915	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))	('inv', 'Gene', '27130', (59, 62))	('cLCIS', 'Chemical', '-', (63, 68))	('LCIS', 'Phenotype', 'HP:0030076', (64, 68))	('cLCIS', 'Chemical', '-', (28, 33))	('pure', 'molecular_function', 'GO:0034023', ('23', '27'))	('inv', 'Gene', (59, 62))	('mutations', 'Var', (96, 105))
5916	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))
5917	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))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('LCIS', 'Phenotype', 'HP:0030076', (54, 58))
5918	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))
5919	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))
5922	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))
5923	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))
5933	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))	('pure', 'molecular_function', 'GO:0034023', ('58', '62'))	('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))
5937	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.	('MCPH1', 'Gene', (144, 149))	('IDC', 'Disease', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('tumour', 'Disease', (163, 169))	('lobular cancers', 'Disease', (61, 76))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('lobular cancer', 'Phenotype', 'HP:0030076', (61, 75))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('breast cancer', 'Disease', (259, 272))	('MCPH1', 'Gene', '79648', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('described', 'Reg', (26, 35))	('DNA damage response', 'biological_process', 'GO:0006974', ('197', '216'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lobular cancers', 'Disease', 'MESH:D013274', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('Deletions', 'Var', (0, 9))
5938	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))
5942	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))	('pure', 'molecular_function', 'GO:0034023', ('121', '125'))	('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))
5943	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))
5945	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))	('cyclin', 'molecular_function', 'GO:0016538', ('69', '75'))	('over-expression', 'PosReg', (50, 65))	('cyclin D1', 'Gene', (69, 78))
5948	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))
5954	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))
5955	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))
5956	28095868	PIK3CA mutations have previously been reported by Christgen et al.	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
5959	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))	('pure', 'molecular_function', 'GO:0034023', ('184', '188'))	('LCIS', 'Phenotype', 'HP:0030076', (190, 194))	('PIK3CA', 'Gene', (142, 148))	('cLCIS', 'Chemical', '-', (189, 194))	('LCIS', 'Phenotype', 'HP:0030076', (167, 171))
5960	28095868	The only other study to assess PIK3CA mutations in pure LCIS was by Sakr et al.	('pure', 'molecular_function', 'GO:0034023', ('51', '55'))	('PIK3CA', 'Gene', (31, 37))	('LCIS', 'Phenotype', 'HP:0030076', (56, 60))	('PIK3CA', 'Gene', '5290', (31, 37))	('mutations', 'Var', (38, 47))
5962	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))
5963	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))
5964	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))	('pure', 'molecular_function', 'GO:0034023', ('127', '131'))	('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))
5966	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))
5968	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))	('signalling', 'biological_process', 'GO:0023052', ('173', '183'))	('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))	('MAP2K', 'molecular_function', 'GO:0004708', ('101', '106'))	('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))
5971	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))	('PI3K', 'molecular_function', 'GO:0016303', ('235', '239'))	('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))
5973	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))	('sub-clonal', 'Var', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('increase', 'PosReg', (126, 134))	('invasive lobular carcinoma', 'Disease', (164, 190))
5975	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))
5976	28095868	Driver mutations that are sub-clonal in the pre-invasive state then become clonal in the invasive stage.	('inv', 'Gene', '27130', (89, 92))	('inv', 'Gene', (89, 92))	('pre', 'molecular_function', 'GO:0003904', ('44', '47'))	('inv', 'Gene', '27130', (48, 51))	('inv', 'Gene', (48, 51))	('mutations', 'Var', (7, 16))
5979	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))
6056	28124996	Univariate analysis found associations of shorter disease-free survival with CPT-1 positivity (p = 0.004) and acyl-CoA oxidase 1 positivity (p = 0.032) and of shorter overall survival with acyl-CoA oxidase 1 positivity (p = 0.027).	('shorter', 'NegReg', (42, 49))	('CPT', 'molecular_function', 'GO:0004142', ('77', '80'))	('acyl-CoA oxidase 1', 'Gene', '51', (189, 207))	('CPT', 'molecular_function', 'GO:0004095', ('77', '80'))	('shorter', 'NegReg', (159, 166))	('acyl-CoA oxidase 1', 'Gene', (189, 207))	('CPT-1', 'Gene', '1376', (77, 82))	('positivity', 'Var', (83, 93))	('disease-free survival', 'CPA', (50, 71))	('CPT-1', 'Gene', (77, 82))	('overall', 'MPA', (167, 174))	('acyl-CoA oxidase 1', 'Gene', (110, 128))	('acyl-CoA oxidase 1', 'Gene', '51', (110, 128))	('positivity', 'Var', (129, 139))
6082	28124996	In a univariate analysis of ILC, CPT-1 positivity (p = 0.004) and acyl-CoA oxidase 1 positivity (p = 0.032) were associated with a shorter disease-free survival (DFS; Table 4 and Figure 4); however, no significantly predictive protein expression status was identified in a multivariate analysis (Table S3).	('positivity', 'Var', (85, 95))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('acyl-CoA oxidase 1', 'Gene', '51', (66, 84))	('disease-free survival', 'CPA', (139, 160))	('CPT', 'molecular_function', 'GO:0004142', ('33', '36'))	('CPT-1', 'Gene', (33, 38))	('CPT-1', 'Gene', '1376', (33, 38))	('acyl-CoA oxidase 1', 'Gene', (66, 84))	('positivity', 'Var', (39, 49))	('shorter', 'NegReg', (131, 138))	('CPT', 'molecular_function', 'GO:0004095', ('33', '36'))	('ILC', 'Disease', (28, 31))
6083	28124996	In a univariate analysis of all invasive breast cancers (n = 584), a shorter DFS was associated with HSL negativity (p = 0.024) and acyl-CoA oxidase 1 positivity (p = 0.028), whereas a shorter overall survival (OS) was associated only with acyl-CoA oxidase 1 positivity (p = 0.027) (Table 5).	('DFS', 'MPA', (77, 80))	('overall survival', 'MPA', (193, 209))	('shorter', 'NegReg', (185, 192))	('HSL', 'Gene', '3991', (101, 104))	('acyl-CoA oxidase 1', 'Gene', '51', (240, 258))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancers', 'Phenotype', 'HP:0003002', (41, 55))	('positivity', 'Var', (151, 161))	('acyl-CoA oxidase 1', 'Gene', (240, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('invasive breast cancers', 'Disease', (32, 55))	('shorter', 'NegReg', (69, 76))	('invasive breast cancers', 'Disease', 'MESH:D001943', (32, 55))	('HSL', 'molecular_function', 'GO:0033878', ('101', '104'))	('acyl-CoA oxidase 1', 'Gene', '51', (132, 150))	('HSL', 'Gene', (101, 104))	('acyl-CoA oxidase 1', 'Gene', (132, 150))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
6084	28124996	In a prognostic analysis of all invasive breast cancers according to molecular subtype, FABP4 positivity (p = 0.023) and CPT-1 positivity (p = 0.027) were associated with a shorter DFS among triple negative breast cancers (TNBCs) (Figure 4).	('positivity', 'Var', (127, 137))	('CPT-1', 'Gene', (121, 126))	('CPT-1', 'Gene', '1376', (121, 126))	('positivity', 'Var', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('FABP4', 'Gene', '2167', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('DFS', 'MPA', (181, 184))	('CPT', 'molecular_function', 'GO:0004095', ('121', '124'))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('breast cancers', 'Disease', 'MESH:D001943', (41, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('invasive breast cancers', 'Disease', 'MESH:D001943', (32, 55))	('breast cancers', 'Disease', 'MESH:D001943', (207, 221))	('breast cancers', 'Disease', (207, 221))	('breast cancers', 'Phenotype', 'HP:0003002', (41, 55))	('invasive breast cancers', 'Disease', (32, 55))	('CPT', 'molecular_function', 'GO:0004142', ('121', '124'))	('shorter', 'NegReg', (173, 180))	('breast cancers', 'Phenotype', 'HP:0003002', (207, 221))	('FABP4', 'Gene', (88, 93))
6098	28124996	Aberrant CPT-1 expression has been found to be associate with high-grade glioma, suggesting a correlation between lipid metabolism-related protein expression and a higher tumor grade.	('CPT', 'molecular_function', 'GO:0004095', ('9', '12'))	('glioma', 'Disease', (73, 79))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('CPT-1', 'Gene', (9, 14))	('CPT-1', 'Gene', '1376', (9, 14))	('lipid', 'Chemical', 'MESH:D008055', (114, 119))	('associate', 'Reg', (47, 56))	('glioma', 'Disease', 'MESH:D005910', (73, 79))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('lipid metabolism', 'biological_process', 'GO:0006629', ('114', '130'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('CPT', 'molecular_function', 'GO:0004142', ('9', '12'))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
6099	28124996	In ILC, CPT-1 positivity and acyl-CoA oxidase 1 positivity were found to correlate with poor prognosis.	('acyl-CoA oxidase 1', 'Gene', (29, 47))	('positivity', 'Var', (14, 24))	('CPT-1', 'Gene', (8, 13))	('CPT-1', 'Gene', '1376', (8, 13))	('acyl-CoA oxidase 1', 'Gene', '51', (29, 47))	('ILC', 'Disease', (3, 6))	('CPT', 'molecular_function', 'GO:0004142', ('8', '11'))	('CPT', 'molecular_function', 'GO:0004095', ('8', '11'))
6101	28124996	We also found the association between expression of lipid metabolism-related proteins and poor prognosis in the breast cancer subtypes: HSL negativity and acyl-CoA oxidase 1 positivity in invasive breast cancer, and FABP4 positivity and CPT-1 positivity in the TNBC subgroup.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('CPT', 'molecular_function', 'GO:0004095', ('237', '240'))	('breast cancer', 'Disease', (112, 125))	('positivity', 'Var', (174, 184))	('HSL', 'Gene', (136, 139))	('lipid', 'Chemical', 'MESH:D008055', (52, 57))	('HSL', 'Gene', '3991', (136, 139))	('FABP4', 'Gene', '2167', (216, 221))	('acyl-CoA oxidase 1', 'Gene', (155, 173))	('invasive breast cancer', 'Disease', (188, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('invasive breast cancer', 'Disease', 'MESH:D001943', (188, 210))	('HSL', 'molecular_function', 'GO:0033878', ('136', '139'))	('CPT', 'molecular_function', 'GO:0004142', ('237', '240'))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('positivity', 'Var', (243, 253))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('expression', 'MPA', (38, 48))	('CPT-1', 'Gene', (237, 242))	('CPT-1', 'Gene', '1376', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('acyl-CoA oxidase 1', 'Gene', '51', (155, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('FABP4', 'Gene', (216, 221))	('lipid metabolism', 'biological_process', 'GO:0006629', ('52', '68'))
6159	27303480	Other nonspecific, mammographic findings of ILC are asymmetry and developing density, noted when images are compared with a patient's previous study.	('asymmetry', 'Var', (52, 61))	('patient', 'Species', '9606', (124, 131))	('ILC', 'Disease', (44, 47))	('developing density', 'CPA', (66, 84))
6161	27303480	The most common was an asymmetric density without definable margins, likely caused by thickened tissue from tumor infiltration.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('asymmetric', 'Var', (23, 33))	('tumor', 'Disease', (108, 113))
6166	27303480	A change in this nipple-to-pectoralis line would result in a physical change noted on clinical exam, and the patients in our series had no abnormal physical findings on clinical breast examinations.	('result', 'Reg', (49, 55))	('physical change', 'MPA', (61, 76))	('patients', 'Species', '9606', (109, 117))	('change', 'Var', (2, 8))
6217	25837163	The pleomorphic type showed significant association with older age (p=0.033), a higher nuclear grade (p<0.001), a higher histologic grade (p<0.001), a higher T stage (p=0.026), PR negativity (p=0.005), HER-2 positivity (p=0.002), a higher Ki-67 LI (p<0.001), and the non-luminal A subtype (p<0.001) compared with the classic type.	('nuclear grade', 'CPA', (87, 100))	('Ki-67 LI', 'CPA', (239, 247))	('higher', 'PosReg', (232, 238))	('T stage', 'CPA', (158, 165))	('PR', 'Gene', '5241', (177, 179))	('histologic grade', 'CPA', (121, 137))	('higher', 'PosReg', (80, 86))	('higher', 'PosReg', (151, 157))	('non-luminal A subtype', 'CPA', (267, 288))	('positivity', 'Var', (208, 218))	('HER-2', 'Gene', '2064', (202, 207))	('HER-2', 'Gene', (202, 207))	('higher', 'PosReg', (114, 120))
6233	25837163	Low sarcosine type was most common in ILC, whereas null type was most common in IDC.	('IDC', 'Gene', (80, 83))	('ILC', 'Disease', (38, 41))	('common', 'Reg', (28, 34))	('Low sarcosine type', 'Var', (0, 18))	('IDC', 'Gene', '4000', (80, 83))	('sarcosine', 'Chemical', 'MESH:D012521', (4, 13))
6307	25357113	However, PAM50 generated a medium ROR-S score (subtype-weighted) score in 5% (1 of 20) and medium ROR-P score (proliferation weighted) scores in 35% (7 of 20) of patients.	('patients', 'Species', '9606', (162, 170))	('PAM50', 'Var', (9, 14))	('ROR', 'Gene', '100885779', (98, 101))	('ROR', 'Gene', '100885779', (34, 37))	('ROR', 'Gene', (98, 101))	('ROR', 'Gene', (34, 37))
6388	21155040	Clinicopathlogic and Immunohistochemical Characteristics of Triple Negative Invasive Lobular Carcinoma Our study is performed to find out clinicopathlogic and immunohistochemical (IHC) characteristics of triple negative invasive lobular carcinoma (ILC), as has been demonstrated in their invasive ductal counterparts.	('invasive lobular carcinoma', 'Disease', (220, 246))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (229, 246))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (220, 246))	('Lobular Carcinoma', 'Disease', (85, 102))	('Lobular Carcinoma', 'Disease', 'MESH:D018275', (85, 102))	('Carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('triple negative', 'Var', (204, 219))	('Lobular Carcinoma', 'Phenotype', 'HP:0030076', (85, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
6391	21155040	Galectin-3 was expressed with higher incidence in tumor cells of TNC (62.5%) than those of non-TNC (7.3%) (p = 0.000).	('Galectin-3', 'Gene', (0, 10))	('TNC', 'Var', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Galectin-3', 'Gene', '3958', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Galectin', 'molecular_function', 'GO:0001577', ('0', '8'))	('tumor', 'Disease', (50, 55))
6392	21155040	In contrast, galectin-3 was expressed with higher incidence in stromal cells of non-TNC (53.2%) than those of TNC (12.5%) (p = 0.029).	('galectin-3', 'Gene', (13, 23))	('galectin', 'molecular_function', 'GO:0001577', ('13', '21'))	('galectin-3', 'Gene', '3958', (13, 23))	('non-TNC', 'Var', (80, 87))
6401	21155040	TNC has no effective modalities because of TNC is estrogen receptor (ER) and progesterone receptor (PR) negative for hormone treatment, and HER2 negative for trastuzumab treatment.	('PR', 'Gene', '5241', (100, 102))	('TNC', 'Var', (43, 46))	('trastuzumab', 'Chemical', 'MESH:D000068878', (158, 169))	('ER', 'Gene', '2099', (141, 143))	('ER', 'Gene', '2099', (69, 71))	('estrogen receptor', 'Gene', (50, 67))	('negative', 'NegReg', (104, 112))	('progesterone receptor', 'Gene', (77, 98))	('HER2', 'Gene', (140, 144))	('progesterone receptor', 'Gene', '5241', (77, 98))	('estrogen receptor', 'Gene', '2099', (50, 67))	('HER2', 'Gene', '2064', (140, 144))
6440	21155040	Galectin-3 was expressed with higher incidence in stromal cells of non-TNC (53.2%) than those of TNC (12.5%) (p = 0.029).	('Galectin-3', 'Gene', (0, 10))	('Galectin-3', 'Gene', '3958', (0, 10))	('Galectin', 'molecular_function', 'GO:0001577', ('0', '8'))	('non-TNC', 'Var', (67, 74))
6484	21155040	In conclusion, TNC in ILC showed some clinicopathologic and IHC characteristics, such as higher histologic grade, and increased expression of galectin-3, differing from non-TNC in ILC.	('galectin-3', 'Gene', (142, 152))	('ILC', 'Disease', (22, 25))	('increased', 'PosReg', (118, 127))	('higher', 'PosReg', (89, 95))	('galectin-3', 'Gene', '3958', (142, 152))	('increased expression of galectin-3', 'Phenotype', 'HP:0032205', (118, 152))	('expression', 'MPA', (128, 138))	('TNC', 'Var', (15, 18))	('galectin', 'molecular_function', 'GO:0001577', ('142', '150'))
6539	31992958	However, despite the high Ki-67 rate there was a low tpCR rate after PCT in this subgroup of patients.	('patients', 'Species', '9606', (93, 101))	('low', 'NegReg', (49, 52))	('tpCR', 'MPA', (53, 57))	('Ki-67', 'Var', (26, 31))
6547	30798422	While SNAIL knockdown had a minor impact on the 4OHT partial agonism in estrogen-depleted conditions, it led to a surprising increase in cell proliferation in full serum.	('cell proliferation', 'CPA', (137, 155))	('increase', 'PosReg', (125, 133))	('knockdown', 'Var', (12, 21))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('SNAIL', 'Gene', '6615', (6, 11))	('SNAIL', 'Gene', (6, 11))	('4OHT', 'Chemical', 'MESH:C032278', (48, 52))	('4OHT partial agonism', 'MPA', (48, 68))
6563	30798422	In breast cancer, high expression of EMT-TFs is associated with increased tumor grade, progression and metastasis.	('EMT', 'biological_process', 'GO:0001837', ('37', '40'))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('EMT-TFs', 'Gene', (37, 44))	('tumor', 'Disease', (74, 79))	('high', 'Var', (18, 22))	('increased', 'PosReg', (64, 73))	('progression', 'CPA', (87, 98))	('metastasis', 'CPA', (103, 113))
6564	30798422	Consistent with this, SNAIL expression has been shown to promote cellular resistance to programmed cell death, and to alter response to genotoxic stress.	('genotoxic stress', 'Disease', 'MESH:D000079225', (136, 152))	('genotoxic stress', 'Disease', (136, 152))	('programmed cell death', 'biological_process', 'GO:0012501', ('88', '109'))	('promote', 'PosReg', (57, 64))	('SNAIL', 'Gene', '6615', (22, 27))	('SNAIL', 'Gene', (22, 27))	('response to genotoxic stress', 'biological_process', 'GO:0006974', ('124', '152'))	('expression', 'Var', (28, 38))	('death', 'Disease', 'MESH:D003643', (104, 109))	('death', 'Disease', (104, 109))	('alter', 'Reg', (118, 123))
6596	30798422	Immunoblot analysis in these two cell lines confirmed that E2 and 4OHT lead to induction of SNAIL protein as well (Fig.	('SNAIL', 'Gene', '6615', (92, 97))	('SNAIL', 'Gene', (92, 97))	('4OHT', 'Var', (66, 70))	('E2', 'Chemical', 'MESH:D004958', (59, 61))	('induction', 'MPA', (79, 88))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('4OHT', 'Chemical', 'MESH:C032278', (66, 70))
6609	30798422	All ILC cell lines utilized were first confirmed to have expression of ER and the ILC-hallmark loss of E-cadherin protein, with the exception of MDA-MB-330, which does express E-cadherin but has loss of adherens junctions due to a mutation in alpha catenin (Supplementary Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('178', '186'))	('ILC-hallmark loss', 'Disease', (82, 99))	('adherens', 'MPA', (203, 211))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (145, 155))	('cadherin', 'molecular_function', 'GO:0008014', ('105', '113'))	('E-cadherin', 'Gene', '999', (103, 113))	('alpha catenin', 'Protein', (243, 256))	('loss', 'NegReg', (195, 199))	('E-cadherin', 'Gene', (103, 113))	('E-cadherin', 'Gene', (176, 186))	('E-cadherin', 'Gene', '999', (176, 186))	('mutation', 'Var', (231, 239))	('ILC-hallmark loss', 'Disease', 'MESH:D014786', (82, 99))
6616	30798422	We initially knocked down SNAI1 in MDA-MB-134-VI cells using siRNAs following E2-deprivation and assessed cell proliferation over 14 days.	('cell proliferation', 'CPA', (106, 124))	('E2', 'Chemical', 'MESH:D004958', (78, 80))	('SNAI1', 'Gene', '6615', (26, 31))	('SNAI1', 'Gene', (26, 31))	('knocked', 'Var', (13, 20))	('MDA-MB-134-VI', 'CellLine', 'CVCL:0617', (35, 48))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))
6619	30798422	We next transiently knocked down SNAI1 in full serum in MDA-MB-134-VI cells, which exhibit the highest levels of endogenous SNAIL expression.	('SNAIL', 'Gene', '6615', (124, 129))	('SNAIL', 'Gene', (124, 129))	('SNAI1', 'Gene', '6615', (33, 38))	('SNAI1', 'Gene', (33, 38))	('knocked down', 'Var', (20, 32))	('MDA-MB-134-VI', 'CellLine', 'CVCL:0617', (56, 69))
6620	30798422	We confirmed successful SNAI1 knockdown, which was sustained over the 6-day experimental course (Fig.	('SNAI1', 'Gene', (24, 29))	('SNAI1', 'Gene', '6615', (24, 29))	('knockdown', 'Var', (30, 39))
6623	30798422	We also checked the effect of transient SNAI1 knockdown on the expression of the downstream EMT-TF target genes and observed that only FN1 was significantly decreased while there was no effect on VIM or CDH2 (Fig.	('FN1', 'Gene', (135, 138))	('SNAI1', 'Gene', '6615', (40, 45))	('knockdown', 'Var', (46, 55))	('VIM', 'Gene', '7431', (196, 199))	('EMT', 'biological_process', 'GO:0001837', ('92', '95'))	('SNAI1', 'Gene', (40, 45))	('CDH2', 'Gene', (203, 207))	('FN1', 'Gene', '2335', (135, 138))	('CDH2', 'Gene', '1000', (203, 207))	('decreased', 'NegReg', (157, 166))	('VIM', 'Gene', (196, 199))
6646	30798422	The Cancer Genome Atlas (TCGA) ILC working group was among the first to publish a clear molecular distinction between ILC and IDC, including significant differences in PTEN, PI3K, FOXA1 and GATA3 mutations/activation between ILC and IDC.	('PI3K', 'molecular_function', 'GO:0016303', ('174', '178'))	('PTEN', 'Gene', (168, 172))	('GATA3', 'Gene', (190, 195))	('mutations/activation', 'PosReg', (196, 216))	('PTEN', 'Gene', '5728', (168, 172))	('FOXA1', 'Gene', (180, 185))	('PI3K', 'Gene', (174, 178))	('GATA3', 'Gene', '2625', (190, 195))	('mutations/activation', 'Var', (196, 216))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('FOXA1', 'Gene', '3169', (180, 185))	('differences', 'Reg', (153, 164))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
6651	30798422	Our gene expression data is complemented by results from ChIP assays showing direct binding of ER to the promoter region of SNAI1, thereby providing additional support for the hypothesis that 4OHT can act as an agonist in ILC as opposed to an antagonist.	('SNAI1', 'Gene', '6615', (124, 129))	('4OHT', 'Var', (192, 196))	('SNAI1', 'Gene', (124, 129))	('4OHT', 'Chemical', 'MESH:C032278', (192, 196))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('ILC', 'Disease', (222, 225))	('binding', 'Interaction', (84, 91))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
6691	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', 'molecular_function', 'GO:0005154', ('81', '104'))	('MDL tumours', 'Disease', (12, 23))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('epidermal', 'MPA', (81, 90))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
6692	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))	('growth pattern', 'biological_process', 'GO:0040007', ('149', '163'))	('DNA', 'cellular_component', 'GO:0005574', ('283', '286'))	('invasive tumours', 'Disease', (107, 123))	('growth pattern', 'biological_process', 'GO:0007150', ('149', '163'))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
6696	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))	('Ser', 'cellular_component', 'GO:0005790', ('273', '276'))	('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))
6699	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))
6700	29344954	NCOR1, p.Ser1117*, high effect, none recorded in COSMIC; PARP4, p.Gln147Glu, moderate effect, alternative missense mutations recorded in COSMIC).	('Ser', 'cellular_component', 'GO:0005790', ('9', '12'))	('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))
6701	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))	('PLC', 'cellular_component', 'GO:0042824', ('175', '178'))
6702	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))
6713	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))
6714	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))
6715	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))
6721	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.	('breast cancer', 'Disease', (94, 107))	('predict', 'Reg', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('harbour', 'Reg', (65, 72))	('mutations', 'Var', (73, 82))
6739	31803564	Under-estimating pre-surgical tumor size may lead to incomplete margins and consequently to re-excision .	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('lead', 'Reg', (45, 49))	('pre', 'molecular_function', 'GO:0003904', ('17', '20'))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('Under-estimating', 'Var', (0, 16))
6782	31803564	The relatively large number of architectural distortions that determined tumor size discrepancies could be interpreted as the difficulty in correct measuring a cancer presenting as a distortions in DBT.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Disease', (160, 166))	('distortions', 'Var', (183, 194))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('DBT', 'Disease', (198, 201))	('DBT', 'Disease', 'MESH:D061325', (198, 201))
6904	29281999	In line with this evidence, our work showed that IMPC in HER2-positive breast cancer is associated with ER expression, younger patients and poor benefit to standard adjuvant trastuzumab and chemotherapy.	('ER', 'Gene', '2099', (58, 60))	('IMPC', 'Var', (49, 53))	('trastuzumab', 'Chemical', 'MESH:D000068878', (174, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('HER2-positive breast cancer', 'Disease', (57, 84))	('ER', 'Gene', '2099', (104, 106))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (57, 84))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
6910	29281999	We also showed that IMPC in HER2-positive breast cancer is associated with ER expression, younger patients and poor benefit to standard adjuvant trastuzumab and chemotherapy.	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (28, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (98, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('ER', 'Gene', '2099', (29, 31))	('trastuzumab', 'Chemical', 'MESH:D000068878', (145, 156))	('ER', 'Gene', '2099', (75, 77))	('HER2-positive breast cancer', 'Disease', (28, 55))	('IMPC', 'Var', (20, 24))
6934	28584792	Histology reports were collected from patients with ILC who had MRIs including DWI and FDG PET/CT and had their diagnoses confirmed by biopsy and underwent surgery between June 2007 and September 2013.	('MRIs', 'Var', (64, 68))	('ILC', 'Disease', (52, 55))	('patients', 'Species', '9606', (38, 46))
6942	28584792	The ADC value was calculated according to the formula: ADC=[1/(b2-b1)] ln (S2/S1), where S1 and S2 are the signal intensities in the regions of interest (ROI) obtained by two gradient factors, b2 and b1 (b1=0 and b2=1,000 s/mm2 for the 1.5 T scanner; b1=0 and b2=750 s/mm2 for the 3.0 T scanner).	('b2 and b1', 'Gene', '28907;941', (193, 202))	('mm2', 'Gene', '10687', (224, 227))	('mm2', 'Gene', '10687', (269, 272))	('mm2', 'Gene', (224, 227))	('mm2', 'Gene', (269, 272))	('b1=0', 'Var', (251, 255))
6975	28584792	explained that non-nodular tumors are more influenced by partial-volume effects, and SUV measurements are greatly affected by partial-volume effects.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('non-nodular tumors', 'Disease', 'MESH:D020518', (15, 33))	('influenced', 'Reg', (43, 53))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('partial-volume', 'Var', (57, 71))	('affected', 'Reg', (114, 122))	('non-nodular tumors', 'Disease', (15, 33))
6988	30728399	Here, we compared The Cancer Genome Atlas (TCGA) and the Genomics Evidence Neoplasia Information Exchange (GENIE) breast cancer genomic datasets (array and next generation sequencing (NGS) data) in detecting genomic alterations in clinically relevant genes.	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Cancer Genome Atlas', 'Disease', (22, 41))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Neoplasia', 'Disease', 'MESH:D009369', (75, 84))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (22, 41))	('Neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('genomic alterations', 'Var', (208, 227))	('Neoplasia', 'Disease', (75, 84))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))
6989	30728399	We performed an in silico analysis to determine the concordance in the frequencies of actionable mutations and copy number alterations/aberrations (CNAs) in the two most common breast cancer histologies, invasive lobular and invasive ductal carcinoma.	('mutations', 'Var', (97, 106))	('breast cancer', 'Disease', (177, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (225, 250))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('copy number alterations/aberrations', 'Var', (111, 146))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (234, 250))	('invasive ductal carcinoma', 'Disease', (225, 250))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('invasive lobular', 'Disease', (204, 220))
6996	30728399	However, the vast heterogeneity of lesions observed in mutations and copy number alterations (CNAs) varies for different genes and tumor histologies.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('copy number alterations', 'Var', (69, 92))	('tumor', 'Disease', (131, 136))
6999	30728399	The United States Food and Drug Administration (FDA) has recently approved the NGS-based FoundationOne CDx test that identifies actionable alterations in cancer-related genes and can guide treatment decisions.	('CDx', 'Chemical', '-', (103, 106))	('alterations', 'Var', (139, 150))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
7008	30728399	However, we identified consistency in the mutation frequencies across 40 clinically relevant genes including frequent mutations in PIK3CA, TP53, MAP2K1, NF1 and GATA3 in both of the datasets (Fig.	('NF1', 'Gene', (153, 156))	('MAP2K1', 'Gene', (145, 151))	('mutations', 'Var', (118, 127))	('MAP2K', 'molecular_function', 'GO:0004708', ('145', '150'))	('NF1', 'Gene', '4763', (153, 156))	('TP53', 'Gene', '7157', (139, 143))	('GATA3', 'Gene', (161, 166))	('PIK3CA', 'Gene', (131, 137))	('TP53', 'Gene', (139, 143))	('GATA3', 'Gene', '2625', (161, 166))	('PIK3CA', 'Gene', '5290', (131, 137))	('MAP2K1', 'Gene', '5604', (145, 151))
7009	30728399	1(d,e)), which is consistent with previous reports of an association between these gene mutations with breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('association', 'Interaction', (57, 68))
7010	30728399	Hotspot mutations have been annotated with COSMIC database and non-hotspots have been annotated with the Oncology Knowledge Base (OncoKB) and the Clinical Interpretation of Variants in Cancer (CIViC) databases.	('Oncology', 'Phenotype', 'HP:0002664', (105, 113))	('mutations', 'Var', (8, 17))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Cancer', 'Disease', (185, 191))	('Cancer', 'Disease', 'MESH:D009369', (185, 191))
7012	30728399	The genes that had a higher number of mutations in the GENIE cohort as compared to TCGA cohort were BRCA2 (57 versus 12, p-0.035 for missense mutations), NOTCH1 (38 versus 5, p-0.04 for missense mutations), and BRCA1 (36 versus 14, p = 0.02 for missense mutations).	('BRCA2', 'Gene', (100, 105))	('BRCA1', 'Gene', (211, 216))	('NOTCH1', 'Gene', '4851', (154, 160))	('NOTCH1', 'Gene', (154, 160))	('BRCA2', 'Gene', '675', (100, 105))	('BRCA1', 'Gene', '672', (211, 216))	('mutations', 'Var', (38, 47))
7013	30728399	We also observed 20 mutations in the ESR1 gene in the IDC subtype in the GENIE dataset that were not identified in the same tumor subtype in TCGA.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('ESR1', 'Gene', '2099', (37, 41))	('tumor', 'Disease', (124, 129))	('IDC', 'Disease', (54, 57))	('ESR1', 'Gene', (37, 41))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
7014	30728399	Among these, the 2 main mutations (D538G and E380Q) confer acquired resistance to aromatase inhibitors.	('resistance to aromatase inhibitors', 'MPA', (68, 102))	('E380Q', 'Mutation', 'rs1057519827', (45, 50))	('E380Q', 'Var', (45, 50))	('D538G', 'Var', (35, 40))	('D538G', 'Mutation', 'p.D538G', (35, 40))
7019	30728399	The frequency of copy number gain alterations in FGFR1 across ILC samples was 22-fold higher in the TCGA cohort as compared to the GENIE cohort (22% versus 1%, p < 0.0001).	('copy number gain alterations', 'Var', (17, 45))	('TCGA', 'Disease', (100, 104))	('higher', 'PosReg', (86, 92))	('FGFR1', 'Gene', (49, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('alterations', 'Var', (34, 45))	('FGFR1', 'Gene', '2260', (49, 54))
7020	30728399	RPTOR also harbored frequent copy number gain alterations in 15% of TCGA cases compared to GENIE (0%).	('TCGA', 'Disease', (68, 72))	('copy number gain alterations', 'Var', (29, 57))	('RPTOR', 'Gene', (0, 5))	('RPTOR', 'Gene', '57521', (0, 5))
7021	30728399	We also observed higher frequencies of patients having hemizygous deletions in the hormone receptors in ILC TCGA data set that were not observed in GENIE, including AR (8% versus 0%, p < 0.0001), ESR1 (23% versus 2%, p < 0.0001) and PGR (42% versus 0%, p < 0.0001) (Fig.	('PGR', 'Gene', '5241', (233, 236))	('patients', 'Species', '9606', (39, 47))	('hormone receptor', 'Gene', (83, 99))	('hormone receptor', 'Gene', '3164', (83, 99))	('PGR', 'Gene', (233, 236))	('ESR1', 'Gene', '2099', (196, 200))	('deletions', 'Var', (66, 75))	('ILC', 'Gene', (104, 107))	('ESR1', 'Gene', (196, 200))
7022	30728399	The most frequent actionable alterations in the TCGA IDC dataset in comparison to GENIE were amplification in the regions of 15 genes (AKT3, ESR1, BARD1, BRCA1, PALB2, CD274, GATA3, NOTCH1, NOTCH4, MET, CDK4, CCND3, CCND2, CCNE1, CDK6, p < 0.0001) and deletion in 9 genes (PGR, ATM, BRCA2, BARD1, FGFR1, RB1, BRAF, KRAS, FBXW7, p < 0.05) (Fig.	('KRAS', 'Gene', '3845', (315, 319))	('ATM', 'Gene', '472', (278, 281))	('CCNE1', 'Gene', '898', (223, 228))	('ESR1', 'Gene', (141, 145))	('CCND2', 'Gene', (216, 221))	('AKT3', 'Gene', (135, 139))	('NOTCH1', 'Gene', (182, 188))	('CCND3', 'Gene', (209, 214))	('KRAS', 'Gene', (315, 319))	('GATA3', 'Gene', (175, 180))	('BRAF', 'Gene', (309, 313))	('BRAF', 'Gene', '673', (309, 313))	('CDK6', 'Gene', '1021', (230, 234))	('CDK4', 'Gene', (203, 207))	('BRCA1', 'Gene', '672', (154, 159))	('FBXW7', 'Gene', '55294', (321, 326))	('CCND2', 'Gene', '894', (216, 221))	('CDK', 'molecular_function', 'GO:0004693', ('203', '206'))	('NOTCH4', 'Gene', (190, 196))	('BRCA1', 'Gene', (154, 159))	('NOTCH4', 'Gene', '4855', (190, 196))	('FGFR1', 'Gene', '2260', (297, 302))	('CDK6', 'Gene', (230, 234))	('NOTCH1', 'Gene', '4851', (182, 188))	('ATM', 'Gene', (278, 281))	('CDK4', 'Gene', '1019', (203, 207))	('PGR', 'Gene', '5241', (273, 276))	('CDK', 'molecular_function', 'GO:0004693', ('230', '233'))	('deletion', 'Var', (252, 260))	('CD274', 'Gene', '29126', (168, 173))	('BRCA2', 'Gene', (283, 288))	('CCND3', 'Gene', '896', (209, 214))	('PALB2', 'Gene', (161, 166))	('RB1', 'Gene', (304, 307))	('FGFR', 'molecular_function', 'GO:0005007', ('297', '301'))	('GATA3', 'Gene', '2625', (175, 180))	('FGFR1', 'Gene', (297, 302))	('FBXW7', 'Gene', (321, 326))	('PALB2', 'Gene', '79728', (161, 166))	('BARD1', 'Gene', '580', (290, 295))	('BARD1', 'Gene', '580', (147, 152))	('BARD1', 'Gene', (290, 295))	('AKT3', 'Gene', '10000', (135, 139))	('CCNE1', 'Gene', (223, 228))	('PGR', 'Gene', (273, 276))	('CD274', 'Gene', (168, 173))	('BRCA2', 'Gene', '675', (283, 288))	('RB1', 'Gene', '5925', (304, 307))	('BARD1', 'Gene', (147, 152))	('ESR1', 'Gene', '2099', (141, 145))
7024	30728399	For deletions, we found common and distinct regions that were deleted in breast cancer-associated genes in both datasets in the ILC (Fig.	('deleted', 'Var', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('deletions', 'Var', (4, 13))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
7028	30728399	In NSCLC alone, we observed higher frequencies of CNAs in many actionable genes in TCGA than in GENIE, such as FGFR1 (9% versus 2%, p < 0.0001) and PIK3CA (18% versus 1%, p < 0.0001) for amplification and CDKN2A (13% versus 0%, p < 0.0001), CDKN2B (20% versus 4%, p < 0.0001) for deletions (Fig.	('PIK3CA', 'Gene', '5290', (148, 154))	('CDKN2B', 'Gene', '1030', (241, 247))	('NSCLC', 'Disease', (3, 8))	('FGFR1', 'Gene', '2260', (111, 116))	('CDKN2A', 'Gene', (205, 211))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('CDKN2A', 'Gene', '1029', (205, 211))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('CNAs', 'MPA', (50, 54))	('PIK3CA', 'Gene', (148, 154))	('CDKN2B', 'Gene', (241, 247))	('FGFR1', 'Gene', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('deletions', 'Var', (280, 289))	('TCGA', 'Gene', (83, 87))
7029	30728399	In colorectal cancer, the genes that were significantly enriched for copy number gain in TCGA versus GENIE were BRCA2 (60% versus 23%, p < 0.0001), BRAF (48% versus 11%, p < 0.0001) and KRAS (22% versus 3%, p < 0.0001) (Fig.	('gain', 'PosReg', (81, 85))	('KRAS', 'Gene', (186, 190))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('BRCA2', 'Gene', (112, 117))	('KRAS', 'Gene', '3845', (186, 190))	('colorectal cancer', 'Disease', (3, 20))	('copy number', 'Var', (69, 80))	('TCGA', 'Gene', (89, 93))	('BRAF', 'Gene', '673', (148, 152))	('BRCA2', 'Gene', '675', (112, 117))	('BRAF', 'Gene', (148, 152))
7031	30728399	However, the total number of mutations (including missense, truncating and inframe) in the TP53 gene was greater in GENIE than in TCGA (1709 versus 791, p < 0.0001).	('TP53', 'Gene', '7157', (91, 95))	('TP53', 'Gene', (91, 95))	('truncating', 'MPA', (60, 70))	('missense', 'Var', (50, 58))
7033	30728399	Likewise, TP53 was highly enriched for mutations in the GENIE colorectal cancer data as compared to TCGA data (1629 versus 122, p-0.0064).	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('TP53', 'Gene', (10, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (39, 48))	('colorectal cancer', 'Disease', (62, 79))	('TP53', 'Gene', '7157', (10, 14))
7034	30728399	We also observed higher number of mutational hotspots in 3 actionable genes in KRAS (1164 versus 219, p < 0.0001, q-0.0005), EGFR (814 versus 103, p < 0.0001, q-0.0005) and TP53 (1195 versus 499, p < 0.0001, q-0.0005) in GENIE than in TCGA in NSCLC cases.	('814', 'Var', (131, 134))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('KRAS', 'Gene', '3845', (79, 83))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (125, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (243, 248))	('mutational', 'Var', (34, 44))	('TP53', 'Gene', '7157', (173, 177))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('TP53', 'Gene', (173, 177))	('1195', 'Var', (179, 183))	('KRAS', 'Gene', (79, 83))	('NSCLC', 'Disease', (243, 248))
7035	30728399	This study represents an integrated comparison of whole exome, SNP-based array and targeted gene panel sequencing in terms of their ability to detect mutations and CNAs in potentially clinical actionable genes from two-large breast cancer cohort studies.	('-large breast', 'Phenotype', 'HP:0010313', (218, 231))	('mutations', 'Var', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('CNAs', 'Var', (164, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', (225, 238))
7038	30728399	The MSK-IMPACT tumor profiling assay may distinguish mismatch repair deficiency (MMR-D) and proficient (MMR-P) tumors on the basis of mutational burden in colorectal cancer.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mismatch repair', 'biological_process', 'GO:0006298', ('53', '68'))	('MMR', 'biological_process', 'GO:0006298', ('81', '84'))	('MMR-P) tumors', 'Disease', 'MESH:C536143', (104, 117))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('MMR', 'biological_process', 'GO:0006298', ('104', '107'))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (15, 20))	('colorectal cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mismatch', 'Var', (53, 61))
7039	30728399	identifies that 69% of the mutations from tumor-only WES pipeline were false-positive and even for matched-normal DNA only 36-78% were found consistently in replicate pairs.	('mutations', 'Var', (27, 36))	('false', 'biological_process', 'GO:0071878', ('71', '76'))	('tumor', 'Disease', (42, 47))	('false', 'biological_process', 'GO:0071877', ('71', '76'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
7040	30728399	Torga and colleagues reported very low congruence in tumor-specific genetic alterations for patient-paired samples between the PlasmaSELECT and Guardant360 tests that could lead to different treatment decisions.	('patient', 'Species', '9606', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('genetic alterations', 'Var', (68, 87))	('tumor', 'Disease', (53, 58))	('lead to', 'Reg', (173, 180))
7041	30728399	The differences in the CNAs frequency across different platforms would also affect the ability to identify the subtype-specific patterns of alterations (for example, TERT amplification in lung cancer squamous cell carcinoma) and the driver genes that have been mutated by genomic duplication and deletion.	('affect', 'Reg', (76, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('lung cancer squamous cell carcinoma', 'Disease', (188, 223))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('lung cancer squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 223))	('TERT', 'Gene', (166, 170))	('deletion', 'Var', (296, 304))	('TERT', 'Gene', '7015', (166, 170))
7089	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))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('colorectal', 'Disease', (112, 122))	('PKC', 'molecular_function', 'GO:0004697', ('17', '20'))	('beta-Catenin', 'Gene', (65, 77))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (26, 35))	('nuclear translocation of', 'MPA', (40, 64))
7090	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))	('PKC', 'molecular_function', 'GO:0004697', ('118', '121'))	('PKC-zeta', 'Gene', (118, 126))	('inhibition', 'Var', (104, 114))	('actin polymerization', 'CPA', (178, 198))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('actin polymerization', 'biological_process', 'GO:0030041', ('178', '198'))
7170	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))	('PKC', 'molecular_function', 'GO:0004697', ('30', '33'))	('HSD', 'Disease', 'OMIM:143095', (168, 171))	('PKC-zeta', 'Gene', '5590', (30, 38))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
7172	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))	('gene silencing', 'biological_process', 'GO:0016458', ('120', '134'))	('PRKCZ', 'Gene', '5590', (114, 119))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (10, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('F-actin', 'cellular_component', 'GO:0031941', ('138', '145'))	('gene', 'Var', (120, 124))
7173	30675210	The silencing of PRKCZ caused the reorganization of F-actin around the cell cytoskeleton (Fig.	('PRKCZ', 'Gene', (17, 22))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('76', '88'))	('PRKCZ', 'Gene', '5590', (17, 22))	('F-actin', 'Protein', (52, 59))	('F-actin', 'cellular_component', 'GO:0031941', ('52', '59'))	('silencing', 'Var', (4, 13))	('reorganization', 'Reg', (34, 48))
7176	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))	('Zonula occludens', 'cellular_component', 'GO:0005923', ('156', '172'))	('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))	('PKC', 'molecular_function', 'GO:0004697', ('53', '56'))	('PKC-zeta', 'Gene', '5590', (53, 61))	('Zonula occludens-1', 'Gene', '7082', (156, 174))	('cadherin', 'molecular_function', 'GO:0008014', ('188', '196'))	('epithelial', 'MPA', (129, 139))	('ZO-1', 'Gene', (176, 180))	('Zonula occludens-1', 'Gene', (156, 174))	('reduced', 'NegReg', (62, 69))
7186	30675210	However, previous studies illustrated an increase in E-cadherin levels in PKC-zeta knockdown MDA-MB-231 cells.	('increase', 'PosReg', (41, 49))	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('PKC-zeta', 'Gene', '5590', (74, 82))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (93, 103))	('PKC', 'molecular_function', 'GO:0004697', ('74', '77'))	('cadherin', 'molecular_function', 'GO:0008014', ('55', '63'))	('knockdown', 'Var', (83, 92))	('PKC-zeta', 'Gene', (74, 82))
7199	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))	('PKC', 'molecular_function', 'GO:0004697', ('31', '34'))	('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))
7279	31263747	ILC with a poor outcome as predicted by LobSig were enriched with mutations in ERBB2, ERBB3, TP53, AKT1 and ROS1.	('mutations', 'Var', (66, 75))	('AKT1', 'Gene', (99, 103))	('ERBB3', 'Gene', '2065', (86, 91))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('ERBB2', 'Gene', (79, 84))	('ERBB3', 'Gene', (86, 91))	('ERBB2', 'Gene', '2064', (79, 84))	('ROS1', 'Gene', (108, 112))	('ILC', 'Disease', (0, 3))	('ROS1', 'Gene', '6098', (108, 112))	('AKT1', 'Gene', '207', (99, 103))
7287	31263747	CDH1 gene mutation, deletion and/or methylation account for the absence of functional E-cadherin complex, contributing to the lack of cellular cohesion and resulting invasive growth pattern.	('absence', 'NegReg', (64, 71))	('invasive growth', 'biological_process', 'GO:0007125', ('166', '181'))	('invasive growth', 'biological_process', 'GO:0036267', ('166', '181'))	('mutation', 'Var', (10, 18))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('cadherin', 'molecular_function', 'GO:0008014', ('88', '96'))	('growth pattern', 'biological_process', 'GO:0007150', ('175', '189'))	('invasive growth', 'biological_process', 'GO:0044409', ('166', '181'))	('deletion', 'Var', (20, 28))	('lack', 'NegReg', (126, 130))	('invasive growth', 'biological_process', 'GO:0001404', ('166', '181'))	('CDH1', 'Gene', '999', (0, 4))	('invasive growth', 'biological_process', 'GO:0044412', ('166', '181'))	('cellular cohesion', 'CPA', (134, 151))	('growth pattern', 'biological_process', 'GO:0040007', ('175', '189'))	('invasive growth', 'biological_process', 'GO:0051831', ('166', '181'))	('invasive growth pattern', 'CPA', (166, 189))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))	('CDH1', 'Gene', (0, 4))
7290	31263747	The genomic profile of ILC has been explored in some depth, revealing that these tumors are more likely to be diploid than IC-NST, and harbor recurrent gains of chromosome 1q, 8q, 16p; deletions of 8p23-p21, 11q14.1-q25, and 16q; and complex, high-level amplifications at 1q32, 8p12, and 11q13.	('gains', 'PosReg', (152, 157))	('p21', 'Gene', (203, 206))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('deletions', 'Var', (185, 194))	('p21', 'Gene', '644914', (203, 206))	('ILC', 'Disease', (23, 26))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('11q14.1-q25', 'Gene', (208, 219))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
7291	31263747	For instance, ILC are typified by CDH1 and PTEN loss, enhanced AKT activation, mutations in TBX3 and FOXA1, and amplification of ESR1.	('loss', 'NegReg', (48, 52))	('AKT', 'Gene', (63, 66))	('TBX3', 'Gene', '6926', (92, 96))	('activation', 'PosReg', (67, 77))	('FOXA1', 'Gene', '3169', (101, 106))	('TBX3', 'Gene', (92, 96))	('amplification', 'Var', (112, 125))	('ESR1', 'Gene', '2099', (129, 133))	('CDH1', 'Gene', '999', (34, 38))	('PTEN', 'Gene', (43, 47))	('FOXA1', 'Gene', (101, 106))	('PTEN', 'Gene', '5728', (43, 47))	('AKT', 'Gene', '207', (63, 66))	('ESR1', 'Gene', (129, 133))	('enhanced', 'PosReg', (54, 62))	('ILC', 'Disease', (14, 17))	('mutations', 'Var', (79, 88))	('CDH1', 'Gene', (34, 38))
7292	31263747	Of great interest is the enrichment for potentially actionable mutations in ERBB2 (HER2, 5.1%) and ERBB3 (HER3, 3.6%).	('mutations', 'Var', (63, 72))	('ERBB3', 'Gene', '2065', (99, 104))	('ERBB3', 'Gene', (99, 104))	('actionable', 'Reg', (52, 62))	('HER2', 'Gene', (83, 87))	('HER3', 'Gene', (106, 110))	('ERBB2', 'Gene', (76, 81))	('ERBB2', 'Gene', '2064', (76, 81))	('HER2', 'Gene', '2064', (83, 87))	('HER3', 'Gene', '2065', (106, 110))
7293	31263747	Indeed, HER2-negative ILC with high-grade features show an increased frequency of ERBB2 mutations (15%), especially the pleomorphic variant (26%), far higher than that reported for breast cancer generally (<=1%, TCGA), but with no significant impact on prognosis.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('ERBB2', 'Gene', '2064', (82, 87))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('HER2', 'Gene', (8, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('ILC', 'Disease', (22, 25))	('ERBB2', 'Gene', (82, 87))	('breast cancer', 'Disease', (181, 194))	('mutations', 'Var', (88, 97))	('HER2', 'Gene', '2064', (8, 12))
7294	31263747	ERBB2 mutation in CDH1-mutated patients shows a significantly worse outcome than control groups, and indeed in CDH1-mutated cancers that have relapsed, there is a high ERBB2 mutation rate.	('ERBB2', 'Gene', '2064', (0, 5))	('CDH1', 'Gene', (18, 22))	('mutation', 'Var', (174, 182))	('CDH1', 'Gene', (111, 115))	('mutation', 'Var', (6, 14))	('ERBB2', 'Gene', (0, 5))	('ERBB2', 'Gene', (168, 173))	('CDH1', 'Gene', '999', (18, 22))	('ERBB2', 'Gene', '2064', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (31, 39))	('CDH1', 'Gene', '999', (111, 115))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
7306	31263747	Previously defined recurrent alterations were identified in this pooled ILC cohort, with large chromosome level gains seen on 1q, 8q, 11q and 16p; and deletions on 1p, 6q, 8p23-p21, 11q14.1-q25, 13q, 16q and 22.	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('p21', 'Gene', (177, 180))	('gains', 'PosReg', (112, 117))	('deletions', 'Var', (151, 160))	('p21', 'Gene', '644914', (177, 180))	('chromosome', 'MPA', (95, 105))
7307	31263747	Recurrent, high-level amplifications were also identified 8p12-p11.2 (7%), 11q13.3 (12%) and 17q12 (2%; Fig.	('p11', 'Gene', (63, 66))	('p11', 'Gene', '6281', (63, 66))	('11q13.3', 'Var', (75, 82))
7310	31263747	Key prognostic regions of deletion as assessed by Logrank include 19p13.3 (P = 0.0031); 2q23.1 (P = 0.0034); 8p21.2 (P = 0.0036); 14q32.12 (P = 0.0192); and 1p21.2 (P = 0.0218) (Supplementary Fig.	('p21', 'Gene', '644914', (158, 161))	('deletion', 'Var', (26, 34))	('p21', 'Gene', (110, 113))	('p21', 'Gene', '644914', (110, 113))	('p21', 'Gene', (158, 161))
7311	31263747	A poorer prognosis is associated with the presence of amplifications in any of the following three regions, or combinations of, 11q13.3, 8p11.23, and 17q12 (P = 0.0383) (Supplementary Fig.	('p11', 'Gene', '6281', (138, 141))	('p11', 'Gene', (138, 141))	('17q12', 'Var', (150, 155))	('11q13.3', 'Var', (128, 135))	('amplifications', 'Var', (54, 68))
7312	31263747	Interestingly, of the nine ILC tumors with amplification at 8p12-11.2, three (33%) had co-amplification with 11q13-q14.1, as previously reported (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('ILC tumors', 'Disease', 'MESH:D009369', (27, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('ILC tumors', 'Disease', (27, 37))	('amplification at', 'Var', (43, 59))
7317	31263747	ILC cases from the METABRIC cohort, with both gene expression and clinical follow up data, were interrogated to determine if gene expression changes were associated with patient survival (n = 101; Supplementary Fig.	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('gene expression', 'biological_process', 'GO:0010467', ('125', '140'))	('changes', 'Var', (141, 148))	('associated', 'Reg', (154, 164))	('patient', 'Species', '9606', (170, 177))
7334	31263747	There was a significant enrichment of TP53 mutation in the LobSig high group, consistent with a poor outcome tumor type (Fig.	('mutation', 'Var', (43, 51))	('TP53', 'Gene', (38, 42))	('LobSig', 'Disease', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('TP53', 'Gene', '7157', (38, 42))
7335	31263747	This analysis showed LobSig high tumors were enriched for mutations in ERBB3 (P = 0.00007), ERBB2 (P = 0.0002), BIRC6 (P = 0.005), AKT1 mutations (P = 0.02), ROS1 (P < 0.01); amplifications of PRMT2 (P = 7.329e-08), S100B (P = 7.33e-08) and DIP2A (P = 7.99e-07; 21q22.3); and for deletions of CTCF (16q22.1; P = 8.41e-11), C17ORF39 (17p11.2; P = 4.597e-09) and ARID1A (1p36.11; P = 8.045e-06).	('mutations', 'Var', (58, 67))	('S100B', 'Gene', (216, 221))	('DIP2A', 'Gene', (241, 246))	('BIRC6', 'Gene', '57448', (112, 117))	('ARID1A', 'Gene', '8289', (361, 367))	('PRMT2', 'Gene', (193, 198))	('CTCF', 'Gene', '10664', (293, 297))	('C17ORF39', 'Gene', '79018', (323, 331))	('deletions', 'Var', (280, 289))	('C17ORF39', 'Gene', (323, 331))	('ROS1', 'Gene', (158, 162))	('p11', 'Gene', '6281', (335, 338))	('AKT1', 'Gene', '207', (131, 135))	('BIRC6', 'Gene', (112, 117))	('S100B', 'Gene', '6285', (216, 221))	('ERBB3', 'Gene', (71, 76))	('p11', 'Gene', (335, 338))	('ERBB2', 'Gene', (92, 97))	('CTCF', 'Gene', (293, 297))	('LobSig high tumors', 'Disease', (21, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('AKT1', 'Gene', (131, 135))	('DIP2A', 'Gene', '23181', (241, 246))	('ERBB2', 'Gene', '2064', (92, 97))	('ROS1', 'Gene', '6098', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('LobSig high tumors', 'Disease', 'MESH:D009369', (21, 39))	('PRMT2', 'Gene', '3275', (193, 198))	('ARID1A', 'Gene', (361, 367))	('ERBB3', 'Gene', '2065', (71, 76))
7348	31263747	LobSig high tumors were enriched for the Luminal B subtype, an expected finding independently confirming previous data that luminal B ILCs have a poorer outcome than luminal A ILC.	('LobSig high tumors', 'Disease', (0, 18))	('LobSig high tumors', 'Disease', 'MESH:D009369', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('luminal', 'Var', (124, 131))
7354	31263747	The signature captures a biology driven by the combination of multiple different genomic alterations (amplifications of 1q, 8p, 11q, 17q12; mutations in TP53, ERBB2/3; losses of 13q).	('ERBB2', 'Gene', '2064', (159, 164))	('TP53', 'Gene', (153, 157))	('TP53', 'Gene', '7157', (153, 157))	('mutations', 'Var', (140, 149))	('ERBB2', 'Gene', (159, 164))	('losses', 'Var', (168, 174))
7357	31263747	There was a notable prevalence of ERBB2 (20%), ERBB3 (14.28%), AKT1 (8.57%) and ROS1 (8.57%) mutations in the LobSig high group, raising exciting possibilities for applying targeted therapies in LobSig high tumors, with evidence emerging of the value of anti-HER2 therapies, AKT inhibitors and the recently described ROS1 inhibitors via synthetic lethal interaction with CDH1 mutant ILC.	('AKT', 'Gene', (63, 66))	('CDH1', 'Gene', '999', (371, 375))	('HER2', 'Gene', (259, 263))	('AKT1', 'Gene', (63, 67))	('mutant', 'Var', (376, 382))	('ERBB2', 'Gene', '2064', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('ROS1', 'Gene', (317, 321))	('CDH1', 'Gene', (371, 375))	('ROS1', 'Gene', (80, 84))	('AKT', 'Gene', (275, 278))	('AKT', 'Gene', '207', (63, 66))	('ERBB3', 'Gene', (47, 52))	('LobSig high tumors', 'Disease', (195, 213))	('mutations', 'Var', (93, 102))	('HER2', 'Gene', '2064', (259, 263))	('ROS1', 'Gene', '6098', (317, 321))	('AKT', 'Gene', '207', (275, 278))	('ROS1', 'Gene', '6098', (80, 84))	('AKT1', 'Gene', '207', (63, 67))	('LobSig high tumors', 'Disease', 'MESH:D009369', (195, 213))	('ERBB2', 'Gene', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('ERBB3', 'Gene', '2065', (47, 52))
7371	31263747	GAIN, LOSS, AMP (amplification), HOMD (homozygous deletion)) were predefined for METABRIC samples.	('LOSS', 'NegReg', (6, 10))	('GAIN', 'PosReg', (0, 4))	('AMP', 'Var', (12, 15))	('AMP', 'Chemical', '-', (12, 15))
7389	26730350	Because of this staging system, it is important to report an accurate measurement of primary tumor size since 1 mm variation in the measurement can lead to a change in T-stage classification, which in turn will alter the patient's treatment options.	('treatment options', 'CPA', (231, 248))	('change', 'Reg', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('alter', 'Reg', (211, 216))	('T-stage classification', 'CPA', (168, 190))	('tumor', 'Disease', (93, 98))	('variation', 'Var', (115, 124))	('patient', 'Species', '9606', (221, 228))	('lead to', 'Reg', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
7437	26730350	Our study demonstrated that micro-CT yields a slightly larger size than the pathological invasive tumor size in 37 cases out of 72 cases (51%).	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('micro-CT', 'Var', (28, 36))	('invasive tumor', 'Disease', 'MESH:D009369', (89, 103))	('invasive tumor', 'Disease', (89, 103))
7604	32782013	Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified.	('estrogen receptor', 'Gene', '2099', (82, 99))	('estrogen receptor alpha', 'Gene', '2099', (314, 337))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (227, 244))	('ERBB2', 'Gene', '2064', (11, 16))	('primary breast cancers', 'Disease', 'MESH:D001943', (274, 296))	('lobular breast carcinoma', 'Disease', (138, 162))	('breast carcinoma', 'Phenotype', 'HP:0003002', (146, 162))	('breast cancers', 'Phenotype', 'HP:0003002', (282, 296))	('mutation', 'Var', (17, 25))	('primary breast cancers', 'Disease', (274, 296))	('ERBB2', 'Gene', (357, 362))	('breast cancer', 'Phenotype', 'HP:0003002', (282, 295))	('ERBB2', 'Gene', (110, 115))	('estrogen receptor', 'Gene', (82, 99))	('estrogen receptor alpha', 'Gene', (314, 337))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('ERBB2', 'Gene', '2064', (357, 362))	('Invasive lobular carcinoma', 'Disease', 'MESH:D018275', (218, 244))	('ERBB2', 'Gene', '2064', (110, 115))	('Invasive lobular carcinoma', 'Disease', (218, 244))	('lobular breast carcinoma', 'Disease', 'MESH:D001943', (138, 162))	('ERBB2', 'Gene', (11, 16))	('estrogen receptor', 'Gene', '2099', (314, 331))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))
7606	32782013	We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets.	('ERBB2/3', 'Gene', (57, 64))	('ERBB2/3', 'Gene', '2064;2065', (57, 64))	('mutations', 'Var', (65, 74))
7610	32782013	Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in silico model of response to neratinib derived from breast cancer cell lines.	('ERBB2', 'Gene', (41, 46))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('mutation', 'Var', (47, 55))	('ERBB2', 'Gene', '2064', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('neratinib', 'Chemical', 'MESH:C487932', (168, 177))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
7612	32782013	Mutations in ERBB2 were enriched in ILC vs. IDC cases (5.7%, N = 16 vs. 1.4%, N = 18, p < 0.0001) and clustered in the tyrosine kinase domain of HER2.	('HER2', 'Gene', (145, 149))	('IDC', 'Gene', '4000', (44, 47))	('HER2', 'Gene', '2064', (145, 149))	('IDC', 'Gene', (44, 47))	('ILC', 'Disease', (36, 39))	('ERBB2', 'Gene', '2064', (13, 18))	('ERBB2', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))
7613	32782013	ERBB3 mutations were not enriched in ILC (1.1%, N = 3 vs. 1.8%, N = 23; p = 0.604).	('ILC', 'Disease', (37, 40))	('ERBB3', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('ERBB3', 'Gene', '2065', (0, 5))
7615	32782013	Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS:but only in ILC (hazard ratio, HR = 3.7, 95% CI 1.2-11.0; p = 0.021).	('OS', 'Disease', (83, 85))	('ERBB2', 'Gene', '2064', (11, 16))	('ERBB2', 'Gene', (11, 16))	('mutational status', 'Var', (17, 34))
7616	32782013	Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC = 2.3, 95% CI 1.04-5.05; p = 0.040).	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', '2064', (38, 43))	('mutation', 'Var', (44, 52))
7617	32782013	Targetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes.	('primary ILC', 'Disease', (43, 54))	('ERBB2', 'Gene', (11, 16))	('ERBB2', 'Gene', '2064', (11, 16))	('mutations', 'Var', (17, 26))	('patient', 'Species', '9606', (139, 146))
7625	32782013	Recent evidence indicates that in ERBB2 non-amplified breast cancer, somatic mutation of ERBB2 (ERBB2mut) and/or ERBB3 (ERBB3mut) may provide an alternative mechanism for upregulation of HER2 activity that is therapeutically tractable using second generation HER2 tyrosine kinase inhibitors such as neratinib.	('HER2', 'Gene', (187, 191))	('ERBB2mut', 'Gene', (96, 104))	('HER2', 'Gene', (259, 263))	('mutation', 'Var', (77, 85))	('ERBB2', 'Gene', (89, 94))	('ERBB2', 'Gene', '2064', (34, 39))	('ERBB2', 'Gene', (96, 101))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Disease', (54, 67))	('ERBB3', 'Gene', (120, 125))	('ERBB3', 'Gene', (113, 118))	('ERBB2', 'Gene', '2064', (89, 94))	('ERBB3mut', 'Gene', '2065', (120, 128))	('ERBB2', 'Gene', '2064', (96, 101))	('ERBB2mut', 'Gene', '2064', (96, 104))	('HER2', 'Gene', '2064', (187, 191))	('HER2', 'Gene', '2064', (259, 263))	('ERBB3mut', 'Gene', (120, 128))	('upregulation', 'PosReg', (171, 183))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ERBB3', 'Gene', '2065', (120, 125))	('ERBB3', 'Gene', '2065', (113, 118))	('ERBB2', 'Gene', (34, 39))	('neratinib', 'Chemical', 'MESH:C487932', (299, 308))	('activity', 'MPA', (192, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
7629	32782013	Mutations in ERBB2 cluster in the tyrosine kinase and extra-cellular domains of HER2 and exert their oncogenic effects by activating tyrosine kinase activity or increasing HER2 dimerization, respectively.	('activating', 'PosReg', (122, 132))	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('ERBB2', 'Gene', '2064', (13, 18))	('dimerization', 'MPA', (177, 189))	('tyrosine kinase activity', 'MPA', (133, 157))	('increasing', 'PosReg', (161, 171))	('Mutations', 'Var', (0, 9))	('ERBB2', 'Gene', (13, 18))	('kinase activity', 'molecular_function', 'GO:0016301', ('142', '157'))	('HER2', 'Gene', (172, 176))	('HER2', 'Gene', '2064', (172, 176))
7630	32782013	In vitro studies of HER2 activity in cell line and xenograft models identified 13 mutations (listed in the "Patients and methods" section) that enhanced proliferation and/or demonstrated growth inhibition with the irreversible HER2/EGFR tyrosine kinase inhibitor, neratinib.	('EGF', 'Gene', (232, 235))	('HER2', 'Gene', '2064', (227, 231))	('growth inhibition', 'CPA', (187, 204))	('EGF', 'Gene', '1950', (232, 235))	('enhanced', 'PosReg', (144, 152))	('mutations', 'Var', (82, 91))	('proliferation', 'CPA', (153, 166))	('neratinib', 'Chemical', 'MESH:C487932', (264, 273))	('HER2', 'Gene', (20, 24))	('HER2', 'Gene', '2064', (20, 24))	('Patients', 'Species', '9606', (108, 116))	('HER2', 'Gene', (227, 231))
7631	32782013	Mutations in HER3, a critical binding partner for HER2, have been shown to promote ligand (EGF)-independent transformation of breast epithelial cells only in the presence of kinase-active HER2.	('EGF', 'molecular_function', 'GO:0005154', ('91', '94'))	('ligand', 'molecular_function', 'GO:0005488', ('83', '89'))	('EGF', 'Gene', (91, 94))	('promote', 'PosReg', (75, 82))	('HER2', 'Gene', (50, 54))	('HER2', 'Gene', (188, 192))	('HER2', 'Gene', '2064', (50, 54))	('HER2', 'Gene', '2064', (188, 192))	('EGF', 'Gene', '1950', (91, 94))	('binding', 'molecular_function', 'GO:0005488', ('30', '37'))	('Mutations', 'Var', (0, 9))	('HER3', 'Gene', (13, 17))	('HER3', 'Gene', '2065', (13, 17))
7632	32782013	This indicates that known oncogenic mutations in ERBB3, e.g., G284R and E928G, may also be therapeutically targetable via HER2 inhibition.	('G284R', 'Mutation', 'rs1057519803', (62, 67))	('G284R', 'Var', (62, 67))	('E928G', 'Var', (72, 77))	('ERBB3', 'Gene', '2065', (49, 54))	('E928G', 'Mutation', 'p.E928G', (72, 77))	('HER2', 'Gene', (122, 126))	('ERBB3', 'Gene', (49, 54))	('HER2', 'Gene', '2064', (122, 126))
7633	32782013	ERBB2 mutations have previously been linked with worse prognosis in CDH1-altered ILC: a study of ILC cases in the TCGA dataset (N = 169) found that ERBB2 mutations (N = 6) occurred exclusively in CDH1-altered tumors (N = 100).	('CDH1', 'Gene', '999', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('CDH1', 'Gene', '999', (196, 200))	('ERBB2', 'Gene', '2064', (0, 5))	('CDH1', 'Gene', (196, 200))	('ERBB2', 'Gene', (0, 5))	('CDH1-altered tumors', 'Disease', (196, 215))	('CDH1', 'Gene', (68, 72))	('ERBB2', 'Gene', '2064', (148, 153))	('CDH1-altered tumors', 'Disease', 'MESH:D004408', (196, 215))	('mutations', 'Var', (154, 163))	('ERBB2', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('occurred', 'Reg', (172, 180))
7636	32782013	A study of relapsed CDH1-mutated ILC found ERBB2mut in 18% of cases (N = 4 of 22), suggesting further acquisition of ERBB2 mutations in CDH1-altered ILC due to the selective pressure of treatment.	('CDH1', 'Gene', '999', (136, 140))	('ERBB2', 'Gene', '2064', (43, 48))	('mutations', 'Var', (123, 132))	('ERBB2', 'Gene', (43, 48))	('CDH1', 'Gene', '999', (20, 24))	('ERBB2', 'Gene', (117, 122))	('ERBB2', 'Gene', '2064', (117, 122))	('ERBB2mut', 'Gene', (43, 51))	('ERBB2mut', 'Gene', '2064', (43, 51))	('CDH1', 'Gene', (136, 140))	('CDH1', 'Gene', (20, 24))
7637	32782013	In the MA12 trial comprising 328 premenopausal patients with ER+ primary breast cancer of all histological subtypes, non-silent ERBB2 mutations occurred in 5.2% of patients (N = 17) and were adversely prognostic of OS (p = 0.0114).	('ERBB2', 'Gene', '2064', (128, 133))	('prognostic', 'Reg', (201, 211))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('patients', 'Species', '9606', (47, 55))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('mutations', 'Var', (134, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('patients', 'Species', '9606', (164, 172))	('ERBB2', 'Gene', (128, 133))
7639	32782013	An ILC-specific study of 630 cases of primary ILC found ERBB2 and ERBB3 mutations in 5.1 and 3.6% of tumors, respectively.	('mutations', 'Var', (72, 81))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('ERBB3', 'Gene', (66, 71))	('ERBB3', 'Gene', '2065', (66, 71))	('ERBB2', 'Gene', '2064', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('ERBB2', 'Gene', (56, 61))	('tumors', 'Disease', (101, 107))
7640	32782013	Comparison of cases of ER+, HER2- ILC from the same study (N = 371) with cases of ER+, HER2- IDC from TCGA (N = 338) indicated significant enrichment of both ERBB2 and ERBB3 mutations in ILC (4.3 and 3.5% in ILC vs. 1.5 and 0.6% in IDC).	('HER2', 'Gene', '2064', (28, 32))	('HER2', 'Gene', '2064', (87, 91))	('ILC', 'Disease', (187, 190))	('IDC', 'Gene', (232, 235))	('ERBB3', 'Gene', '2065', (168, 173))	('ERBB3', 'Gene', (168, 173))	('ILC', 'Disease', (208, 211))	('ERBB2', 'Gene', '2064', (158, 163))	('ERBB2', 'Gene', (158, 163))	('IDC', 'Gene', '4000', (93, 96))	('mutations', 'Var', (174, 183))	('IDC', 'Gene', '4000', (232, 235))	('HER2', 'Gene', (28, 32))	('HER2', 'Gene', (87, 91))	('IDC', 'Gene', (93, 96))
7641	32782013	The study reported limited statistical evidence of a time-dependent effect of ERBB2 mutational status associated with short-term breast cancer-specific survival.	('breast cancer', 'Disease', (129, 142))	('ERBB2', 'Gene', '2064', (78, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('associated', 'Reg', (102, 112))	('ERBB2', 'Gene', (78, 83))	('mutational status', 'Var', (84, 101))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
7644	32782013	We tested these hypotheses by mining a combined dataset of the three largest primary breast cancer series with data on tumor ERBB2 and ERBB3 mutational status, gene expression, clinicopathological features, and patient survival outcomes.	('tumor', 'Disease', (119, 124))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('mutational', 'Var', (141, 151))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('gene expression', 'biological_process', 'GO:0010467', ('160', '175'))	('ERBB3', 'Gene', (135, 140))	('ERBB3', 'Gene', '2065', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('ERBB2', 'Gene', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ERBB2', 'Gene', '2064', (125, 130))	('patient', 'Species', '9606', (211, 218))
7645	32782013	Our overall goal was to determine the association between targetable ERBB2/3 mutations and survival in primary ER+ ILC, and thereby provide evidence for a clinically actionable strategy to improve patient outcomes.	('association', 'Interaction', (38, 49))	('ERBB2/3', 'Gene', (69, 76))	('ERBB2/3', 'Gene', '2064;2065', (69, 76))	('mutations', 'Var', (77, 86))	('patient', 'Species', '9606', (197, 204))	('primary ER+ ILC', 'Disease', (103, 118))
7651	32782013	Variables included ERBB2 and ERBB3 mutational status.	('ERBB2', 'Gene', '2064', (19, 24))	('ERBB2', 'Gene', (19, 24))	('mutational status', 'Var', (35, 52))	('ERBB3', 'Gene', '2065', (29, 34))	('ERBB3', 'Gene', (29, 34))
7652	32782013	ERBB2mut status was subcategorized as oncogenic or uncharacterized by cross-reference with existing data that identified mutations targetable by HER2-inhibition: G309A/E, S310F, L755S, del755-759, S760A, D769H, D769Y, V777L, P780ins, V842I, and R896C.	('L755S', 'Mutation', 'rs121913470', (178, 183))	('HER2', 'Gene', '2064', (145, 149))	('D769H', 'Mutation', 'rs121913468', (204, 209))	('D769Y', 'Var', (211, 216))	('P780ins', 'Var', (225, 232))	('V842I', 'Mutation', 'rs1057519738', (234, 239))	('R896C', 'Mutation', 'rs758222990', (245, 250))	('V842I', 'Var', (234, 239))	('R896C', 'Var', (245, 250))	('G309A', 'SUBSTITUTION', 'None', (162, 167))	('D769Y', 'Mutation', 'rs121913468', (211, 216))	('G309A', 'Var', (162, 167))	('ERBB2mut', 'Gene', (0, 8))	('S310F', 'Var', (171, 176))	('P780ins', 'Mutation', 'p.780insP', (225, 232))	('S760A', 'Mutation', 'p.S760A', (197, 202))	('V777L', 'Mutation', 'rs121913471', (218, 223))	('HER2', 'Gene', (145, 149))	('D769H', 'Var', (204, 209))	('S760A', 'Var', (197, 202))	('V777L', 'Var', (218, 223))	('S310F', 'Mutation', 'rs1057519816', (171, 176))	('ERBB2mut', 'Gene', '2064', (0, 8))	('L755S', 'Var', (178, 183))	('del755-759', 'Var', (185, 195))	('del755-759', 'Mutation', 'c.755_759del', (185, 195))
7653	32782013	Cases were denominated oncERBB2mut if tumors harbored at least one oncogenic ERBB2 mutation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('ERBB2', 'Gene', '2064', (77, 82))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', (77, 82))	('ERBB2', 'Gene', '2064', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mutation', 'Var', (83, 91))	('ERBB2mut', 'Gene', (26, 34))	('ERBB2mut', 'Gene', '2064', (26, 34))
7655	32782013	Enrichment for cases with mutations in candidate genes (ERBB2/3mut) by histological subtype (ILC vs. IDC) was determined by chi2 test for association between categorical variables.	('IDC', 'Gene', (101, 104))	('ERBB2/3', 'Gene', (56, 63))	('mutations', 'Var', (26, 35))	('ERBB2/3', 'Gene', '2064;2065', (56, 63))	('IDC', 'Gene', '4000', (101, 104))
7680	32782013	In IDC, all kinase domain mutations were known oncogenic (N = 8) and non-characterized mutations were distributed evenly across protein domains (see Fig.	('mutations', 'Var', (26, 35))	('IDC', 'Gene', '4000', (3, 6))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('IDC', 'Gene', (3, 6))
7681	32782013	The most frequently occurring ERBB3mut coded for E928G, which lies in the tyrosine kinase domain of HER3 (N = 7 out of 26; 27%).	('HER3', 'Gene', '2065', (100, 104))	('E928G', 'Var', (49, 54))	('ERBB3mut', 'Gene', (30, 38))	('E928G', 'Mutation', 'p.E928G', (49, 54))	('ERBB3mut', 'Gene', '2065', (30, 38))	('HER3', 'Gene', (100, 104))
7688	32782013	To test the effect of therapeutically actionable ERBB2 mutations on a clinically relevant endpoint, we stratified 10-year OS by oncERBB2mut status.	('mutations', 'Var', (55, 64))	('ERBB2mut', 'Gene', (131, 139))	('ERBB2mut', 'Gene', '2064', (131, 139))	('ERBB2', 'Gene', (49, 54))	('ERBB2', 'Gene', '2064', (49, 54))	('ERBB2', 'Gene', (131, 136))	('ERBB2', 'Gene', '2064', (131, 136))
7690	32782013	Unselected ERBB2mut status (including oncogenic and uncharacterized mutations) was also adversely prognostic of 10-year OS in univariate analysis (HR 3.66, 95% CI 1.54-8.73; p = 0.003), but in contrast to characterized oncERBB2mut, this prognostic effect was not independent of LN stage, tumor grade, and/or size.	('tumor', 'Disease', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('ERBB2mut', 'Gene', (11, 19))	('ERBB2mut', 'Gene', '2064', (11, 19))	('mutations', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('ERBB2mut', 'Gene', '2064', (222, 230))	('ERBB2mut', 'Gene', (222, 230))
7693	32782013	Our aim was to establish a novel signature that reflects HER2 pathway activity more completely than existing signatures, whether induced by ERBB2 mutations or amplifications, and to be able to apply it in a wider range of patients.	('mutations', 'Var', (146, 155))	('ERBB2', 'Gene', '2064', (140, 145))	('HER2', 'Gene', (57, 61))	('patients', 'Species', '9606', (222, 230))	('ERBB2', 'Gene', (140, 145))	('HER2', 'Gene', '2064', (57, 61))
7694	32782013	A list of up and downregulated ERBB2 "mutant" DEGs (N = 20) was generated by combining the overlap between DEGs for METABRIC ERBB2 amplified vs. non-amplified, ERBB2 mutated vs. wild-type (ERBB2mut and oncERBB2mut separately), and TCGA HER2+ vs. HER2- (Fig.	('ERBB2mut', 'Gene', '2064', (189, 197))	('mutated', 'Var', (166, 173))	('HER2', 'Gene', (236, 240))	('DEGs', 'Gene', (46, 50))	('ERBB2', 'Gene', (160, 165))	('ERBB2mut', 'Gene', (205, 213))	('ERBB2', 'Gene', (189, 194))	('HER2', 'Gene', '2064', (246, 250))	('ERBB2', 'Gene', (125, 130))	('ERBB2', 'Gene', (31, 36))	('DEGs', 'Gene', '8560', (46, 50))	('ERBB2', 'Gene', (205, 210))	('ERBB2', 'Gene', '2064', (160, 165))	('ERBB2mut', 'Gene', (189, 197))	('DEGs', 'Gene', (107, 111))	('ERBB2', 'Gene', '2064', (189, 194))	('HER2', 'Gene', '2064', (236, 240))	('ERBB2', 'Gene', '2064', (31, 36))	('ERBB2', 'Gene', '2064', (125, 130))	('ERBB2', 'Gene', '2064', (205, 210))	('ERBB2mut', 'Gene', '2064', (205, 213))	('HER2', 'Gene', (246, 250))	('DEGs', 'Gene', '8560', (107, 111))
7700	32782013	This suggests that a gene signature may have value in predicting targetable ERBB2 alterations including ERBB2mut in HER2- breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('ERBB2', 'Gene', (76, 81))	('breast cancer', 'Disease', (122, 135))	('ERBB2mut', 'Gene', '2064', (104, 112))	('ERBB2', 'Gene', '2064', (76, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('ERBB2mut', 'Gene', (104, 112))	('HER2', 'Gene', (116, 120))	('alterations', 'Var', (82, 93))	('HER2', 'Gene', '2064', (116, 120))	('ERBB2', 'Gene', '2064', (104, 109))	('ERBB2', 'Gene', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
7704	32782013	In this study, we mined clinical and NGS data from the largest clinical cohorts with data in the public domain to test whether there was an ILC-specific association of ERBB2 mutations with OS.	('mutations', 'Var', (174, 183))	('association', 'Interaction', (153, 164))	('ERBB2', 'Gene', (168, 173))	('ERBB2', 'Gene', '2064', (168, 173))
7705	32782013	In our meta-cohort of ER+, ERBB2 non-amplified cases of ILC and IDC, we found that ERBB2 mutations are enriched ILC, cluster in the functional kinase domain of HER2, and robustly associate with adverse clinical outcomes:independently of known prognostic clinicopathological features including LN status and tumor grade.	('associate with', 'Reg', (179, 193))	('HER2', 'Gene', (160, 164))	('IDC', 'Gene', '4000', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('HER2', 'Gene', '2064', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('IDC', 'Gene', (64, 67))	('ILC', 'Disease', (112, 115))	('ERBB2', 'Gene', (83, 88))	('tumor', 'Disease', (307, 312))	('ERBB2', 'Gene', '2064', (27, 32))	('ERBB2', 'Gene', '2064', (83, 88))	('mutations', 'Var', (89, 98))	('ERBB2', 'Gene', (27, 32))
7708	32782013	Hazard proportionality in the study by Desmedt et al 2016 suggested that ERBB2 mutational status had a time-dependent effect associated with short-term risk of breast cancer relapse.	('associated', 'Reg', (125, 135))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ERBB2', 'Gene', (73, 78))	('breast cancer', 'Disease', (160, 173))	('ERBB2', 'Gene', '2064', (73, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('mutational status', 'Var', (79, 96))
7709	32782013	The current study adds data on the prognostic effect of specific ERBB2 mutations that were previously shown in cell line, in vitro and xenograft studies to respond to existing clinical compounds such as trastuzumab or neratinib.	('neratinib', 'Chemical', 'MESH:C487932', (218, 227))	('trastuzumab', 'Chemical', 'MESH:D000068878', (203, 214))	('ERBB2', 'Gene', (65, 70))	('ERBB2', 'Gene', '2064', (65, 70))	('mutations', 'Var', (71, 80))
7710	32782013	We demonstrated that the status of these therapeutically targetable ERBB2 mutations is an independent adverse prognostic marker of overall survival in a large cohort of patients with ILC.	('ILC', 'Disease', (183, 186))	('patients', 'Species', '9606', (169, 177))	('ERBB2', 'Gene', '2064', (68, 73))	('mutations', 'Var', (74, 83))	('ERBB2', 'Gene', (68, 73))
7711	32782013	Findings from the current study imply that targeted sequencing of ILC tumors for ERBB2 mutations may be an actionable and viable strategy to improve outcomes for patients with primary ILC by providing a biomarker for HER2-targeted therapy in the adjuvant setting.	('patients', 'Species', '9606', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ERBB2', 'Gene', (81, 86))	('ERBB2', 'Gene', '2064', (81, 86))	('ILC tumors', 'Disease', 'MESH:D009369', (66, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('improve', 'PosReg', (141, 148))	('ILC tumors', 'Disease', (66, 76))	('HER2', 'Gene', (217, 221))	('primary ILC', 'Disease', (176, 187))	('mutations', 'Var', (87, 96))	('HER2', 'Gene', '2064', (217, 221))
7718	32782013	In the current cohort of primary ER+, HER2- ILC and IDC, ERBB2 mutations in ILC tumors clustered almost exclusively in the active HER2 tyrosine kinase domain (N = 15 of 16).	('mutations', 'Var', (63, 72))	('IDC', 'Gene', (52, 55))	('ERBB2', 'Gene', '2064', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ERBB2', 'Gene', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('HER2', 'Gene', (130, 134))	('ILC tumors', 'Disease', 'MESH:D009369', (76, 86))	('ILC tumors', 'Disease', (76, 86))	('IDC', 'Gene', '4000', (52, 55))	('HER2', 'Gene', '2064', (130, 134))	('HER2', 'Gene', (38, 42))	('HER2', 'Gene', '2064', (38, 42))
7719	32782013	Our retrospective clinical outcome data indicates an ILC-specific adverse survival association for patients with ERBB2 non-amplified tumors harboring potentially targetable ERBB2 mutations.	('ERBB2', 'Gene', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('non-amplified', 'Var', (119, 132))	('ERBB2', 'Gene', (113, 118))	('ERBB2', 'Gene', '2064', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (179, 188))	('ERBB2', 'Gene', '2064', (173, 178))	('adverse', 'NegReg', (66, 73))
7722	32782013	Taken together, these new findings suggest that focusing early phase studies of HER2-inhibition (e.g., with neratinib) in patients with ERBB2 non-amplified, ERBB2mut primary ILC may be an effective strategy to demonstrate feasibility and clinical benefit in the (neo) adjuvant setting.	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('ERBB2', 'Gene', '2064', (136, 141))	('ERBB2', 'Gene', (157, 162))	('ERBB2', 'Gene', '2064', (157, 162))	('ERBB2', 'Gene', (136, 141))	('non-amplified', 'Var', (142, 155))	('patients', 'Species', '9606', (122, 130))	('neratinib', 'Chemical', 'MESH:C487932', (108, 117))	('ERBB2mut', 'Gene', (157, 165))	('ERBB2mut', 'Gene', '2064', (157, 165))
7726	32782013	However, in IDC there was enrichment of the known oncogenic HER3 kinase domain mutation, E928G.	('E928G', 'Mutation', 'p.E928G', (89, 94))	('IDC', 'Gene', (12, 15))	('HER3', 'Gene', (60, 64))	('HER3', 'Gene', '2065', (60, 64))	('IDC', 'Gene', '4000', (12, 15))	('E928G', 'Var', (89, 94))
7727	32782013	To demonstrate the prognostic effect of mutations affecting HER3, larger datasets will be required.	('HER3', 'Gene', (60, 64))	('mutations', 'Var', (40, 49))	('HER3', 'Gene', '2065', (60, 64))
7730	32782013	This implies an underestimation of the adverse impact of ERBB2 mutations on 10-year survival outcomes in the current study.	('mutations', 'Var', (63, 72))	('ERBB2', 'Gene', (57, 62))	('ERBB2', 'Gene', '2064', (57, 62))
7731	32782013	Since the METABRIC dataset did not have complete HER2 IHC or reverse-phase protein array data, it was not possible to associate activating ERBB2mut directly with downstream HER2 protein expression.	('HER2', 'Gene', (173, 177))	('HER2', 'Gene', '2064', (173, 177))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('activating', 'Var', (128, 138))	('ERBB2mut', 'Gene', (139, 147))	('ERBB2mut', 'Gene', '2064', (139, 147))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (49, 53))
7733	32782013	Targetable kinase domain ERBB2 mutations are enriched in primary ILC and their detection by targeted sequencing or validated gene signature surrogate may provide an actionable strategy to improve patient outcomes.	('mutations', 'Var', (31, 40))	('patient', 'Species', '9606', (196, 203))	('ERBB2', 'Gene', '2064', (25, 30))	('ERBB2', 'Gene', (25, 30))	('primary ILC', 'Disease', (57, 68))
7734	32782013	Biomarker-led clinical trials of adjuvant HER2-targeted therapy to treat breast tumors with activating ERBB2 mutations are warranted in HER2- primary ILC.	('HER2', 'Gene', '2064', (42, 46))	('breast tumors', 'Disease', (73, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('ERBB2', 'Gene', (103, 108))	('HER2', 'Gene', (136, 140))	('ERBB2', 'Gene', '2064', (103, 108))	('breast tumors', 'Phenotype', 'HP:0100013', (73, 86))	('mutations', 'Var', (109, 118))	('HER2', 'Gene', '2064', (136, 140))	('HER2', 'Gene', (42, 46))	('breast tumors', 'Disease', 'MESH:D001943', (73, 86))	('activating', 'PosReg', (92, 102))
7735	32782013	CI Confidence interval DEG Differentially expressed gene EGF Epidermal growth factor ER Estrogen receptor alpha ERBB2/3mut ERBB2/3 mutant HER2/3 Human epidermal growth factor receptor 2/3 HR Hazard ratio IDC Invasive ductal carcinoma of the breast IHC Immunohistochemistry ILC Invasive lobular carcinoma of the breast ISH In situ hybridization KM Kaplan-Meier LN Lymph node NGS Next-generation sequencing oncERBB2mut Oncogenic ERBB2 mutant OS Overall survival RECIST Response evaluation criteria in solid tumors WAD Weighted average difference Supplementary information accompanies this paper at 10.1186/s13058-020-01324-4.	('ERBB2', 'Gene', (112, 117))	('EGF', 'Gene', (57, 60))	('ERBB2', 'Gene', '2064', (408, 413))	('Invasive ductal carcinoma of the breast', 'Disease', (208, 247))	('ERBB2', 'Gene', '2064', (123, 128))	('ERBB2mut', 'Gene', '2064', (408, 416))	('HER2', 'Gene', (138, 142))	('Invasive ductal carcinoma of the breast', 'Disease', 'MESH:D001943', (208, 247))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('151', '174'))	('ERBB2', 'Gene', '2064', (112, 117))	('Invasive lobular carcinoma of the breast', 'Disease', 'MESH:D001943', (277, 317))	('tumors', 'Phenotype', 'HP:0002664', (505, 511))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('Invasive lobular carcinoma of the breast', 'Disease', (277, 317))	('ERBB2/3', 'Gene', (112, 119))	('IDC', 'Gene', '4000', (204, 207))	('IDC', 'Gene', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (505, 510))	('ERBB2/3', 'Gene', '2064;2065', (123, 130))	('ERBB2', 'Gene', (427, 432))	('epidermal growth factor receptor 2', 'Gene', '2064', (151, 185))	('tumors', 'Disease', (505, 511))	('WAD', 'Disease', 'MESH:C536695', (512, 515))	('WAD', 'Disease', (512, 515))	('EGF', 'Gene', '1950', (57, 60))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (286, 303))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (224, 247))	('ERBB2mut', 'Gene', (408, 416))	('mutant', 'Var', (433, 439))	('Estrogen receptor', 'Gene', '2099', (88, 105))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('61', '84'))	('ERBB2', 'Gene', '2064', (427, 432))	('HER2', 'Gene', '2064', (138, 142))	('epidermal growth factor receptor 2', 'Gene', (151, 185))	('Estrogen receptor', 'Gene', (88, 105))	('EGF', 'molecular_function', 'GO:0005154', ('57', '60'))	('ERBB2', 'Gene', (408, 413))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (294, 317))	('tumors', 'Disease', 'MESH:D009369', (505, 511))	('ERBB2', 'Gene', (123, 128))	('Human', 'Species', '9606', (145, 150))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (217, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('ERBB2/3', 'Gene', (123, 130))	('ERBB2/3', 'Gene', '2064;2065', (112, 119))
7747	19591788	Classical cytogenetic methods have been used to detect such copy number changes in tumors, which have deepened our understanding of the genomic hallmarks of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('copy number changes', 'Var', (60, 79))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
7788	19591788	suggested that the second event in multistep carcinogenesis is usually chromosome loss, mitotic recombination, or partial chromosome deletion after oncogene amplifications and tumor suppressor gene mutations.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor suppressor', 'biological_process', 'GO:0051726', ('176', '192'))	('tumor', 'Disease', (176, 181))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('176', '192'))	('chromosome', 'cellular_component', 'GO:0005694', ('122', '132'))	('mitotic recombination', 'biological_process', 'GO:0006312', ('88', '109'))	('partial chromosome deletion', 'Var', (114, 141))	('chromosome loss', 'CPA', (71, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('mitotic recombination', 'CPA', (88, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('carcinogenesis', 'Disease', (45, 59))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
7790	19591788	Our finding that "normal" cells harbor such alterations suggests that the aberrations in question might be important in relation to tumor initiation and development and also be responsible for breast cancer relapse after surgery.	('breast cancer', 'Disease', (193, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('tumor initiation', 'Disease', 'MESH:D009369', (132, 148))	('responsible for', 'Reg', (177, 192))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor initiation', 'Disease', (132, 148))	('aberrations', 'Var', (74, 85))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))
7806	19591788	For breast cancers, amplification and/or overexpression of HER2/neu occurs in up to 30% of the cases and is associated with aggressive biological behavior that reduces relapse-free and survival time.	('HER2/neu', 'Gene', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancers', 'Phenotype', 'HP:0003002', (4, 18))	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (124, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancers', 'Disease', 'MESH:D001943', (4, 18))	('breast cancers', 'Disease', (4, 18))	('reduces', 'NegReg', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('HER2/neu', 'Gene', '2064', (59, 67))	('amplification', 'Var', (20, 33))	('overexpression', 'PosReg', (41, 55))
7814	19591788	ER-negative tumors are more aggressive than ER-positive tumors, and the loss of ERs in tumor cells is associated with poor prognosis and poor response to hormonal therapy.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ER', 'Gene', '2099', (80, 82))	('loss', 'Var', (72, 76))	('tumors', 'Disease', (56, 62))	('tumor', 'Disease', (12, 17))	('ER', 'Gene', '2099', (0, 2))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', (12, 18))	('ER', 'Gene', '2099', (44, 46))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('aggressive', 'CPA', (28, 38))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
7815	19591788	In previous studies, ER-negative tumors predominantly had amplifications in 17q12, whereas ER-positive tumors had amplifications in 8q, gains in 1q, and losses in 1p and 16q.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('amplifications', 'Var', (58, 72))	('losses', 'NegReg', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('ER', 'Gene', '2099', (91, 93))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('amplifications', 'Var', (114, 128))	('gains', 'PosReg', (136, 141))	('ER', 'Gene', '2099', (21, 23))	('tumors', 'Disease', (33, 39))	('17q12', 'Protein', (76, 81))
7858	19591788	Cy3-dCTP and Cy5-dCTP (Amersham Biosciences) were used for labeling of the tumor samples and reference DNA, respectively.	('Cy5-dCTP', 'Chemical', 'MESH:C544355', (13, 21))	('Cy5-dCTP', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Cy3-dCTP', 'Chemical', '-', (0, 8))	('tumor', 'Disease', (75, 80))
7868	12085259	In our two previously published groups (Trojani et al, 1987a,b) of patients (grouped together in the present study under the name 'study 1'-1987), nodal metastases detected by immunohistochemistry were associated with shorter metastasis-free probability (MFP) and overall survival probability (OSP) in the infiltrating ductal carcinoma node-negative group of patients (IDC, median follow-up: 10 years, Trojani et al, 1987a) but not in the infiltrating lobular carcinoma node-negative group of patients (ILC, median follow-up: 6.5 years, Trojani et al, 1987b).	('overall survival probability', 'CPA', (264, 292))	('ILC', 'Gene', (503, 506))	('immunohistochemistry', 'Var', (176, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (319, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('lobular carcinoma', 'Disease', 'MESH:D018275', (452, 469))	('carcinoma', 'Disease', (326, 335))	('carcinoma', 'Disease', (460, 469))	('nodal metastases', 'Disease', (147, 163))	('lobular carcinoma', 'Disease', (452, 469))	('shorter', 'NegReg', (218, 225))	('patients', 'Species', '9606', (67, 75))	('metastasis-free probability', 'CPA', (226, 253))	('carcinoma', 'Disease', 'MESH:D002277', (326, 335))	('carcinoma', 'Disease', 'MESH:D002277', (460, 469))	('patients', 'Species', '9606', (359, 367))	('ILC', 'Gene', '10850', (503, 506))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (452, 469))	('patients', 'Species', '9606', (493, 501))	('nodal metastases', 'Disease', 'MESH:D009362', (147, 163))	('OSP', 'Chemical', '-', (294, 297))
7896	12085259	Furthermore, as regards patients who received radiotherapy vs those who did not, it has been proved that radiotherapy decreases locoregional recurrences but has no influence on MFP or OSP in node-negative patients (Rutqvist et al, 1993).	('patients', 'Species', '9606', (205, 213))	('radiotherapy', 'Var', (105, 117))	('OSP', 'Chemical', '-', (184, 187))	('locoregional recurrences', 'CPA', (128, 152))	('decreases', 'NegReg', (118, 127))	('patients', 'Species', '9606', (24, 32))
7925	32839548	However, loss of E-cadherin does not preclude multicellular invasion and metastasis in invasive lobular carcinoma (ILC).	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (87, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('metastasis', 'CPA', (73, 83))	('E-cadherin', 'Protein', (17, 27))	('loss', 'Var', (9, 13))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (96, 113))	('multicellular invasion', 'CPA', (46, 68))	('invasive lobular carcinoma', 'Disease', (87, 113))
7931	32839548	Using molecular-targeted deregulation of E-cadherin expression in breast cancer cells, we tested whether weakening of cell-cell junctions drives invasion plasticity, including a transition from collective to single-cell migration.	('cell-cell junctions', 'Protein', (118, 137))	('deregulation', 'Var', (25, 37))	('collective', 'CPA', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('cell migration', 'biological_process', 'GO:0016477', ('215', '229'))	('invasion plasticity', 'CPA', (145, 164))	('breast cancer', 'Disease', (66, 79))	('weakening', 'NegReg', (105, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('E-cadherin', 'Protein', (41, 51))	('rat', 'Species', '10116', (223, 226))
7960	32839548	To further investigate the prediction that ECM confinement dictates collective migration of cells with negligible or fully absent cell-cell adhesion, we transiently downregulated adherens junction proteins in MCF-7-shCDH1 cells, including E-cadherin, N-cadherin, P-cadherin, alpha-catenin, beta-catenin and p120-catenin, and measured the migration mode in the collagen interface model (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('265', '273'))	('adherens junction proteins', 'Protein', (179, 205))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('130', '148'))	('alpha-catenin', 'Protein', (275, 288))	('rat', 'Species', '10116', (341, 344))	('collagen', 'molecular_function', 'GO:0005202', ('360', '368'))	('beta-catenin', 'Protein', (290, 302))	('cadherin', 'molecular_function', 'GO:0008014', ('241', '249'))	('P-cadherin', 'Protein', (263, 273))	('E-cadherin', 'Protein', (239, 249))	('adherens junction', 'cellular_component', 'GO:0005912', ('179', '196'))	('dictates', 'Reg', (59, 67))	('downregulated', 'NegReg', (165, 178))	('N-cadherin', 'Protein', (251, 261))	('p120-catenin', 'Var', (307, 319))	('MCF-7', 'CellLine', 'CVCL:0031', (209, 214))	('cadherin', 'molecular_function', 'GO:0008014', ('253', '261'))	('migration mode in the collagen interface model', 'CPA', (338, 384))	('measured', 'Reg', (325, 333))	('rat', 'Species', '10116', (82, 85))
7961	32839548	Co-repression of E-cadherin and beta-catenin or p120-catenin indeed enhanced individualization in low-density collagen, but collective sheets migrated when collagen density was high (Fig.	('enhanced', 'PosReg', (68, 76))	('beta-catenin', 'Protein', (32, 44))	('collagen', 'molecular_function', 'GO:0005202', ('110', '118'))	('individualization', 'CPA', (77, 94))	('E-cadherin', 'Protein', (17, 27))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('collagen', 'molecular_function', 'GO:0005202', ('156', '164'))	('collective sheets migrated', 'CPA', (124, 150))	('rat', 'Species', '10116', (145, 148))	('p120-catenin', 'Var', (48, 60))
7966	32839548	We aimed to confirm that adherens junctions and extracellular confinement jointly define the stepwise fluidization of collective migration in 3D ECM culture and tracked CDH1high and CDH1low 4T1 cells emigrating from spheroids maintained in the interface assay (Fig.	('CDH1low 4T1', 'Var', (182, 193))	('rat', 'Species', '10116', (132, 135))	('CDH1high', 'Var', (169, 177))	('extracellular', 'cellular_component', 'GO:0005576', ('48', '61'))	('rat', 'Species', '10116', (204, 207))	('collective migration', 'CPA', (118, 138))
8003	32839548	7630) and human lung fibroblasts MRC-5 (CCL-171, ATCC) were maintained in DMEM supplemented with 10% fetal bovine serum (Sigma-Aldrich), penicillin (100 U ml-1, PAA), streptomycin (100 mug ml-1, PAA), 1 mM sodium pyruvate and 1 mM l-glutamine (both from ThermoFisher).	('l-glutamine', 'Chemical', 'MESH:D005973', (231, 242))	('human', 'Species', '9606', (10, 15))	('sodium pyruvate', 'Chemical', '-', (206, 221))	('CCL', 'molecular_function', 'GO:0044101', ('40', '43'))	('MRC-5', 'CellLine', 'CVCL:0440', (33, 38))	('bovine', 'Species', '9913', (107, 113))	('penicillin', 'Chemical', 'MESH:D010406', (137, 147))	('DMEM', 'Chemical', '-', (74, 78))	('PAA', 'cellular_component', 'GO:1990295', ('161', '164'))	('streptomycin', 'Chemical', 'MESH:D013307', (167, 179))	('mug', 'molecular_function', 'GO:0043739', ('185', '188'))	('ml-1', 'Gene', (189, 193))	('100', 'Var', (181, 184))	('ml-1', 'Gene', '112744', (189, 193))	('CCL', 'Chemical', 'MESH:D002433', (40, 43))	('ml-1', 'Gene', (155, 159))	('PAA', 'cellular_component', 'GO:1990295', ('195', '198'))	('ml-1', 'Gene', '112744', (155, 159))
8005	32839548	4T1 cells (CRL-2539, ATCC) were grown in RPMI media (ThermoFisher) supplemented with 10% fetal bovine serum (Sigma-Aldrich), penicillin (100 U ml-1, PAA) and streptomycin (100 mug ml-1, PAA), 1 mM sodium pyruvate and 1 mM l-glutamine (both from ThermoFisher Scientific).	('PAA', 'cellular_component', 'GO:1990295', ('186', '189'))	('l-glutamine', 'Chemical', 'MESH:D005973', (222, 233))	('ml-1', 'Gene', (143, 147))	('penicillin', 'Chemical', 'MESH:D010406', (125, 135))	('ml-1', 'Gene', '112744', (143, 147))	('RPMI media', 'Chemical', '-', (41, 51))	('PAA', 'cellular_component', 'GO:1990295', ('149', '152'))	('mug', 'molecular_function', 'GO:0043739', ('176', '179'))	('sodium pyruvate', 'Chemical', '-', (197, 212))	('100', 'Var', (172, 175))	('ml-1', 'Gene', (180, 184))	('streptomycin', 'Chemical', 'MESH:D013307', (158, 170))	('ml-1', 'Gene', '112744', (180, 184))	('bovine', 'Species', '9913', (95, 101))
8017	32839548	MCF-7 cells were transfected with pSUPER-Ecadherin-shRNA (MCF-7-shCDH1) or pSUPER-Control-shRNA (MCF-7-shNT) using Lipofectamine RNAiMAX (ThermoFisher) and stable clones were selected using G418 to stably knock down E-cadherin, as described.	('E-cadherin', 'Protein', (216, 226))	('cadherin', 'molecular_function', 'GO:0008014', ('218', '226'))	('knock', 'Var', (205, 210))	('MCF-7', 'CellLine', 'CVCL:0031', (0, 5))	('MCF-7', 'CellLine', 'CVCL:0031', (58, 63))	('MCF-7', 'CellLine', 'CVCL:0031', (97, 102))
8049	32839548	Intravital imaging was performed on a customized upright TrimScope II multiphoton microscope (LaVision BioTec, Miltenyi Biotec) equipped with three tunable Ti:Sa lasers (Coherent, Ultra I and II) and an Optical Parametric Oscillator (Coherent/APE) using a x20 Olympus XLUMPlanFI x20/0.95 NA water-immersion objective with a custom-made objective heater (37  C) and up to 5 photomultipliers (Hamamatsu, Alkali H6780-01, H6780-20 or GaAsP H7422A-40) with the following filter configuration: 395/11 nm (third harmonic generation), 447/60 nm (DAPI), 525/50 nm (eGFP), 593/11 nm (second harmonic generation), 593/40 nm or 620/60 nm (mCherry); 675/67 nm (Alexa Fluor 647) (Semrock or Chroma Technology).	('H7422A', 'Var', (437, 443))	('water', 'Chemical', 'MESH:D014867', (291, 296))	('rat', 'Species', '10116', (595, 598))	('TrimScope II multiphoton', 'Disease', 'MESH:C537730', (57, 81))	('TrimScope II multiphoton', 'Disease', (57, 81))	('H6780-01', 'CellLine', 'CVCL:2220', (409, 417))	('H7422A', 'SUBSTITUTION', 'None', (437, 443))	('rat', 'Species', '10116', (481, 484))	('DAPI', 'Chemical', 'MESH:C007293', (539, 543))	('rat', 'Species', '10116', (519, 522))
8223	32164210	Since both, metastatic invasive lobular carcinoma of the breast and primary endometrial carcinoma demonstrate positivity for ER and PR, immunostaining for hormone receptors is not helpful in distinguishing tumors of metastatic mammary origin from those of primary endometrial origin.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('invasive lobular carcinoma of the breast and primary endometrial carcinoma', 'Disease', 'MESH:D001943', (23, 97))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (32, 49))	('ER', 'Gene', '2099', (125, 127))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('PR', 'Gene', '5241', (132, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('positivity', 'Var', (110, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (76, 97))
8292	31139180	In this model, the effect was mediated by NK cells, as depletion via anti-asialo GM1 resulted in complete abrogation of chemerin's tumor suppressive effects.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('abrogation', 'NegReg', (106, 116))	('depletion', 'MPA', (55, 64))	('anti-asialo', 'Var', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('GM1', 'Gene', '210582', (81, 84))	('GM1', 'Gene', (81, 84))	('chemerin', 'Protein', (120, 128))
8334	31139180	For CD4+, CD8+ T cell depletion, mice were injected i.p.	('CD8', 'Gene', '925', (10, 13))	('CD8', 'Gene', (10, 13))	('mice', 'Species', '10090', (33, 37))	('CD4+', 'Var', (4, 8))
8335	31139180	with 250 mug/500 mul PBS of anti-CD4 (clone GK1.5, BioXCell), anti-CD8beta (Lyt 3.2) (clone 53-5.8, BioXCell) or both, and rat IgG (Sigma) for control.	('mug', 'molecular_function', 'GO:0043739', ('9', '12'))	('CD8beta', 'Gene', (67, 74))	('CD8beta', 'Gene', '12526', (67, 74))	('PBS', 'Chemical', 'MESH:D007854', (21, 24))	('rat', 'Species', '10116', (123, 126))	('anti-CD4', 'Var', (28, 36))
8336	31139180	Depletion efficiency was determined by staining blood cells collected via retro-orbital bleed with CD45, CD3, CD4, and CD8 antibodies (Biolegend) and analyzed by FACS.	('FACS', 'Gene', (162, 166))	('CD8', 'Gene', (119, 122))	('CD4', 'Gene', (110, 113))	('FACS', 'Gene', '14081', (162, 166))	('CD8', 'Gene', '925', (119, 122))	('CD45', 'Var', (99, 103))	('Depletion', 'MPA', (0, 9))	('CD3', 'Gene', (105, 108))	('CD3', 'Gene', '28134', (105, 108))
8370	31139180	Subsequently, to examine the association between reduced RARRES2 expression and patient survival outcome, we analyzed two sets of mRNA microarray data with cohort sizes of 33 breast cancer patients and 135 early-stage breast cancer patients, respectively, and found that low chemerin levels significantly correlated with poor survival outcomes in both groups (Figures 1C,D).	('breast cancer', 'Disease', (218, 231))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('reduced', 'NegReg', (49, 56))	('RARRES2', 'Gene', (57, 64))	('patients', 'Species', '9606', (232, 240))	('chemerin levels', 'MPA', (275, 290))	('breast cancer', 'Disease', (175, 188))	('patient', 'Species', '9606', (189, 196))	('low', 'Var', (271, 274))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('patients', 'Species', '9606', (189, 197))	('patient', 'Species', '9606', (232, 239))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('patient', 'Species', '9606', (80, 87))
8406	31139180	Taken together, these data show high-chemerin expression within the EMT6 TME results in significant tumor growth suppression and a favorable anti-tumor skewing of both NK cells and T cells, as a percentage of total TIL.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (100, 105))	('EMT', 'biological_process', 'GO:0001837', ('68', '71'))	('tumor growth suppression', 'Disease', 'MESH:D006130', (100, 124))	('tumor', 'Disease', (146, 151))	('EMT6', 'Gene', (68, 72))	('high-chemerin expression', 'Var', (32, 56))	('tumor growth suppression', 'Disease', (100, 124))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
8410	31139180	Control and chemerin-expressing lines were inoculated into mice treated with control sera or anti-asialo GM1 (Wako Chemicals) sera.	('mice', 'Species', '10090', (59, 63))	('anti-asialo', 'Var', (93, 104))	('sera', 'molecular_function', 'GO:0004617', ('126', '130'))	('GM1', 'Gene', (105, 108))	('sera', 'molecular_function', 'GO:0004617', ('85', '89'))	('GM1', 'Gene', '210582', (105, 108))
8420	31139180	Interestingly, CD4+ T cell depletion alone in chemerin-expressing tumors resulted in improved tumor growth suppression (Figure 5D).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CD4+ T', 'Var', (15, 21))	('improved', 'PosReg', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor growth suppression', 'Disease', 'MESH:D006130', (94, 118))	('tumor growth suppression', 'Disease', (94, 118))
8421	31139180	Recently published data show that CD4+ T cell depletion in the EMT6 model results in a significant increase in CD45+ TIL, with a ~3-fold increase in IFNgamma+CD8+ T cells in the draining lymph nodes compared to controls.	('CD4+ T', 'Var', (34, 40))	('CD45+ TIL', 'MPA', (111, 120))	('increase', 'PosReg', (137, 145))	('IFNgamma+CD8', 'Gene', (149, 161))	('IFNgamma+CD8', 'Gene', '15978', (149, 161))	('increase', 'PosReg', (99, 107))	('EMT', 'biological_process', 'GO:0001837', ('63', '66'))
8426	31139180	Our group was the first to show tumor suppression via therapeutic modulation of chemerin in a mouse tumor model, with now several studies confirming the role of chemerin as a tumor suppressor in various settings.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (175, 180))	('modulation', 'Var', (66, 76))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'biological_process', 'GO:0051726', ('175', '191'))	('mouse', 'Species', '10090', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('175', '191'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
8431	31139180	Breast cancer subtypes with high TILs may also show higher expression of checkpoint molecules such as PD-1 and CTLA-4, which may play a role in higher response rates to checkpoint inhibitors in these tumor subtypes (e.g., ER/PR-HER2-, HER2+).	('HER2', 'Gene', (228, 232))	('rat', 'Species', '10116', (160, 163))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('HER2', 'Gene', (235, 239))	('expression', 'MPA', (59, 69))	('tumor', 'Disease', (200, 205))	('higher', 'PosReg', (52, 58))	('HER2', 'Gene', '13866', (235, 239))	('HER2', 'Gene', '13866', (228, 232))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('CTLA-4', 'Gene', (111, 117))	('TILs', 'Var', (33, 37))	('PD-1', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('higher', 'PosReg', (144, 150))	('Breast cancer', 'Disease', (0, 13))	('CTLA-4', 'Gene', '12477', (111, 117))
8466	28850621	The risk of recurrence and indication to administer chemotherapy is largely dependent on the classical clinic-pathological prognostic factors of tumour size, involvement of lymph nodes, histologic grade, expression of hormone receptors, and human epidermal growth factor receptor 2 (HER2) amplification.	('amplification', 'Var', (289, 302))	('tumour', 'Disease', (145, 151))	('HER2', 'Gene', (283, 287))	('human epidermal growth factor receptor 2', 'Gene', (241, 281))	('HER2', 'Gene', '2064', (283, 287))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('human epidermal growth factor receptor 2', 'Gene', '2064', (241, 281))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('247', '270'))
8548	28850621	The genes analysed are related to various characteristics of cancer cells including self-sufficiency in growth signals, insensitivity to anti-growth signals, deregulation of apoptosis, limitless replication, tissue invasion and metastasis, and sustained angiogenesis.	('limitless replication', 'CPA', (185, 206))	('deregulation', 'Var', (158, 170))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('metastasis', 'CPA', (228, 238))	('cancer', 'Disease', (61, 67))	('apoptosis', 'CPA', (174, 183))	('tissue invasion', 'biological_process', 'GO:0001404', ('208', '223'))	('angiogenesis', 'biological_process', 'GO:0001525', ('254', '266'))	('self-sufficiency', 'Disease', 'MESH:D012652', (84, 100))	('self-sufficiency', 'Disease', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tissue invasion', 'CPA', (208, 223))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (89, 110))
8598	24137245	Tests showed ER 80%, PR 70%, CerbB-2 (-) and Ki-67 (-).	('Ki-67', 'Var', (45, 50))	('CerbB-2', 'Gene', (29, 36))	('CerbB-2', 'Gene', '2064', (29, 36))	('PR', 'Gene', '5241', (21, 23))	('ER', 'Gene', '2099', (13, 15))
8653	33276802	The ED03 (ER+/PR-/HER2-/lobular) and EDW01 (ER+/PR-/HER2-/ductal) PDXs were both classified as molecular subtype luminal A. ED03 xenografts exhibited mutated E-cadherin with minimal expression, but remained vimentin-negative across all passages.	('HER2', 'Gene', '2064', (18, 22))	('ER', 'Gene', '2069', (19, 21))	('ER', 'Gene', '2069', (10, 12))	('HER2', 'Gene', (52, 56))	('vimentin', 'Gene', '7431', (207, 215))	('vimentin', 'Gene', (207, 215))	('luminal', 'Chemical', 'MESH:D010634', (113, 120))	('E-cadherin', 'Protein', (158, 168))	('HER2', 'Gene', (18, 22))	('PR', 'Gene', '5241', (14, 16))	('vimentin', 'cellular_component', 'GO:0045098', ('207', '215'))	('ER', 'Gene', '2069', (53, 55))	('EDW01', 'Gene', (37, 42))	('cadherin', 'molecular_function', 'GO:0008014', ('160', '168'))	('HER2', 'Gene', '2064', (52, 56))	('ER', 'Gene', '2069', (44, 46))	('mutated', 'Var', (150, 157))	('PR', 'Gene', '5241', (48, 50))	('vimentin', 'cellular_component', 'GO:0045099', ('207', '215'))	('exhibited', 'Reg', (140, 149))
8667	33276802	These patterns are intimately linked to E-cadherin: ILCs do not express CDH1 due to the presence of inactivating mutations or silencing via methylation, or copy loss, and hence grow as individual and linear arrays of tumour cells.	('methylation', 'biological_process', 'GO:0032259', ('140', '151'))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('methylation', 'Var', (140, 151))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('inactivating mutations', 'Var', (100, 122))	('CDH1', 'Gene', (72, 76))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('tumour', 'Disease', (217, 223))	('CDH1', 'Gene', '999', (72, 76))	('copy loss', 'Var', (156, 165))	('silencing', 'NegReg', (126, 135))
8671	33276802	Similarly, not all IDC-derived cell lines undergo EMT upon CDH1 silencing, while some do.	('EMT', 'biological_process', 'GO:0001837', ('50', '53'))	('silencing', 'Var', (64, 73))	('CDH1', 'Gene', '999', (59, 63))	('CDH1', 'Gene', (59, 63))
8673	33276802	TGFbeta-induced EMT in NMuMG mouse mammary cancer cells results in the downregulation of epithelial ITGA6/B4 expression (which mediates contact with the basement membrane) through epigenetically silencing of the gene encoding integrin beta4.	('downregulation', 'NegReg', (71, 85))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('expression', 'MPA', (109, 119))	('TGFbeta', 'Gene', '21802', (0, 7))	('cancer', 'Disease', (43, 49))	('EMT', 'biological_process', 'GO:0001837', ('16', '19'))	('TGFbeta', 'Gene', (0, 7))	('basement membrane', 'cellular_component', 'GO:0005604', ('153', '170'))	('integrin beta4', 'Gene', '192897', (226, 240))	('mouse', 'Species', '10090', (29, 34))	('NMuMG', 'CellLine', 'CVCL:0075', (23, 28))	('epigenetically silencing', 'Var', (180, 204))	('ITGA6', 'Gene', '16403', (100, 105))	('ITGA6', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('integrin beta4', 'Gene', (226, 240))
8693	33276802	The membrane-associated proteins (E-cadherin, beta-catenin, P120-RasGAP, CD24, CD44, carbonic anhydrase IX (CAIX)) were scored as cytoplasmic or membranous, and whether they were heterogeneous or homogeneous in these areas.	('beta-catenin', 'Gene', (46, 58))	('CD24', 'Var', (73, 77))	('beta-catenin', 'Gene', '1499', (46, 58))	('P120-RasGAP', 'Gene', '5921', (60, 71))	('P120-RasGAP', 'Gene', (60, 71))	('carbonic anhydrase IX', 'Gene', '768', (85, 106))	('cadherin', 'molecular_function', 'GO:0008014', ('36', '44'))	('CD44', 'Gene', (79, 83))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('carbonic anhydrase IX', 'Gene', (85, 106))
8723	33276802	In ED03, the stromal collagen was evident only under higher magnification as it was finer and more pericellular compared with EDW01, in which the thicker stromal cords separated lobules of tumour.	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('ED03', 'Var', (3, 7))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))	('collagen', 'molecular_function', 'GO:0005202', ('21', '29'))
8729	33276802	Progesterone receptor (PR) expression was negative in ED03 in all passages and was weak (< 15%) in EDW01 at p3, disappearing by p4.	('Progesterone receptor', 'Gene', '5241', (0, 21))	('negative', 'NegReg', (42, 50))	('PR', 'Gene', '5241', (23, 25))	('Progesterone receptor', 'Gene', (0, 21))	('ED03', 'Var', (54, 58))
8736	33276802	Consistent with this, less than 1% of cells expressed E-cadherin in any ED03 PDX passage in mice (Fig.	('ED03', 'Var', (72, 76))	('E-cadherin', 'Protein', (54, 64))	('mice', 'Species', '10090', (92, 96))	('cadherin', 'molecular_function', 'GO:0008014', ('56', '64'))
8741	33276802	3) were observed in EDW01 PDXs whereas VIM mRNA and protein in ED03 were almost negligible (Figs.	('EDW01', 'Var', (20, 25))	('VIM', 'Gene', '7431', (39, 42))	('VIM', 'Gene', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
8745	33276802	Within EDW01, but not ED03, there were regions of tumour cells that appeared to lack both CD24 and CD44 (Fig.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('EDW01', 'Var', (7, 12))	('CD44', 'Protein', (99, 103))	('lack', 'NegReg', (80, 84))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('CD24', 'Protein', (90, 94))
8755	33276802	CD24 is an epithelial-associated marker with relevance to breast cancer stem cells, where its expression is reduced in comparison to luminal breast cancer cells; its expression has been shown to indirectly stimulate cell adhesion to fibronectin, collagens I and IV and laminin through the activation of integrin activity.	('expression', 'Var', (166, 176))	('cell adhesion', 'biological_process', 'GO:0007155', ('216', '229'))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('activation', 'PosReg', (289, 299))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('laminin', 'Protein', (269, 276))	('breast cancer', 'Disease', (141, 154))	('stimulate', 'PosReg', (206, 215))	('collagens', 'Protein', (246, 255))	('integrin', 'Protein', (303, 311))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('cell adhesion', 'CPA', (216, 229))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', (58, 71))	('CD24', 'Gene', (0, 4))	('activity', 'MPA', (312, 320))	('luminal', 'Chemical', 'MESH:D010634', (133, 140))
8770	33276802	EGF treatment caused these cells to increase their migration, whereas ITGB1, ITGA2 and ILK silencing each significantly reduced migration in both assays under EGF-stimulated conditions (Fig.	('ITGA2', 'Gene', (77, 82))	('EGF', 'molecular_function', 'GO:0005154', ('0', '3'))	('ILK', 'Gene', (87, 90))	('EGF', 'Gene', '1950', (0, 3))	('migration', 'CPA', (51, 60))	('increase', 'PosReg', (36, 44))	('migration', 'CPA', (128, 137))	('ITGB1', 'Gene', (70, 75))	('EGF', 'Gene', (0, 3))	('EGF', 'Gene', (159, 162))	('silencing', 'Var', (91, 100))	('EGF', 'molecular_function', 'GO:0005154', ('159', '162'))	('reduced', 'NegReg', (120, 127))	('EGF', 'Gene', '1950', (159, 162))
8774	33276802	We have shown that the EDW01 PDX model displayed evidence of EMT with progressive passages through mice, which was not seen in ED03.	('mice', 'Species', '10090', (99, 103))	('EMT', 'CPA', (61, 64))	('EDW01', 'Var', (23, 28))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))
8777	33276802	The partial EMT observed in EDW01 was associated with a rising hypoxia leading to Twist1 expression in early-mid passages, repressing E-cadherin expression and orchestrating vimentin upregulation, and accompanied by upregulation of ITGB1 and ITGA2 expression.	('upregulation', 'PosReg', (183, 195))	('vimentin', 'cellular_component', 'GO:0045098', ('174', '182'))	('EDW01', 'Var', (28, 33))	('expression', 'MPA', (145, 155))	('ITGB1', 'Gene', (232, 237))	('ITGA2', 'Gene', (242, 247))	('Twist1', 'Gene', (82, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('Twist1', 'Gene', '7291', (82, 88))	('E-cadherin', 'Protein', (134, 144))	('expression', 'MPA', (248, 258))	('vimentin', 'Gene', '7431', (174, 182))	('hypoxia', 'Disease', (63, 70))	('vimentin', 'cellular_component', 'GO:0045099', ('174', '182'))	('vimentin', 'Gene', (174, 182))	('EMT', 'biological_process', 'GO:0001837', ('12', '15'))	('hypoxia', 'Disease', 'MESH:D000860', (63, 70))	('repressing', 'PosReg', (123, 133))	('upregulation', 'PosReg', (216, 228))
8781	33276802	These molecules were more significantly upregulated in increasing EDW01 passages through mice than ED03 (Figs.	('EDW01', 'Var', (66, 71))	('mice', 'Species', '10090', (89, 93))	('upregulated', 'PosReg', (40, 51))
8787	33276802	The PDX models of ED03 and EDW01 were characterised as luminal A (ER positive, Her2 negative, PR low or absent) whereas the PMC42-ET breast cancer cell line used in this study was of the Basal B molecular phenotype.	('breast cancer', 'Disease', (133, 146))	('ER', 'Gene', '2069', (66, 68))	('PR', 'Gene', '5241', (94, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('EDW01', 'Var', (27, 32))	('luminal', 'Chemical', 'MESH:D010634', (55, 62))	('ED03', 'Var', (18, 22))	('Her2', 'Gene', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Her2', 'Gene', '2064', (79, 83))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
8792	33276802	Vimentin and Twist1 positivity was observed in close proximity to necrotic areas in early passages and less commonly found at the centre of tumour 'islands' (Fig.	('Twist1', 'Gene', (13, 19))	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('Vimentin', 'Gene', '7431', (0, 8))	('positivity', 'Var', (20, 30))	('Vimentin', 'cellular_component', 'GO:0045098', ('0', '8'))	('necrotic', 'Disease', (66, 74))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('Twist1', 'Gene', '7291', (13, 19))	('tumour', 'Disease', (140, 146))	('Vimentin', 'cellular_component', 'GO:0045099', ('0', '8'))	('necrotic', 'Disease', 'MESH:D009336', (66, 74))	('Vimentin', 'Gene', (0, 8))
8804	33276802	We have previously demonstrated that EDW01 evoked greater expression of MMPs (-2, -9, -11 and MT1-MMP) in the murine stroma than ED03.	('EDW01', 'Gene', (37, 42))	('MMP', 'molecular_function', 'GO:0004235', ('98', '101'))	('MT1-MMP', 'Var', (94, 101))	('MT1', 'molecular_function', 'GO:0047152', ('94', '97'))	('expression', 'MPA', (58, 68))	('MT1', 'molecular_function', 'GO:0043834', ('94', '97'))	('greater', 'PosReg', (50, 57))	('MMPs (-2, -9, -11', 'Gene', '17390;17395;17385', (72, 89))	('murine', 'Species', '10090', (110, 116))	('MT1', 'molecular_function', 'GO:0043791', ('94', '97'))
8805	33276802	Furthermore, EDW01 displayed MT1-MMP and MMP-13 at the tumour-stromal boundary, but did not express these factors or MMP-2 and MMP-9 within the tumour mass itself.	('tumour', 'Disease', (55, 61))	('MT1', 'molecular_function', 'GO:0043791', ('29', '32'))	('MMP-9', 'Gene', (127, 132))	('MMP-13', 'molecular_function', 'GO:0030404', ('41', '47'))	('MMP-13', 'Gene', (41, 47))	('MT1-MMP', 'Var', (29, 36))	('MMP-2', 'molecular_function', 'GO:0004228', ('117', '122'))	('MMP-2', 'Gene', (117, 122))	('MT1', 'molecular_function', 'GO:0047152', ('29', '32'))	('MT1', 'molecular_function', 'GO:0043834', ('29', '32'))	('MMP-9', 'molecular_function', 'GO:0004229', ('127', '132'))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', (144, 150))	('MMP-13', 'Gene', '4322', (41, 47))	('EDW01', 'Gene', (13, 18))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('MMP', 'molecular_function', 'GO:0004235', ('33', '36'))	('MMP-2', 'Gene', '4313', (117, 122))	('MMP-9', 'Gene', '4318', (127, 132))
8806	33276802	As shown in the current study, the EDW01 tumours grew as islands traversed by thick collagenous stromal bands whereas the ED03 had delicate pericellular stroma dispersed throughout (Fig.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('EDW01', 'Var', (35, 40))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))
8809	33276802	We found that murine (stromal) Itgb1 expression aligned with human (tumoural) expression of the same integrin; in fact for EDW01, stromal Itgb1 expression was approximately 22-fold higher than tumoural ITGB1 at passage 7 (Fig.	('murine', 'Species', '10090', (14, 20))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('EDW01', 'Var', (123, 128))	('expression', 'MPA', (144, 154))	('tumoural', 'Disease', 'MESH:D009369', (193, 201))	('tumoural', 'Disease', (193, 201))	('higher', 'PosReg', (181, 187))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('tumoural', 'Disease', 'MESH:D009369', (68, 76))	('Itgb1', 'Gene', (138, 143))	('human', 'Species', '9606', (61, 66))	('tumoural', 'Disease', (68, 76))
8812	33276802	In a meta-analysis of 16 studies of 5697 breast cancers, CD24 was found to be significantly associated with poorer survival, presumably due to non EMP functions.	('CD24', 'Var', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('survival', 'MPA', (115, 123))	('breast cancers', 'Phenotype', 'HP:0003002', (41, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('breast cancers', 'Disease', 'MESH:D001943', (41, 55))	('poorer', 'NegReg', (108, 114))	('breast cancers', 'Disease', (41, 55))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
8815	33276802	CD44 may be shed from the cell by the action of MMPs, namely MMP-9 and MT1-MMP, resulting in the loss of cell membrane CD44.	('MT1', 'molecular_function', 'GO:0043791', ('71', '74'))	('MMP-9', 'molecular_function', 'GO:0004229', ('61', '66'))	('loss', 'NegReg', (97, 101))	('MT1', 'molecular_function', 'GO:0047152', ('71', '74'))	('cell membrane', 'cellular_component', 'GO:0005886', ('105', '118'))	('MT1-MMP', 'Var', (71, 78))	('MT1', 'molecular_function', 'GO:0043834', ('71', '74'))	('MMPs', 'Gene', '4313;17390;4318;17395;17385;4322;4323;17387', (48, 52))	('MMP-9', 'Gene', (61, 66))	('MMPs', 'Gene', (48, 52))	('cell membrane CD44', 'MPA', (105, 123))	('MMP', 'molecular_function', 'GO:0004235', ('75', '78'))	('MMP-9', 'Gene', '4318', (61, 66))
8816	33276802	As previously mentioned in our earlier studies, EDW01 evoked greater expression of MMPs (-2, -9, -11 and MT1-MMP) in the murine stroma than ED03.	('EDW01', 'Var', (48, 53))	('expression', 'MPA', (69, 79))	('MT1', 'molecular_function', 'GO:0043791', ('105', '108'))	('MMP', 'molecular_function', 'GO:0004235', ('109', '112'))	('murine', 'Species', '10090', (121, 127))	('MMPs (-2, -9, -11', 'Gene', '17390;17395;17385', (83, 100))	('MT1', 'molecular_function', 'GO:0047152', ('105', '108'))	('MT1', 'molecular_function', 'GO:0043834', ('105', '108'))
8817	33276802	4, the homogeneous versus heterogeneous CD44 expression in ED03 compared with EDW01 associates with the interruption of growing tumour by murine stroma, as illustrated by Masson's Trichrome staining, where connective tissue stains blue.	('tumour', 'Disease', (128, 134))	('CD44', 'Gene', (40, 44))	('interruption', 'NegReg', (104, 116))	('ED03', 'Var', (59, 63))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('murine', 'Species', '10090', (138, 144))
8818	33276802	A greater level of CD44 cleavage and shedding may have occurred in EDW01 PDX tumours than ED03, facilitated by stromal MMPs, resulting in the observed heterogeneous pattern.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('CD44', 'Protein', (19, 23))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('MMPs', 'Gene', '4313;17390;4318;17395;17385;4322;4323;17387', (119, 123))	('MMPs', 'Gene', (119, 123))	('tumours', 'Disease', (77, 84))	('heterogeneous pattern', 'MPA', (151, 172))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('cleavage', 'MPA', (24, 32))	('EDW01', 'Var', (67, 72))	('shedding', 'MPA', (37, 45))	('PDX', 'Disease', (73, 76))
8819	33276802	MMP-directed CD44 cleavage results in nuclear translocation of the intracellular CD44 domain, which can result in the transcriptional activation of EMT-associated genes and induction of stemness.	('nuclear translocation', 'MPA', (38, 59))	('EMT', 'biological_process', 'GO:0001837', ('148', '151'))	('MMP', 'Gene', (0, 3))	('transcriptional', 'MPA', (118, 133))	('intracellular', 'cellular_component', 'GO:0005622', ('67', '80'))	('cleavage', 'Var', (18, 26))	('EMT-associated genes', 'Gene', (148, 168))	('MMP', 'Gene', '4313;17390;4318;17395;17385;4322;4323;17387', (0, 3))	('activation', 'PosReg', (134, 144))	('MMP', 'molecular_function', 'GO:0004235', ('0', '3'))	('induction', 'PosReg', (173, 182))	('stemness', 'CPA', (186, 194))	('result in', 'Reg', (104, 113))
8821	33276802	PTS and JRK performed P120, Ki67 and beta-catenin IHC and PTS provided direct guidance in scoring.	('JRK', 'Gene', '8629', (8, 11))	('beta-catenin', 'Gene', (37, 49))	('Ki67', 'Var', (28, 32))	('JRK', 'Gene', (8, 11))	('P120', 'Var', (22, 26))	('beta-catenin', 'Gene', '1499', (37, 49))
8822	33276802	AER performed ED03 CDH1 mutation analyses.	('ER', 'Gene', '2069', (1, 3))	('AER', 'biological_process', 'GO:0070914', ('0', '3'))	('CDH1', 'Gene', (19, 23))	('mutation', 'Var', (24, 32))	('CDH1', 'Gene', '999', (19, 23))
8853	30941235	Patients with CD9 expression had worse overall survival (p = 0.051) and disease-free survival (DFS, p = 0.014) compared to patients without CD9 expression.	('patients', 'Species', '9606', (123, 131))	('disease-free survival', 'CPA', (72, 93))	('Patients', 'Species', '9606', (0, 8))	('worse', 'NegReg', (33, 38))	('overall survival', 'CPA', (39, 55))	('CD9', 'Gene', (14, 17))	('expression', 'Var', (18, 28))
8894	30941235	Patients with CD9 expression had shorter DFS (p = 0.014) and tended to have worse OS (p = 0.051) compared to patients without CD9 expression (Figure 2).	('patients', 'Species', '9606', (109, 117))	('CD9 expression', 'Var', (14, 28))	('DFS', 'MPA', (41, 44))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (33, 40))
8897	30941235	We observed CD9 expression in 42.5% of patients with ILC and high CD9 expression was associated with a poor clinical outcome.	('patients', 'Species', '9606', (39, 47))	('high', 'Var', (61, 65))	('associated', 'Reg', (85, 95))	('ILC', 'Disease', (53, 56))	('CD9', 'Gene', (66, 69))	('expression', 'MPA', (70, 80))	('CD9', 'MPA', (12, 15))
8900	30941235	The study had revealed that patients with CD9 expression had shorter DFS compared to patients without CD9 expression.	('shorter', 'NegReg', (61, 68))	('CD9 expression', 'Var', (42, 56))	('patients', 'Species', '9606', (85, 93))	('DFS', 'MPA', (69, 72))	('patients', 'Species', '9606', (28, 36))
8911	30941235	CD9 crosslinking can induce matrix metalloproteinase 2 (MMP2) transcription by activating intracellular signaling molecules such as PI4K and Src homology 2, which result in increased invasiveness of TCs.	('MMP2', 'Gene', '4313', (56, 60))	('activating', 'PosReg', (79, 89))	('TCs', 'Chemical', '-', (199, 202))	('Src', 'Gene', (141, 144))	('increased', 'PosReg', (173, 182))	('TCs', 'Disease', (199, 202))	('invasiveness', 'CPA', (183, 195))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('transcription', 'MPA', (62, 75))	('Src', 'Gene', '6714', (141, 144))	('crosslinking', 'Var', (4, 16))	('MMP2', 'Gene', (56, 60))	('CD9', 'Protein', (0, 3))	('matrix metalloproteinase 2', 'Gene', '4313', (28, 54))	('induce', 'PosReg', (21, 27))	('intracellular signaling molecules', 'MPA', (90, 123))	('intracellular', 'cellular_component', 'GO:0005622', ('90', '103'))	('matrix metalloproteinase 2', 'Gene', (28, 54))	('MMP2', 'molecular_function', 'GO:0004228', ('56', '60'))	('transcription', 'biological_process', 'GO:0006351', ('62', '75'))	('PI4K', 'molecular_function', 'GO:0004430', ('132', '136'))
8914	30941235	One such study shows that CD9-deficient breast cancer cells (MDA-MB-231) exhibit decreased invasion into a layer of multipotent mesenchymal stromal cells in vitro, and CD9 knockdown inhibited tumor growth and metastasis of MDA-MB-231 in mouse xenograft.	('decreased', 'NegReg', (81, 90))	('tumor', 'Disease', (192, 197))	('mouse', 'Species', '10090', (237, 242))	('CD9-deficient breast cancer', 'Disease', (26, 53))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (223, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('CD9', 'Gene', (168, 171))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (61, 71))	('deficient breast', 'Phenotype', 'HP:0003187', (30, 46))	('inhibited', 'NegReg', (182, 191))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('metastasis', 'CPA', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('knockdown', 'Var', (172, 181))	('CD9-deficient breast cancer', 'Disease', 'MESH:D001943', (26, 53))
8915	30941235	reported that CD9 was overexpressed in osteotropic breast and prostate cancer cell lines and when the osteotropic cancer cell xenografts were treated with anti-CD9 antibodies in vivo, the rate of bone destruction was significantly decreased.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('anti-CD9', 'Var', (155, 163))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('anti-CD9', 'Gene', (155, 163))	('bone destruction', 'CPA', (196, 212))	('cancer', 'Disease', (71, 77))	('osteotropic cancer', 'Phenotype', 'HP:0002669', (102, 120))	('bone destruction', 'Phenotype', 'HP:0002797', (196, 212))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (51, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('overexpressed', 'PosReg', (22, 35))	('decreased', 'NegReg', (231, 240))	('CD9', 'Gene', (14, 17))	('cancer', 'Disease', (114, 120))
8924	30941235	They also found that the treatment with anti-CD9 monoclonal antibodies specifically inhibited the transendothelial migration of melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('melanoma', 'Disease', (128, 136))	('anti-CD9', 'Var', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('inhibited', 'NegReg', (84, 93))
8925	30941235	reported that CD9 expression was increased in chemoresistant small cell lung cancer (SCLC) and inhibition of CD9 by monoclonal antibodies or small interfering RNA induced apoptosis of CD9-expressing chemoresistant SCLC cells.	('CD9', 'Gene', (109, 112))	('SCLC', 'Disease', (85, 89))	('CD9', 'Gene', (14, 17))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))	('SCLC', 'Disease', 'MESH:D018288', (214, 218))	('apoptosis', 'CPA', (171, 180))	('small cell lung cancer', 'Disease', 'MESH:D055752', (61, 83))	('expression', 'MPA', (18, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('small interfering', 'Var', (141, 158))	('small cell lung cancer', 'Disease', (61, 83))	('inhibition', 'Var', (95, 105))	('increased', 'PosReg', (33, 42))	('SCLC', 'Disease', 'MESH:D018288', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('RNA', 'cellular_component', 'GO:0005562', ('159', '162'))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('SCLC', 'Disease', (214, 218))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('SCLC', 'Phenotype', 'HP:0030357', (214, 218))
8927	30941235	However, further studies are required to determine the potential of anti-CD9 monoclonal antibodies to inhibit tumor growth and improve the clinical outcome in breast cancer patients with CD9 expression.	('expression', 'Var', (191, 201))	('improve', 'PosReg', (127, 134))	('patients', 'Species', '9606', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('inhibit', 'NegReg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('CD9', 'Gene', (187, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
8928	30941235	In conclusion, we suggest that CD9 expression is associated with worse prognosis of patients with ILC by univariate and multivariate analyses.	('ILC', 'Disease', (98, 101))	('CD9', 'Gene', (31, 34))	('expression', 'Var', (35, 45))	('patients', 'Species', '9606', (84, 92))
8940	28567703	This relationship is thought to be primarily hormonally driven as controlled feeding studies have demonstrated that alcohol metabolism increases estrogen levels in postmenopausal women.	('increases estrogen levels', 'Phenotype', 'HP:0025134', (135, 160))	('increases estrogen levels in postmenopausal women', 'Phenotype', 'HP:0008209', (135, 184))	('alcohol', 'Chemical', 'MESH:D000438', (116, 123))	('increases', 'PosReg', (135, 144))	('women', 'Species', '9606', (179, 184))	('estrogen levels', 'MPA', (145, 160))	('alcohol metabolism', 'Var', (116, 134))	('alcohol metabolism', 'biological_process', 'GO:0006066', ('116', '134'))
8954	28567703	Case patients with lobular (ICD-O codes 8520, 8522, and 8524) or ductal (ICD-O code 8500) cancers were identified for recruitment to the study.	('cancers', 'Disease', (90, 97))	('patients', 'Species', '9606', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ductal', 'Disease', (65, 71))	('8522', 'Var', (46, 50))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('lobular', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
8990	28567703	Consistent with previous studies evaluating the role of histologic subtype and hormone receptor status, our results showed that alcohol consumption was associated with a significantly increased risk of ER+ ILC and with a more moderately increased risk of ER+ IDC.	('alcohol consumption', 'Var', (128, 147))	('ER', 'Gene', '2099', (202, 204))	('ER', 'Gene', '2099', (255, 257))	('hormone receptor', 'Gene', '3164', (79, 95))	('hormone receptor', 'Gene', (79, 95))	('alcohol', 'Chemical', 'MESH:D000438', (128, 135))
9112	28165048	First, we wished to survey HERV-K loci that were present at different chromosomal locations (preferably on different chromosomes): HERV-K108 is located on chromosome 7, HERV-K109 on chromosome 6, HERV-K113 on chromosome 19, and HERV-K115 on chromosome 8.	('HERV-K', 'Species', '45617', (196, 202))	('HERV-K', 'Species', '45617', (27, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('241', '251'))	('HERV-K', 'Species', '45617', (131, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('209', '219'))	('chromosome', 'cellular_component', 'GO:0005694', ('182', '192'))	('HERV-K108', 'Gene', (131, 140))	('HERV-K', 'Species', '45617', (228, 234))	('HERV-K', 'Species', '45617', (169, 175))	('HERV-K109', 'Var', (169, 178))	('chromosome', 'cellular_component', 'GO:0005694', ('155', '165'))
9115	28165048	Like HERV-K113, HERV-K115 is a full-length provirus, but it contains a base-pair deletion in the gag gene, making it unlikely that the pro and pol ORFs can be transcribed.	('gag', 'Gene', (97, 100))	('gag', 'Gene', '155030', (97, 100))	('HERV-K115', 'Var', (16, 25))	('HERV-K', 'Species', '45617', (16, 22))	('HERV-K', 'Species', '45617', (5, 11))
9128	28165048	We found that HERV-K targeting with a chimeric antigen receptor decreased expression of Ras (pan-Ras), and recently showed that Ras expression decreased as a result of HERV-K knockdown with an shRNA, suggesting that HERV-K is necessary for full Ras expression.	('expression', 'MPA', (74, 84))	('HERV-K', 'Species', '45617', (168, 174))	('HERV-K', 'Species', '45617', (216, 222))	('HERV-K', 'Gene', (168, 174))	('decreased', 'NegReg', (143, 152))	('HERV-K', 'Species', '45617', (14, 20))	('knockdown', 'Var', (175, 184))	('Ras expression', 'MPA', (128, 142))	('Ras', 'Protein', (88, 91))	('decreased', 'NegReg', (64, 73))
9130	28165048	Using TCGA data, it has been reported that over 30% of basal-like breast cancers display KRAS gene amplifications, and an increase in genomic DNA copy numbers at the KRAS2 locus was reported in 9 of 16 human basal-like tumors.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('human', 'Species', '9606', (202, 207))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('KRAS2', 'Gene', '3845', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancers', 'Disease', 'MESH:D001943', (66, 80))	('breast cancers', 'Disease', (66, 80))	('KRAS', 'Gene', '3845', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('tumors', 'Disease', (219, 225))	('KRAS', 'Gene', '3845', (166, 170))	('KRAS2', 'Gene', (166, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('KRAS', 'Gene', (89, 93))	('amplifications', 'Var', (99, 113))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('KRAS', 'Gene', (166, 170))
9132	28165048	Our own HERV-K targeting data coupled with the TCGA data suggests that expression of HERV-K induces expression of wild-type unmutated Ras in basal breast cancer.	('basal breast cancer', 'Disease', (141, 160))	('basal breast cancer', 'Disease', 'MESH:D001943', (141, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('expression', 'Var', (71, 81))	('HERV-K', 'Species', '45617', (8, 14))	('expression', 'MPA', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('HERV-K', 'Species', '45617', (85, 91))	('HERV-K', 'Gene', (85, 91))	('induces', 'PosReg', (92, 99))
9137	28165048	3e), and abundance of the retinoblastoma tumor suppressor protein (Rb) phosphorylated at sites S807/S811 (Fig.	('retinoblastoma', 'Phenotype', 'HP:0009919', (26, 40))	('retinoblastoma tumor', 'Disease', (26, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('retinoblastoma tumor', 'Disease', 'MESH:D012175', (26, 46))	('S807/S811', 'Var', (95, 104))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('Rb', 'Chemical', 'MESH:D012413', (67, 69))
9156	28165048	The possible association of HERV-K levels with abundance of beta-catenin (P = 0.06-0.08) and p-mTOR-s2448 (P = 0.06-0.11) borders on significance, and the trend is seen for each of the four HERV-K loci studied.	('HERV-K', 'Species', '45617', (28, 34))	('association', 'Interaction', (13, 24))	('HERV-K', 'Species', '45617', (190, 196))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('p-mTOR-s2448', 'Var', (93, 105))
9157	28165048	Alternative splicing of HERV-K transcripts leads to production of the novel nuclear oncoprotein Np9, whose increased accumulation upregulates beta-catenin and promotes the growth of human myeloid and lymphoblastic leukemia cells.	('HERV-K', 'Gene', (24, 30))	('accumulation upregulates', 'PosReg', (117, 141))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (200, 222))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (200, 222))	('beta-catenin', 'Gene', (142, 154))	('human', 'Species', '9606', (182, 187))	('leukemia', 'Phenotype', 'HP:0001909', (214, 222))	('beta-catenin', 'Gene', '1499', (142, 154))	('promotes', 'PosReg', (159, 167))	('lymphoblastic leukemia', 'Disease', (200, 222))	('Alternative splicing', 'Var', (0, 20))	('Np9', 'Gene', (96, 99))	('HERV-K', 'Species', '45617', (24, 30))	('growth', 'CPA', (172, 178))
9161	28165048	However, phosphorylated mTOR and proteins in its pathway have been reported to be downregulated in TNBC cells treated with mTOR inhibitors, and mTOR inhibitors blocked tumor growth by 77 to 99% in TNBC xenografts.	('downregulated', 'NegReg', (82, 95))	('tumor', 'Disease', (168, 173))	('blocked', 'NegReg', (160, 167))	('phosphorylated', 'MPA', (9, 23))	('proteins', 'Protein', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('inhibitors', 'Var', (128, 138))	('mTOR', 'Gene', (24, 28))	('inhibitors', 'Var', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
9172	28165048	The association of increased expression of HERV-K with decreased mutation of wild-type H-Ras persisted in the ILC/other dataset (Fig.	('decreased', 'NegReg', (55, 64))	('increased', 'PosReg', (19, 28))	('mutation', 'Var', (65, 73))	('HERV-K', 'Species', '45617', (43, 49))	('expression', 'MPA', (29, 39))	('HERV-K', 'Protein', (43, 49))
9175	28165048	However, the association between HERV-K expression and CDK6, E2F1, E2F5, and pRb S807/S811 was no longer apparent in the ILC/other dataset (data not presented).	('CDK6', 'Gene', '496334', (55, 59))	('Rb', 'Chemical', 'MESH:D012413', (78, 80))	('pRb S807/S811', 'Var', (77, 90))	('E2F1', 'Var', (61, 65))	('CDK6', 'Gene', (55, 59))	('HERV-K', 'Species', '45617', (33, 39))	('CDK', 'molecular_function', 'GO:0004693', ('55', '58'))	('E2F5', 'Var', (67, 71))	('HERV-K', 'Protein', (33, 39))
9186	28165048	HERV-K reference sequences: Both the reference genome sequences and the gene annotations of HERV-K108, K109, K113, and K115 were downloaded from NCBI GenBank.	('K109', 'Var', (103, 107))	('K115', 'Var', (119, 123))	('HERV-K', 'Species', '45617', (0, 6))	('K113', 'Var', (109, 113))	('HERV-K', 'Species', '45617', (92, 98))	('HERV-K108', 'Gene', (92, 101))
9188	28165048	The raw paired-end reads in FASTQ format were also aligned to the human endogenous virus HERV-K108, K109, K113, and K115 reference genome sequences, respectively.	('HERV-K', 'Species', '45617', (89, 95))	('K113', 'Var', (106, 110))	('K109', 'Var', (100, 104))	('human', 'Species', '9606', (66, 71))
9205	25359301	The three studies which reported this association suggest that it is stronger for ER+/PR+ breast cancer, and that it does not vary by menopausal status, age at first migraine, use of prescription medications for migraine, use of NSAIDS, or among women who avoided migraine triggers (alcohol, smoking, exogenous hormones).	('migraine', 'Disease', (264, 272))	('migraine', 'Disease', 'MESH:D008881', (166, 174))	('migraine', 'Phenotype', 'HP:0002076', (264, 272))	('ER+/PR+', 'Var', (82, 89))	('migraine', 'Disease', 'MESH:D008881', (212, 220))	('alcohol', 'Chemical', 'MESH:D000438', (283, 290))	('men', 'Species', '9606', (248, 251))	('women', 'Species', '9606', (246, 251))	('migraine', 'Disease', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('migraine', 'Phenotype', 'HP:0002076', (166, 174))	('migraine', 'Disease', (212, 220))	('migraine', 'Phenotype', 'HP:0002076', (212, 220))	('menopausal status', 'Phenotype', 'HP:0008209', (134, 151))	('stronger', 'Reg', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('migraine', 'Disease', 'MESH:D008881', (264, 272))	('men', 'Species', '9606', (134, 137))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))
9248	25359301	Polytomous logistic regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) to estimate the risks of ER+ ductal (n=276), ER+ lobular (n=191), ER- ductal (n=46), and ER+ mixed ductal-lobular (n=202) breast cancer associated with various aspects of migraine history.	('ER+ mixed ductal-lobular', 'Var', (198, 222))	('migraine', 'Disease', 'MESH:D008881', (280, 288))	('ER+', 'Disease', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('ER-', 'Disease', (175, 178))	('ER+', 'Disease', (134, 137))	('migraine', 'Disease', (280, 288))	('migraine', 'Phenotype', 'HP:0002076', (280, 288))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('breast cancer', 'Disease', (231, 244))
9254	25359301	ER+ ductal, ER+ lobular, and ER+ mixed ductal-lobular cases were more likely to be nulliparous, current users of estrogen plus progestin menopausal hormone therapy, and to consume at least 7 alcoholic beverages weekly, compared to controls and ER- ductal cases.	('men', 'Species', '9606', (137, 140))	('ER+', 'Var', (29, 32))	('ER+ ductal', 'Var', (0, 10))	('alcohol', 'Chemical', 'MESH:D000438', (191, 198))
9309	24937677	Intermediate immune-susceptible IDC expressing high cleaved caspase-3 or Ki67 showed worse RFP than those with low expression (caspase-3: P=0.004; Ki67: P=0.002); this was not seen for ILC or in high or low immune-susceptible tumour types for either IDC or ILC.	('RFP', 'Gene', '2358', (91, 94))	('caspase-3', 'Gene', '836', (127, 136))	('Ki67', 'Chemical', '-', (147, 151))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('high cleaved', 'Var', (47, 59))	('Ki67', 'Var', (73, 77))	('Ki67', 'Chemical', '-', (73, 77))	('caspase-3', 'Gene', (60, 69))	('tumour', 'Disease', (226, 232))	('RFP', 'Gene', (91, 94))	('caspase-3', 'Gene', (127, 136))	('caspase-3', 'Gene', '836', (60, 69))
9348	24937677	As previously described, sections were incubated overnight with anti-Ki67 (mouse anti-human, M7240 Clone MIB-1: Dako Netherlands, Heverlee, Belgium), anti-cleaved caspase-3 (rabbit anti-human, anti-Asp175 #9661: Cell Signaling, Leiden, The Netherlands), anti-CD8 (mouse anti-human, ab 17147, clone 144B: Abcam, Cambridge, UK), anti-PEN5 (mouse anti-human, IM2354, clone 5H10.21.5: Beckman Coulter, Woerden, The Netherlands), mouse monoclonal anti-HCA2 and -HC10 directed against Classical HLA class I (anti-HLA-A and anti-HLA-B/C, respectively) and non-classical HLA class I molecules using mouse monoclonal antibodies against HLA-E (ab2216, clone MEM-E/02: Abcam) and HLA-G; ultimately, Treg infiltration was determined using anti-FoxP3 antibody (ab 20034, clone 236 A/E7: Abcam) with the predetermined optimal dilutions.	('CD8', 'Gene', (259, 262))	('HC10', 'Gene', (457, 461))	('antibody', 'cellular_component', 'GO:0042571', ('738', '746'))	('HLA-E', 'Gene', '3133', (627, 632))	('Signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('FoxP3', 'Gene', (732, 737))	('HCA2', 'Gene', (447, 451))	('MIB-1', 'Gene', (105, 110))	('HLA-A', 'Gene', '3105', (507, 512))	('HLA-B', 'Gene', (522, 527))	('HLA-G', 'Gene', '3135', (669, 674))	('HC10', 'Gene', '120528', (457, 461))	('FoxP3', 'Gene', '50943', (732, 737))	('MIB-1', 'Gene', '57534', (105, 110))	('antibody', 'cellular_component', 'GO:0019815', ('738', '746'))	('A/E7', 'SUBSTITUTION', 'None', (768, 772))	('mouse', 'Species', '10090', (425, 430))	('human', 'Species', '9606', (349, 354))	('CD8', 'Gene', '925', (259, 262))	('mouse', 'Species', '10090', (591, 596))	('mouse', 'Species', '10090', (338, 343))	('human', 'Species', '9606', (86, 91))	('Ki67', 'Chemical', '-', (69, 73))	('caspase-3', 'Gene', '836', (163, 172))	('rabbit', 'Species', '9986', (174, 180))	('mouse', 'Species', '10090', (75, 80))	('antibody', 'cellular_component', 'GO:0019814', ('738', '746'))	('A/E7', 'Var', (768, 772))	('mouse', 'Species', '10090', (264, 269))	('HLA-G', 'Gene', (669, 674))	('HLA-A', 'Gene', (507, 512))	('caspase-3', 'Gene', (163, 172))	('HLA-B', 'Gene', '3106', (522, 527))	('Treg', 'Chemical', '-', (688, 692))	('HCA2', 'Gene', '139081', (447, 451))	('human', 'Species', '9606', (275, 280))	('HLA-E', 'Gene', (627, 632))	('human', 'Species', '9606', (186, 191))	('antibody', 'molecular_function', 'GO:0003823', ('738', '746'))
9360	24937677	Missing data were imputed (multiple imputation) using a model with IDC/ILC, grade, stage, age, follow-up and recurrence status, tumour immune subtypes, Ki67, caspase-3, molecular subtypes, ER, PR and HER2.	('tumour', 'Disease', (128, 134))	('HER2', 'Gene', (200, 204))	('IDC/ILC', 'Disease', (67, 74))	('caspase-3', 'Gene', '836', (158, 167))	('HER2', 'Gene', '2064', (200, 204))	('PR', 'Gene', '5241', (193, 195))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('caspase-3', 'Gene', (158, 167))	('Ki67', 'Var', (152, 156))	('Ki67', 'Chemical', '-', (152, 156))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
9371	24937677	Also, compared to IDC, ILC showed a significantly lower expression pattern for both cleaved caspase-3 (P=0.0004, HR low: 0.2 (95% CI: 0.1-0.6), HR intermediate: 0.4 (95% CI: 0.1-0.9), HR high: 0.1 (95% CI: 0.01-0.4)) and Ki67 (P=0.03, HR: 0.4, 95% CI: 0.2-0.9) following multivariable analyses.	('lower', 'NegReg', (50, 55))	('cleaved', 'MPA', (84, 91))	('caspase-3', 'Gene', (92, 101))	('expression pattern', 'MPA', (56, 74))	('Ki67', 'Var', (221, 225))	('Ki67', 'Chemical', '-', (221, 225))	('caspase-3', 'Gene', '836', (92, 101))
9380	24937677	When stratified by pathological tumour stage, a significant association with RFP was only found for stage I and II tumours (high Ki67 HR: 1.37, 95% CI 1.01-1.84, P=0.04 and high caspase-3 HR: 1.85, 95% CI: 1.21-2.81, P=0.0004) in IDC.	('high Ki67', 'Var', (124, 133))	('caspase-3', 'Gene', '836', (178, 187))	('RFP', 'Gene', '2358', (77, 80))	('high', 'Var', (173, 177))	('II tumours', 'Disease', (112, 122))	('tumour', 'Disease', (32, 38))	('II tumours', 'Disease', 'MESH:D009369', (112, 122))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('caspase-3', 'Gene', (178, 187))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('RFP', 'Gene', (77, 80))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('Ki67', 'Chemical', '-', (129, 133))	('tumour', 'Disease', (115, 121))	('tumour', 'Disease', 'MESH:D009369', (32, 38))	('IDC', 'Disease', (230, 233))
9385	24937677	With increasing expression rate, both factors showed higher HRs (caspase-3 high: HR: 2.0, 95% CI: 0.9-4.2 and Ki67 high: HR: 2.2, 95% CI: 1.3-3.6).	('higher', 'PosReg', (53, 59))	('expression', 'Var', (16, 26))	('caspase-3', 'Gene', '836', (65, 74))	('HRs', 'MPA', (60, 63))	('Ki67', 'Chemical', '-', (110, 114))	('caspase-3', 'Gene', (65, 74))
9389	24937677	Basal-like tumours also expressed higher levels of Ki67 (P<0.001) (Table 3C).	('Basal-like tumours', 'Phenotype', 'HP:0002671', (0, 18))	('Basal-like tumours', 'Disease', 'MESH:D002280', (0, 18))	('Ki67', 'Chemical', '-', (51, 55))	('higher', 'PosReg', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('Ki67', 'Var', (51, 55))	('Basal-like tumours', 'Disease', (0, 18))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))
9401	24937677	demonstrated that the presence of classical HLA class I and high amounts of Treg infiltration affect prognosis in chemotherapy-treated BC patients only.	('affect', 'Reg', (94, 100))	('prognosis', 'MPA', (101, 110))	('presence', 'Var', (22, 30))	('Treg', 'Chemical', '-', (76, 80))	('patients', 'Species', '9606', (138, 146))
9415	31342392	Women with cT1-4c, cN1-3 HR+ ILC in the National Cancer Data Base (2004-2014) who underwent surgery following neoadjuvant therapy were identified.	('Women', 'Species', '9606', (0, 5))	('cT1-4c', 'Var', (11, 17))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Disease', (49, 55))	('cN1', 'Gene', '84618', (19, 22))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('cN1', 'Gene', (19, 22))
9454	31342392	As compared to women <50 who received NACT (n=1892), NET recipients<50 had more T3 and less T4 disease both at presentation (cT3: NET 47.2% vs NACT 43.0%; cT4: NET 1.4% vs NACT 8.9%, p=0.002) and following systemic therapy (ypT3: NET 27.8% vs NACT 13.2%; ypT4: NET 0% vs NACT 2.4%, p<0.001).	('NET 27', 'Gene', (230, 236))	('NET 27', 'Gene', '83637', (230, 236))	('<50', 'Var', (67, 70))	('women', 'Species', '9606', (15, 20))	('cT3', 'Gene', '285782', (125, 128))	('T4 disease', 'Disease', 'MESH:D005067', (92, 102))	('NET 47', 'Gene', (130, 136))	('cT3', 'Gene', (125, 128))	('NET 47', 'Gene', '7108', (130, 136))	('T4 disease', 'Disease', (92, 102))	('less', 'NegReg', (87, 91))
9470	31342392	Furthermore, we must question the benefit of current practice, in which NACT is administered to approximately 1/3 of node-positive ILC patients (Supplemental Table 5), the vast majority of whom are strongly HR+, and traditionally experience less robust responses to NACT than patients with HER2+ and triple-negative tumors.	('patients', 'Species', '9606', (276, 284))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('HER2', 'Gene', (290, 294))	('ILC', 'Disease', (131, 134))	('HR+', 'Var', (207, 210))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('HER2', 'Gene', '2064', (290, 294))	('tumors', 'Disease', (316, 322))	('tumors', 'Disease', 'MESH:D009369', (316, 322))
9479	31342392	Collectively, our findings raise the possibility that the best sequence of treatment for many patients with ILC may involve receipt of all systemic therapy after surgery, but neoadjuvant therapy could still be an important option for particular groups of patients including those who are strongly HR+ and low-grade but unresectable at presentation due to local invasion and those who are unable to proceed with surgery immediately due, for example, to having a second synchronous tumor or anticoagulation that cannot be interrupted.	('ILC', 'Disease', (108, 111))	('patients', 'Species', '9606', (94, 102))	('HR+', 'Var', (297, 300))	('patients', 'Species', '9606', (255, 263))	('synchronous tumor', 'Disease', 'MESH:D009378', (468, 485))	('tumor', 'Phenotype', 'HP:0002664', (480, 485))	('synchronous tumor', 'Disease', (468, 485))
9666	26435744	This loss results from inactivation of CDH1 gene at 16q22.	('CDH1', 'Gene', (39, 43))	('loss', 'NegReg', (5, 9))	('inactivation', 'Var', (23, 35))	('CDH1', 'Gene', '999', (39, 43))
9667	26435744	Loss of E cadherin expression is associated with abnormalities in catenin expression leading to loss of cell-to-cell adhesion and intracellular and intercellular signalling.	('signalling', 'biological_process', 'GO:0023052', ('162', '172'))	('expression', 'MPA', (74, 84))	('cell-to-cell adhesion', 'CPA', (104, 125))	('abnormalities', 'Var', (49, 62))	('catenin', 'Protein', (66, 73))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))	('Loss', 'NegReg', (0, 4))	('E cadherin', 'Gene', (8, 18))	('E cadherin', 'Gene', '999', (8, 18))	('intracellular', 'cellular_component', 'GO:0005622', ('130', '143'))	('loss', 'NegReg', (96, 100))	('cell adhesion', 'biological_process', 'GO:0007155', ('112', '125'))
9685	26435744	HER-2 protein overexpression or gene amplification have been reported in <1% to 6.2% of all ILC cases.	('protein', 'Protein', (6, 13))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('ILC', 'Disease', (92, 95))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', '2064', (0, 5))	('gene amplification', 'Var', (32, 50))	('overexpression', 'PosReg', (14, 28))
9712	21879268	The SLNs were evaluated intraoperatively by bisecting the SLN.	('SLN', 'Gene', (58, 61))	('bisecting', 'Var', (44, 53))	('SLN', 'Gene', (4, 7))	('SLN', 'Gene', '6588', (58, 61))	('SLN', 'Gene', '6588', (4, 7))
9796	21879268	The trial enrolled patients with clinical T1 or T2N0M0 breast cancer treated with lumpectomy who were found to have 1 or 2 positive SLNs on standard pathologic examination and H&E staining.	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('patients', 'Species', '9606', (19, 27))	('T2N0M0', 'Var', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('SLN', 'Gene', (132, 135))	('H&E', 'Chemical', '-', (176, 179))	('SLN', 'Gene', '6588', (132, 135))
9820	23554916	Via gene rearrangement of variable (V), diversity (D) and joining (J) segments B lymphocytes produce Igs in order to recognize and neutralize various pathogens/antigens, and thus contributing to the host humoral immunity.	('neu', 'Gene', (131, 134))	('contributing', 'Reg', (179, 191))	('gene rearrangement', 'Var', (4, 22))	('neu', 'Gene', '2064', (131, 134))
9826	23554916	amplified VH gene transcripts by nested RT-PCR as either single or dual V(D)J rearrangements in four of six breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('VH gene', 'Gene', (10, 17))	('breast cancer', 'Disease', (108, 121))	('rearrangements', 'Var', (78, 92))
9914	23554916	In addition, previous in vitro experiments showed that blockade of IgG by either antisense DNA or antihuman IgG antibody increased apoptosis and inhibited growth of epithelial cancer cells in vitro .	('epithelial cancer', 'Disease', (165, 182))	('epithelial cancer', 'Disease', 'MESH:D000077216', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('apoptosis', 'CPA', (131, 140))	('IgG antibody', 'cellular_component', 'GO:0071736', ('108', '120'))	('IgG antibody', 'Phenotype', 'HP:0003237', (108, 120))	('human', 'Species', '9606', (102, 107))	('inhibited', 'NegReg', (145, 154))	('IgG', 'Gene', '16059', (108, 111))	('increased', 'PosReg', (121, 130))	('IgG', 'Gene', '16059', (67, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('blockade', 'Var', (55, 63))	('IgG', 'Gene', (108, 111))	('antibody', 'molecular_function', 'GO:0003823', ('112', '120'))	('IgG', 'Gene', (67, 70))	('epithelial cancer', 'Phenotype', 'HP:0031492', (165, 182))
9945	23554916	Second, experiments with nude mice bearing ovarian tumors showed that intraperitoneal injection with RP215 antibodies resulted in significantly decreased tumor size compared with untreated mice.	('mice', 'Species', '10090', (30, 34))	('decreased', 'NegReg', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Disease', (51, 56))	('ovarian tumors', 'Disease', (43, 57))	('ovarian tumors', 'Phenotype', 'HP:0100615', (43, 57))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('ovarian tumors', 'Disease', 'MESH:D010051', (43, 57))	('RP215 antibodies', 'Var', (101, 117))	('nude mice', 'Species', '10090', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', (154, 159))
9959	20842455	Mutations in the CDH1 gene are detected in 30-46% of families that fulfil strong clinical criteria for HDGC and in about 11% of families fulfilling the modified criteria.	('detected', 'Reg', (31, 39))	('CDH1', 'Gene', '999', (17, 21))	('HDGC', 'Disease', 'MESH:D013274', (103, 107))	('HDGC', 'Disease', (103, 107))	('Mutations', 'Var', (0, 9))	('CDH1', 'Gene', (17, 21))
9960	20842455	In the present study, we investigated germline mutations in the CDH1 gene in Polish patients with HDGC.	('HDGC', 'Disease', (98, 102))	('patients', 'Species', '9606', (84, 92))	('HDGC', 'Disease', 'MESH:D013274', (98, 102))	('germline mutations', 'Var', (38, 56))	('CDH1', 'Gene', (64, 68))	('CDH1', 'Gene', '999', (64, 68))
9962	20842455	We found several silent mutations including one common variant (c.2076T>C) present in 56 patients, and three rare variants (c.2253C>T, c.1896C>T, c.2634C>T) detected in 2 patients.	('c.2076T>C', 'Mutation', 'rs1801552', (64, 73))	('c.2253C>T', 'Mutation', 'rs33964119', (124, 133))	('c.2634C>T', 'Mutation', 'rs2229044', (146, 155))	('c.2253C>T', 'Var', (124, 133))	('patients', 'Species', '9606', (171, 179))	('c.2634C>T', 'Var', (146, 155))	('c.2076T>C', 'Var', (64, 73))	('patients', 'Species', '9606', (89, 97))	('c.1896C>T', 'Var', (135, 144))	('c.1896C>T', 'Mutation', 'rs33969373', (135, 144))
9964	20842455	CDH1 gene mutations are not present in Polish families with HDGC defined by the modified clinical criteria.	('HDGC', 'Disease', (60, 64))	('CDH1', 'Gene', '999', (0, 4))	('HDGC', 'Disease', 'MESH:D013274', (60, 64))	('mutations', 'Var', (10, 19))	('CDH1', 'Gene', (0, 4))
9968	20842455	Mutations in CDH1 gene are known to be associated with Hereditary Diffuse Gastric Cancer syndrome (HDGC) and also with lobular breast cancer.	('CDH1', 'Gene', '999', (13, 17))	('lobular breast cancer', 'Disease', (119, 140))	('HDGC', 'Disease', (99, 103))	('lobular breast cancer', 'Disease', 'MESH:D013274', (119, 140))	('Hereditary Diffuse Gastric Cancer syndrome', 'Disease', 'MESH:D013274', (55, 97))	('Hereditary Diffuse Gastric Cancer syndrome', 'Disease', (55, 97))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (74, 88))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (119, 140))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CDH1', 'Gene', (13, 17))	('HDGC', 'Disease', 'MESH:D013274', (99, 103))
9970	20842455	Among patients that fulfill the above clinical criteria about 30-46% of cases carry a mutation in the CDH1 gene.	('CDH1', 'Gene', '999', (102, 106))	('patients', 'Species', '9606', (6, 14))	('CDH1', 'Gene', (102, 106))	('mutation', 'Var', (86, 94))
9973	20842455	It has been shown that among patients fulfilling the modified criteria 11% carry CDH1 mutation.	('patients', 'Species', '9606', (29, 37))	('CDH1', 'Gene', '999', (81, 85))	('mutation', 'Var', (86, 94))	('CDH1', 'Gene', (81, 85))	('carry', 'Reg', (75, 80))
9974	20842455	Patients with germline mutations in the CDH1 have a high risk of developing diffuse gastric cancer and female carriers are at high risk of lobular breast cancer.	('lobular breast cancer', 'Disease', 'MESH:D013274', (139, 160))	('gastric cancer', 'Disease', (84, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (139, 160))	('CDH1', 'Gene', (40, 44))	('Patients', 'Species', '9606', (0, 8))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('CDH1', 'Gene', '999', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('germline mutations', 'Var', (14, 32))	('lobular breast cancer', 'Disease', (139, 160))
9975	20842455	The estimated penetrance of CDH1 mutations is 70-80% for stomach cancer and 39-52% for lobular breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CDH1', 'Gene', (28, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('mutations', 'Var', (33, 42))	('stomach cancer', 'Disease', 'MESH:D013274', (57, 71))	('CDH1', 'Gene', '999', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lobular breast cancer', 'Disease', (87, 108))	('stomach cancer', 'Phenotype', 'HP:0012126', (57, 71))	('stomach cancer', 'Disease', (57, 71))	('lobular breast cancer', 'Disease', 'MESH:D013274', (87, 108))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (87, 108))
9976	20842455	Because of high penetrance of CDH1 mutations and almost 100% mortality of patients with symptomatic DGC prophylactic total gastrectomy during the second decade of life is recommended for CDH1 mutation carriers.	('CDH1', 'Gene', '999', (30, 34))	('DGC', 'cellular_component', 'GO:0016010', ('100', '103'))	('patients', 'Species', '9606', (74, 82))	('CDH1', 'Gene', (187, 191))	('CDH1', 'Gene', '999', (187, 191))	('CDH1', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
9979	20842455	Given the complexity and high mortality of HDGC, not only with regard to the management of the DGC, but also with regard to the risk for other related cancers such as lobular breast cancer or colon cancer, it is very important to identify asymptomatic carriers of CDH1 mutations in order to apply the appropriate surveillance.	('colon cancer', 'Phenotype', 'HP:0003003', (192, 204))	('lobular breast cancer', 'Disease', 'MESH:D013274', (167, 188))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (167, 188))	('DGC', 'cellular_component', 'GO:0016010', ('95', '98'))	('HDGC', 'Disease', (43, 47))	('colon cancer', 'Disease', 'MESH:D015179', (192, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutations', 'Var', (269, 278))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('CDH1', 'Gene', '999', (264, 268))	('HDGC', 'Disease', 'MESH:D013274', (43, 47))	('colon cancer', 'Disease', (192, 204))	('CDH1', 'Gene', (264, 268))	('lobular breast cancer', 'Disease', (167, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('cancers', 'Disease', 'MESH:D009369', (151, 158))
9980	20842455	In the current study we sought to determine prevalence of CDH1 mutations in Polish families with diffuse gastric cancer.	('mutations', 'Var', (63, 72))	('CDH1', 'Gene', (58, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))	('CDH1', 'Gene', '999', (58, 62))	('gastric cancer', 'Disease', (105, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
9989	20842455	This is the first study of CDH1 mutations in the Polish population, in which we screened 86 patients with HDGC.	('CDH1', 'Gene', (27, 31))	('HDGC', 'Disease', (106, 110))	('CDH1', 'Gene', '999', (27, 31))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (32, 41))	('HDGC', 'Disease', 'MESH:D013274', (106, 110))
9990	20842455	We found four different silent mutations: one common (c.2076T>C) and three rare (c.2253C>T, c.1896C>T, c.2634C>T) variants.	('c.1896C>T', 'Mutation', 'rs33969373', (92, 101))	('c.2634C>T', 'Mutation', 'rs2229044', (103, 112))	('c.2634C>T', 'Var', (103, 112))	('c.2076T>C', 'Var', (54, 63))	('c.2253C>T', 'Mutation', 'rs33964119', (81, 90))	('c.2076T>C', 'Mutation', 'rs1801552', (54, 63))	('c.2253C>T', 'Var', (81, 90))	('c.1896C>T', 'Var', (92, 101))
9992	20842455	Germline mutations in CDH1 gene were originally reported in three Maori families with aggregation of diffuse gastric cancer.	('Germline mutations', 'Var', (0, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('CDH1', 'Gene', '999', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('aggregation of diffuse gastric cancer', 'Disease', (86, 123))	('reported', 'Reg', (48, 56))	('CDH1', 'Gene', (22, 26))	('aggregation of diffuse gastric cancer', 'Disease', 'MESH:D013274', (86, 123))
9993	20842455	Since this report, several studies have investigated the role of CDH1 mutations in gastric cancer in different ethnic groups.	('mutations', 'Var', (70, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('CDH1', 'Gene', (65, 69))	('CDH1', 'Gene', '999', (65, 69))	('gastric cancer', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))
9994	20842455	It has been reported that CDH1 mutations underlie approximately 40% of families fulfilling the strong IGCLC criteria for hereditary diffuse gastric cancer (HDGC).	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('mutations', 'Var', (31, 40))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (121, 154))	('hereditary diffuse gastric cancer', 'Disease', (121, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('HDGC', 'Disease', 'MESH:D013274', (156, 160))	('underlie', 'Reg', (41, 49))	('CDH1', 'Gene', (26, 30))	('HDGC', 'Disease', (156, 160))	('CDH1', 'Gene', '999', (26, 30))
9997	20842455	CDH1 mutations have been found in 11% (21/192) of families with FDGC and almost 7% (17/254) of patients with EOGC.	('patients', 'Species', '9606', (95, 103))	('CDH1', 'Gene', '999', (0, 4))	('mutations', 'Var', (5, 14))	('FDGC', 'Disease', (64, 68))	('found', 'Reg', (25, 30))	('CDH1', 'Gene', (0, 4))
10001	20842455	In the study of 160 patients from families fulfilling the restrictive criteria HDGC 67 (42%) point or small frameshift mutations and 6 (4%) large genomic deletions in CDH1 gene were detected.	('CDH1', 'Gene', '999', (167, 171))	('HDGC', 'Disease', 'MESH:D013274', (79, 83))	('frameshift mutations', 'Var', (108, 128))	('point', 'Var', (93, 98))	('HDGC', 'Disease', (79, 83))	('patients', 'Species', '9606', (20, 28))	('CDH1', 'Gene', (167, 171))
10002	20842455	This indicates that large genomic rearrangements constitute only a small proportion of CDH1 mutations (~8%).	('CDH1', 'Gene', '999', (87, 91))	('CDH1', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))
10003	20842455	In summary, results of our study show that CDH1 mutations do not contribute to diffuse gastric cancer in Poland, however, taking into account limitations of our study which are: less restrictive criteria of gastric cancer patients selection and lack of analysis for large genomic deletions, further studies of HDGC in Polish population are needed.	('HDGC', 'Disease', (310, 314))	('gastric cancer', 'Disease', (207, 221))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (207, 221))	('HDGC', 'Disease', 'MESH:D013274', (310, 314))	('patients', 'Species', '9606', (222, 230))	('gastric cancer', 'Phenotype', 'HP:0012126', (207, 221))	('CDH1', 'Gene', (43, 47))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('mutations', 'Var', (48, 57))	('CDH1', 'Gene', '999', (43, 47))
10028	25598762	Further workup showed ferritin 444 ng/ml, TIBC 309 mcg/dl, Iron level 81 mcg/dl, haptoglobin 339 mg/dl, erythropoietin level 131 mlU/ml, c-reactive protein (CRP) < 0.2 mg/dl, absolute reticulocyte 95 B/L, reticulocyte percent 3.7%, Folic acid 17.80 ng/ml, vitamin B12 458 pg/ml and peripheral smear showed anisocytosis 1+, polychromasia 1+ and basophilic stippling 1+.	('c-reactive protein', 'Gene', (137, 155))	('c-reactive protein', 'Gene', '1401', (137, 155))	('erythropoietin', 'Gene', '2056', (104, 118))	('anisocytosis', 'MPA', (306, 318))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('polychromasia', 'Disease', (323, 336))	('CRP', 'Gene', '1401', (157, 160))	('erythropoietin', 'molecular_function', 'GO:0005128', ('104', '118'))	('CRP', 'Gene', (157, 160))	('95 B/L', 'SUBSTITUTION', 'None', (197, 203))	('polychromasia', 'Disease', 'None', (323, 336))	('95 B/L', 'Var', (197, 203))	('anisocytosis', 'Phenotype', 'HP:0011273', (306, 318))	('erythropoietin', 'Gene', (104, 118))
10198	28096693	Despite several chemotherapy and hormone therapy lines consisting of cisplatin-gemcitabine, vinorelbine, liposomal doxorubicin, and other aromatase inhibitors, the patient developed brain metastases and finally died in August 2011.	('brain metastases', 'Disease', (182, 198))	('developed', 'PosReg', (172, 181))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('cisplatin-gemcitabine', 'Var', (69, 90))	('patient', 'Species', '9606', (164, 171))	('gemcitabine', 'Chemical', 'MESH:C056507', (79, 90))	('vinorelbine', 'Chemical', 'MESH:D000077235', (92, 103))	('doxorubicin', 'Chemical', 'MESH:D004317', (115, 126))	('brain metastases', 'Disease', 'MESH:D009362', (182, 198))
10231	28096693	Inactivation of E-cadherin through CDH1 gene mutation, loss of heterozygosity of chromosomal region 16q22.1, and/or gene promoter methylation is an early event reported in more than 95% of ILCs.	('E-cadherin', 'Gene', (16, 26))	('E-cadherin', 'Gene', '999', (16, 26))	('loss', 'Var', (55, 59))	('chromosomal region', 'cellular_component', 'GO:0098687', ('81', '99'))	('cadherin', 'molecular_function', 'GO:0008014', ('18', '26'))	('ILCs', 'Disease', (189, 193))	('methylation', 'biological_process', 'GO:0032259', ('130', '141'))	('CDH1', 'Gene', (35, 39))	('mutation', 'Var', (45, 53))	('CDH1', 'Gene', '999', (35, 39))	('Inactivation', 'NegReg', (0, 12))
10250	28096693	Methylation of CXCL12 promoter in the colonic epithelium favors metastases of tumors in the colon, but further studies are necessary to confirm this hypothesis.	('metastases of tumors in the colon', 'Disease', 'MESH:D009362', (64, 97))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('Methylation', 'Var', (0, 11))	('favors', 'PosReg', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('metastases of tumors in the colon', 'Disease', (64, 97))	('CXCL12', 'Gene', (15, 21))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('CXCL12', 'Gene', '6387', (15, 21))
10278	28096693	Infection with H. pylori causes chronic active gastritis, characterized by inflammatory cells infiltrating the gastric epithelial layer and the underlying lamina propria.	('gastritis', 'Phenotype', 'HP:0005263', (47, 56))	('causes', 'Reg', (25, 31))	('H. pylori', 'Gene', (15, 24))	('active gastritis', 'Disease', 'MESH:D005756', (40, 56))	('Infection', 'Var', (0, 9))	('active gastritis', 'Disease', (40, 56))	('H. pylori', 'Species', '210', (15, 24))
10292	28096693	PAR2 activation induces NF-kappabeta and AP-1-dependent IL-8 production in association with activation of p38 MAPK and ERK1/2.	('activation', 'Var', (5, 15))	('NF-kappabeta', 'Gene', (24, 36))	('ERK1/2', 'Gene', '5595;5594', (119, 125))	('ERK1', 'molecular_function', 'GO:0004707', ('119', '123'))	('p38', 'Protein', (106, 109))	('NF-kappabeta', 'Gene', '4790', (24, 36))	('activation', 'PosReg', (92, 102))	('PAR2', 'Gene', (0, 4))	('IL-8 production', 'biological_process', 'GO:0032637', ('56', '71'))	('IL-8', 'Gene', '3576', (56, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('110', '114'))	('AP-1', 'cellular_component', 'GO:0005907', ('41', '45'))	('IL-8', 'Gene', (56, 60))	('IL-8', 'molecular_function', 'GO:0005153', ('56', '60'))	('ERK1/2', 'Gene', (119, 125))	('PAR2', 'Gene', '2150', (0, 4))
10307	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))	('changes', 'Var', (112, 119))	('DNA', 'Gene', (96, 99))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('copy number changes', 'Var', (100, 119))
10322	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))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('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))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('p-120 catenin', 'Gene', (92, 105))	('beta-catenin', 'Gene', (75, 87))	('beta-catenin', 'Gene', (147, 159))	('p-120 catenin', 'Gene', '1500', (186, 199))
10328	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))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('CK20', 'Gene', '54474', (70, 74))	('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))
10546	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))	('pure', 'molecular_function', 'GO:0034023', ('301', '305'))	('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))
10550	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))	('BRCA1', 'Gene', (228, 233))	('PALB2', 'Gene', (209, 214))	('TP53', 'Gene', '7157', (250, 254))	('BRCA1', 'Gene', '672', (228, 233))	('pathogenic', 'CPA', (44, 54))	('BRCA2', 'Gene', '675', (67, 72))	('CHEK2', 'Gene', '11200', (126, 131))	('TP53', 'Gene', (250, 254))
10551	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).	('pathogenic', 'Reg', (59, 69))	('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))
10552	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))
10553	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))
10558	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))
10562	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))	('pure', 'molecular_function', 'GO:0034023', ('45', '49'))	('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))
10564	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.	('pure', 'molecular_function', 'GO:0034023', ('35', '39'))	('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))
10565	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))
10567	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))	('pure', 'molecular_function', 'GO:0034023', ('159', '163'))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('BRCA1', 'Gene', '672', (113, 118))	('BRCA1', 'Gene', (113, 118))	('women', 'Species', '9606', (197, 202))	('invasive disease', 'Disease', 'MESH:D009362', (177, 193))	('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))
10583	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))	('DCIS', 'Disease', (29, 33))	('TP53', 'Gene', (92, 96))	('BRCA1', 'Gene', '672', (82, 87))	('BRCA2', 'Gene', '675', (61, 66))	('CHEK2', 'Gene', '11200', (68, 73))
10585	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))
10586	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))	('patients', 'Species', '9606', (99, 107))	('c.C9382T:p.R3128X', 'SUBSTITUTION', 'None', (119, 136))	('patients', 'Species', '9606', (144, 152))	('patient', 'Species', '9606', (144, 151))	('patient', 'Species', '9606', (55, 62))	('c.C9382T:p.R3128X', 'Var', (119, 136))	('p.Q2859fs', 'Mutation', 'rs80359718', (82, 91))
10587	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))
10591	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))
10593	31060593	Of the six pathogenic PALB2 variants detected, three were novel frameshifts (two in exon 4, one in exon 5, Fig.	('PALB2', 'Gene', (22, 27))	('pathogenic', 'Reg', (11, 21))	('variants', 'Var', (28, 36))	('PALB2', 'Gene', '79728', (22, 27))
10594	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))	('associated', 'Reg', (93, 103))	('rs180177132', 'Var', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rs180177132', 'Mutation', 'rs180177132', (41, 52))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
10595	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))
10601	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))
10603	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.	('apoptosis', 'biological_process', 'GO:0097194', ('220', '229'))	('TP53', 'Gene', (210, 214))	('apoptosis', 'biological_process', 'GO:0006915', ('220', '229'))	('rs397514495', 'Mutation', 'rs397514495', (77, 88))	('rs397514495', 'Var', (77, 88))	('TP53', 'Gene', '7157', (210, 214))
10604	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))
10605	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))
10606	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))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('woman', 'Species', '9606', (53, 58))	('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))
10607	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))
10608	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))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
10610	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))	('Li-Fraumeni-like syndrome', 'Disease', (97, 122))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('Li-Fraumeni-like syndrome', 'Disease', 'MESH:C567189', (97, 122))	('c.G869A:p.R290H', 'Var', (20, 35))	('associated', 'Reg', (81, 91))
10613	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))
10615	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))
10616	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))
10617	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))	('pure', 'molecular_function', 'GO:0034023', ('82', '86'))	('BRCA1', 'Gene', (25, 30))	('women', 'Species', '9606', (14, 19))	('pure DCIS', 'Disease', (82, 91))	('BRCA2', 'Gene', (35, 40))
10619	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.	('pure', 'molecular_function', 'GO:0034023', ('35', '39'))	('BRCA1', 'Gene', '672', (66, 71))	('BRCA2', 'Gene', (76, 81))	('BRCA1', 'Gene', (66, 71))	('BRCA2', 'Gene', '675', (76, 81))	('mutations', 'Var', (82, 91))
10620	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', 'molecular_function', 'GO:0034023', ('18', '22'))	('pure DCIS', 'Disease', (18, 27))	('mutation', 'Var', (55, 63))	('BRCA1', 'Gene', '672', (85, 90))	('BRCA2', 'Gene', (49, 54))
10621	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))	('pure', 'molecular_function', 'GO:0034023', ('25', '29'))	('BRCA2', 'Gene', (47, 52))	('pure DCIS', 'Disease', (25, 34))	('BRCA1', 'Gene', '672', (88, 93))	('BRCA2', 'Gene', '675', (47, 52))	('variants', 'Var', (53, 61))
10622	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))
10623	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))	('BRCA1', 'Gene', '672', (153, 158))	('BRCA1/2', 'Gene', '672;675', (90, 97))	('BRCA2', 'Gene', '675', (114, 119))	('mutations', 'Var', (98, 107))	('BRCA1', 'Gene', (90, 95))	('mutations', 'Var', (120, 129))	('BRCA1', 'Gene', (153, 158))
10624	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))
10625	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))
10626	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))
10627	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))
10628	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))
10629	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))	('pure', 'molecular_function', 'GO:0034023', ('110', '114'))	('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))
10630	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))
10631	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))
10632	31060593	This high frequency of CHEK2 variants in pure DCIS has not been previously described, although Schmidt et al.	('variants', 'Var', (29, 37))	('pure DCIS', 'Disease', (41, 50))	('CHEK2', 'Gene', '11200', (23, 28))	('CHEK2', 'Gene', (23, 28))	('pure', 'molecular_function', 'GO:0034023', ('41', '45'))
10633	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))
10634	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))	('pure', 'molecular_function', 'GO:0034023', ('154', '158'))	('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))	('pure', 'molecular_function', 'GO:0034023', ('100', '104'))	('CHEK2', 'Gene', '11200', (38, 43))
10635	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))
10637	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.	('women', 'Species', '9606', (80, 85))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('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))	('pure', 'molecular_function', 'GO:0034023', ('91', '95'))
10639	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))
10640	31060593	The frequency of PALB2 variants in our data is supported by the study by Couch et al.	('variants', 'Var', (23, 31))	('PALB2', 'Gene', '79728', (17, 22))	('PALB2', 'Gene', (17, 22))
10641	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))
10642	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))	('Pure', 'molecular_function', 'GO:0034023', ('0', '4'))
10644	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))
10646	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))
10649	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))
10650	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))	('predisposing', 'Reg', (52, 64))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('CHEK2', 'Gene', '11200', (19, 24))	('variants', 'Var', (36, 44))	('CHEK2', 'Gene', (19, 24))
10652	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))
10653	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))
10655	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))
10656	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))
10657	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))
10658	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.	('invasive breast cancer', 'Disease', 'MESH:D001943', (220, 242))	('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))	('BRCA2', 'Gene', '675', (156, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))	('women', 'Species', '9606', (70, 75))
10660	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))
10662	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))
10663	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))
10664	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))
10665	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))
10666	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))
10737	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.	('inactivation', 'Var', (30, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (154, 168))	('embryogenesis', 'biological_process', 'GO:0009792', ('127', '140'))	('carcinogenesis', 'Disease', (154, 168))	('embryogenesis', 'biological_process', 'GO:0009790', ('127', '140'))	('embryogenesis', 'biological_process', 'GO:0009793', ('127', '140'))
10744	30384839	All participants had FFDM and DBT on Siemens Mammomat Inspiration units.	('DBT', 'Var', (30, 33))	('participants', 'Species', '9606', (4, 16))	('men', 'Species', '9606', (40, 43))	('FFDM', 'Disease', (21, 25))	('FFDM', 'Chemical', '-', (21, 25))
10785	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))
10893	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))
11325	27955877	Previous clinical trials have shown that double reading of mammograms results in increased cancer detection.	('double reading', 'Var', (41, 55))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('increased', 'PosReg', (81, 90))
11367	25230018	We have previously reported that the co-expression of AR and 5alphaRed1 in invasive ductal carcinomas was indeed associated with better clinical outcome of the patients with IDC, which is consistent with the overall roles of androgens as tumor suppressors in ER-positive or luminal-type breast carcinoma.	('IDC', 'Gene', '4000', (174, 177))	('IDC', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('co-expression', 'Var', (37, 50))	('luminal-type breast carcinoma', 'Disease', 'MESH:D001943', (274, 303))	('5alphaRed1', 'Gene', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (75, 101))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (84, 100))	('better', 'PosReg', (129, 135))	('breast carcinoma', 'Phenotype', 'HP:0003002', (287, 303))	('tumor', 'Disease', (238, 243))	('patients', 'Species', '9606', (160, 168))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('invasive ductal carcinomas', 'Disease', (75, 101))	('AR', 'Gene', '367', (54, 56))	('luminal-type breast carcinoma', 'Disease', (274, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
11368	25230018	In addition, AIs, considered the gold standard of endocrine therapy of ER-positive postmenopausal breast cancer patients, have been reported to exert antitumor effects through not only decreasing the levels of estrogens available for carcinoma cells but also increasing intratumoral androgen concentrations, most probably due to the precursor-product relationship between intratumoral androgens and estrogens.	('levels of estrogens available', 'MPA', (200, 229))	('tumor', 'Disease', (275, 280))	('carcinoma', 'Disease', 'MESH:D002277', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (154, 159))	('increasing', 'PosReg', (259, 269))	('tumor', 'Disease', (377, 382))	('decreasing', 'NegReg', (185, 195))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('postmenopausal breast cancer', 'Phenotype', 'HP:0008209', (83, 111))	('AIs', 'Var', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('carcinoma', 'Disease', (234, 243))	('breast cancer', 'Disease', (98, 111))	('patients', 'Species', '9606', (112, 120))
11429	25230018	Stage and tumor size were inversely correlated with the status of 17betaHSD2 (P = 0.0049 and 0.0299, respectively), and the mean tumor size was also lower in the 17betaHSD2-positive group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('lower', 'NegReg', (149, 154))	('17betaHSD2', 'Gene', (66, 76))	('inversely', 'NegReg', (26, 35))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('17betaHSD2', 'Gene', '3294', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('17betaHSD2', 'Gene', '3294', (66, 76))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('status', 'Var', (56, 62))	('17betaHSD2', 'Gene', (162, 172))
11519	30832620	Previous breast cancer incidence models show that increasing spacing between the 1st and 2nd child birth increases the overall breast cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('breast cancer', 'Disease', (9, 22))	('spacing', 'Var', (61, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('increases', 'PosReg', (105, 114))	('child', 'Species', '9606', (93, 98))
11592	28943914	A tumor-marker panel was analysed using a radioimmunoassay as previously described before, and the results indicated increased levels of cancer antigen (CA)153 (212.90 U/ml), CA125 (502.90 U/ml), CA199 (45.70 U/ml) and carcinoembryonic antigen (CEA; 21.62 ng/ml).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoembryonic antigen', 'Gene', (219, 243))	('increased', 'PosReg', (117, 126))	('CA125', 'Gene', '94025', (175, 180))	('CEA', 'Gene', (245, 248))	('CEA', 'Gene', '1048', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('carcinoembryonic antigen', 'Gene', '1048', (219, 243))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', (2, 7))	('CA125', 'Gene', (175, 180))	('CA199', 'Var', (196, 201))
11774	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))
11778	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', 'biological_process', 'GO:0070265', ('103', '111'))	('necrosis', 'biological_process', 'GO:0008219', ('103', '111'))	('necrosis', 'Disease', (103, 111))	('necrosis', 'biological_process', 'GO:0019835', ('103', '111'))	('necrosis', 'biological_process', 'GO:0008220', ('103', '111'))	('necrosis', 'biological_process', 'GO:0001906', ('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))
11822	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))
11824	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))
11826	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))
11856	29739984	While ILC generally exhibits lower Ki67 positivity than IDC, it has a higher frequency of HER2 and HER3 mutations, PIK3CA mutations, FOXA1 mutations, ESR1 amplifications, and PTEN loss.	('ESR1', 'Gene', (150, 154))	('FOXA1', 'Gene', '3169', (133, 138))	('HER2', 'Gene', '2064', (90, 94))	('loss', 'NegReg', (180, 184))	('HER3', 'Gene', (99, 103))	('PIK3CA', 'Gene', (115, 121))	('IDC', 'Gene', '4000', (56, 59))	('FOXA1', 'Gene', (133, 138))	('IDC', 'Gene', (56, 59))	('mutations', 'Var', (104, 113))	('HER2', 'Gene', (90, 94))	('amplifications', 'Var', (155, 169))	('PTEN', 'Gene', (175, 179))	('HER3', 'Gene', '2065', (99, 103))	('PIK3CA', 'Gene', '5290', (115, 121))	('mutations', 'Var', (139, 148))	('mutations', 'Var', (122, 131))	('ESR1', 'Gene', '2099', (150, 154))	('PTEN', 'Gene', '5728', (175, 179))
11899	29739984	Although some immune genes, like IL7R, and CD36, were now excluded from the list of DE genes, overall, the CPE correction resulted in changes in less than 10% of the DE genes (Supplementary Fig.	('changes', 'Reg', (134, 141))	('CD36', 'Gene', (43, 47))	('IL7R', 'molecular_function', 'GO:0004917', ('33', '37'))	('CPE', 'Gene', (107, 110))	('correction', 'Var', (111, 121))	('CPE', 'Gene', '1363', (107, 110))	('CD36', 'Species', '42374', (43, 47))
11908	29739984	Furthermore, analysis of key regulators of protein translation initiation and elongation also revealed lower expression in ILC compared to IDC including eIF4G, phospho-4E-BP1 (Ser65), eEF2, ribosome protein S6 (S6), phospho-S6 (Ser235/236, Ser240/244), p70-S6K and phospho-mTOR (Ser2448) (Fig.	('mTOR', 'Gene', (273, 277))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('4E-BP1', 'Gene', (168, 174))	('Ser', 'cellular_component', 'GO:0005790', ('228', '231'))	('p70-S6K', 'Gene', '6198', (253, 260))	('translation initiation', 'biological_process', 'GO:0006413', ('51', '73'))	('Ser', 'cellular_component', 'GO:0005790', ('279', '282'))	('eEF2', 'Gene', '1938', (184, 188))	('Ser', 'cellular_component', 'GO:0005790', ('176', '179'))	('mTOR', 'Gene', '2475', (273, 277))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))	('ribosome', 'cellular_component', 'GO:0005840', ('190', '198'))	('p70-S6K', 'Gene', (253, 260))	('eIF4', 'cellular_component', 'GO:0008304', ('153', '157'))	('lower', 'NegReg', (103, 108))	('ILC', 'Disease', (123, 126))	('eIF4G', 'Gene', (153, 158))	('protein translation', 'biological_process', 'GO:0006412', ('43', '62'))	('Ser240/244', 'Var', (240, 250))	('IDC', 'Gene', '4000', (139, 142))	('expression', 'MPA', (109, 119))	('IDC', 'Gene', (139, 142))	('eEF2', 'Gene', (184, 188))	('4E-BP1', 'Gene', '1978', (168, 174))	('Ser', 'cellular_component', 'GO:0005790', ('240', '243'))	('eIF4G', 'Gene', '1981', (153, 158))
11911	29739984	To more directly assess the differences in protein translation in ILC and IDC, we measured protein synthesis rates in three ILC (MDA-MB-134VI, SUM44PE, and MDA-MB-330) and three IDC (MCF7, T47D, and ZR75.1) cell lines.	('IDC', 'Gene', '4000', (74, 77))	('T47D', 'CellLine', 'CVCL:0553', (189, 193))	('IDC', 'Gene', (74, 77))	('MCF7', 'CellLine', 'CVCL:0031', (183, 187))	('MDA-MB-330', 'Var', (156, 166))	('IDC', 'Gene', '4000', (178, 181))	('MDA-MB-134VI', 'CellLine', 'CVCL:0617', (129, 141))	('IDC', 'Gene', (178, 181))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('protein synthesis', 'MPA', (91, 108))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (156, 166))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('protein translation', 'biological_process', 'GO:0006412', ('43', '62'))	('protein synthesis', 'biological_process', 'GO:0006412', ('91', '108'))
11914	29739984	Finally, we tested the effects of the protein translation inhibitors cycloheximide, 4EGI-1 and salubrinal, and detected a trend towards resistance to protein translation inhibitors in the ILC lines, especially in MDA-MB-134VI and MDA-MB-330 (Fig.	('protein translation inhibitors', 'MPA', (150, 180))	('cycloheximide', 'Chemical', 'MESH:D003513', (69, 82))	('protein translation', 'biological_process', 'GO:0006412', ('150', '169'))	('tested', 'Reg', (12, 18))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (230, 240))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('resistance', 'MPA', (136, 146))	('MDA-MB-134VI', 'CellLine', 'CVCL:0617', (213, 225))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('MDA-MB-330', 'Var', (230, 240))	('protein translation', 'biological_process', 'GO:0006412', ('38', '57'))
11917	29739984	These pathways remained significantly lower in ILC after CPE correction (Fig.	('CPE', 'Gene', (57, 60))	('correction', 'Var', (61, 71))	('CPE', 'Gene', '1363', (57, 60))	('lower', 'NegReg', (38, 43))	('ILC', 'Disease', (47, 50))
11919	29739984	This analysis revealed that all three ILC cell lines (MDA-MB-134VI, SUM44PE, MDA-MB-330) had lower OCR and ECAR rates compared to the IDC cell lines (MCF-7, T47D, and ZR-75.1) (Fig.	('T47D', 'CellLine', 'CVCL:0553', (157, 161))	('OCR', 'Chemical', '-', (99, 102))	('MDA-MB-134VI', 'CellLine', 'CVCL:0617', (54, 66))	('IDC', 'Gene', '4000', (134, 137))	('IDC', 'Gene', (134, 137))	('MDA-MB-330', 'Var', (77, 87))	('lower', 'NegReg', (93, 98))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (77, 87))	('MCF-7', 'CellLine', 'CVCL:0031', (150, 155))
11930	29739984	CPE correction uncovered additional pathways such as those related to protein translation.	('protein translation', 'biological_process', 'GO:0006412', ('70', '89'))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('CPE', 'Gene', (0, 3))	('correction', 'Var', (4, 14))	('CPE', 'Gene', '1363', (0, 3))
11941	29739984	Furthermore, recent studies indicated that cancers with PD-L1 overexpression had better response to anti-PD-1 therapy.	('PD-L1', 'Gene', '29126', (56, 61))	('PD-1', 'Gene', '5133', (105, 109))	('better', 'PosReg', (81, 87))	('overexpression', 'Var', (62, 76))	('response', 'MPA', (88, 96))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('PD-L1', 'Gene', (56, 61))	('PD-1', 'Gene', (105, 109))
11944	29739984	It is well known that dysregulation of protein translation is involved in the development and progression of various tumor types.	('dysregulation', 'Var', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('protein translation', 'biological_process', 'GO:0006412', ('39', '58'))	('tumor', 'Disease', (117, 122))	('involved', 'Reg', (62, 70))	('protein', 'Protein', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
11945	29739984	In breast cancer, high levels of eIF4E and phosphorylation of 4E-BP1 and S6 are correlated with worse survival.	('eIF4E', 'Gene', '1977', (33, 38))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('phosphorylation', 'MPA', (43, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('4E-BP1', 'Gene', '1978', (62, 68))	('eIF4E', 'Gene', (33, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('high', 'Var', (18, 22))	('eIF4', 'cellular_component', 'GO:0008304', ('33', '37'))	('4E-BP1', 'Gene', (62, 68))
11968	29739984	Cycloheximide (C4859; Sigma-Aldrich, St. Louis, MO, USA), 4EGI-1 (S7369; Selleck Chemicals, Houston, TX, USA), and Salubrinal (SC-202332A; Santa Cruz, Dallas, TX, USA) were dissolved in DMSO (4-X; ATCC).	('Cycloheximide', 'Chemical', 'MESH:D003513', (0, 13))	('DMSO', 'Chemical', 'MESH:D004121', (186, 190))	('SC-202332A;', 'Var', (127, 138))	('C4859;', 'Var', (15, 21))
12024	27313924	Laboratory evaluation showed that the cancer antigen 15-3 level had dropped to 4879.0 kU/L compared to 7691.0 kU/L just before Tamoxifen was initiated.	('cancer antigen 15-3', 'Gene', '4582', (38, 57))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('dropped', 'NegReg', (68, 75))	('cancer antigen 15-3', 'Gene', (38, 57))	('4879.0 kU/L', 'Var', (79, 90))	('Tamoxifen', 'Chemical', 'MESH:D013629', (127, 136))
12049	20647335	Multivariable analysis revealed several factors that were associated with a patient undergoing CPM: age younger than 50 years, white ethnicity, family history of breast cancer, BRCA1/2 mutation testing, invasive lobular histology, clinical stage and use of reconstruction.	('BRCA1/2', 'Gene', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('patient', 'Species', '9606', (76, 83))	('mutation testing', 'Var', (185, 201))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('BRCA1/2', 'Gene', '672;675', (177, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))	('CPM', 'Chemical', '-', (95, 98))
12055	20647335	Patients with unilateral breast cancer who have germline mutations in BRCA1/2 have a markedly increased risk of developing CBC .	('unilateral breast cancer', 'Disease', 'MESH:D000069584', (14, 38))	('CBC', 'cellular_component', 'GO:0005846', ('123', '126'))	('BRCA1/2', 'Gene', '672;675', (70, 77))	('Patients', 'Species', '9606', (0, 8))	('unilateral breast', 'Phenotype', 'HP:0012813', (14, 31))	('CBC', 'Disease', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('unilateral breast cancer', 'Disease', (14, 38))	('germline mutations', 'Var', (48, 66))	('BRCA1/2', 'Gene', (70, 77))
12060	20647335	The decision making process should include assessing the patient's risk of CBC, which can vary according to age, genetic factors such as BRCA1/2 mutation status, tumor histology and multicentricity.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('patient', 'Species', '9606', (57, 64))	('CBC', 'cellular_component', 'GO:0005846', ('75', '78'))	('tumor', 'Disease', (162, 167))	('CBC', 'Disease', (75, 78))	('BRCA1/2', 'Gene', '672;675', (137, 144))	('BRCA1/2', 'Gene', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('mutation', 'Var', (145, 153))
12071	20647335	We reviewed patient charts for demographics, disease, and treatment characteristics, including year of surgery, age at the time of diagnosis, ethnicity, marital status, use of hormone replacement therapy, family history of breast cancer, clinical tumor stage, use of pretreatment magnetic resonance imaging (MRI), type of surgery for primary tumor, performance and timing of CPM, reported reasons for undergoing CPM, surgeon characteristics (gender, age), use and type of reconstructive surgery, genetic testing for BRCA 1/2 mutations and results, histology of the primary tumor (invasive lobular carcinoma versus other histology), estrogen receptor (ER) status, and progesterone receptor (PR) status of the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (573, 578))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('CPM', 'Chemical', '-', (375, 378))	('mutations', 'Var', (525, 534))	('breast cancer', 'Disease', (223, 236))	('PR', 'Gene', '5241', (690, 692))	('BRCA 1', 'Gene', '672', (516, 522))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (589, 606))	('tumor', 'Disease', (342, 347))	('tumor', 'Disease', (716, 721))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (580, 606))	('progesterone receptor', 'Gene', (667, 688))	('tumor', 'Disease', (573, 578))	('CPM', 'Chemical', '-', (412, 415))	('progesterone receptor', 'Gene', '5241', (667, 688))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('tumor', 'Disease', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (716, 721))	('tumor', 'Disease', 'MESH:D009369', (573, 578))	('invasive lobular carcinoma', 'Disease', (580, 606))	('patient', 'Species', '9606', (12, 19))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('BRCA 1', 'Gene', (516, 522))	('carcinoma', 'Phenotype', 'HP:0030731', (597, 606))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('tumor', 'Phenotype', 'HP:0002664', (716, 721))
12096	20647335	Patients with younger age, other ethnicity, single status, who had BRCA1/2 genetic testing before surgery, higher clinical tumor stage, and use of reconstructive surgery were more likely to undergo delayed CPM instead of immediate CPM.	('tumor', 'Disease', (123, 128))	('CPM', 'Chemical', '-', (206, 209))	('BRCA1/2', 'Gene', (67, 74))	('Patients', 'Species', '9606', (0, 8))	('delayed CPM', 'MPA', (198, 209))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('BRCA1/2', 'Gene', '672;675', (67, 74))	('genetic testing', 'Var', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('CPM', 'Chemical', '-', (231, 234))
12101	20647335	Eight of these patients had a deleterious BRCA1/2 mutation identified and then proceeded to undergo CPM.	('BRCA1/2', 'Gene', (42, 49))	('patients', 'Species', '9606', (15, 23))	('CPM', 'Chemical', '-', (100, 103))	('BRCA1/2', 'Gene', '672;675', (42, 49))	('mutation', 'Var', (50, 58))
12102	20647335	Interestingly, 10 patients who underwent genetic testing and were found not to carry a deleterious BRCA1/2 mutation still chose to undergo CPM.	('mutation', 'Var', (107, 115))	('BRCA1/2', 'Gene', (99, 106))	('patients', 'Species', '9606', (18, 26))	('BRCA1/2', 'Gene', '672;675', (99, 106))	('CPM', 'Chemical', '-', (139, 142))
12105	20647335	Of 2504 women with stage 0-III unilateral breast cancer who underwent breast-conserving surgery or mastectomy for their primary tumor at our institution, we found that 11.3% underwent CPM.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CPM', 'Chemical', '-', (184, 187))	('women', 'Species', '9606', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('unilateral breast cancer', 'Disease', (31, 55))	('unilateral breast', 'Phenotype', 'HP:0012813', (31, 48))	('CPM', 'Var', (184, 187))	('unilateral breast cancer', 'Disease', 'MESH:D000069584', (31, 55))
12117	20647335	For example, in all patients who underwent surgery for breast cancer and in those who underwent mastectomy for treatment of their primary tumor, Caucasian race was associated with significantly higher CPM rates.	('higher', 'PosReg', (194, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('tumor', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('patients', 'Species', '9606', (20, 28))	('breast cancer', 'Disease', (55, 68))	('Caucasian race', 'Var', (145, 159))	('CPM', 'Chemical', '-', (201, 204))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('CPM', 'CPA', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
12125	20647335	In addition, among BRCA1/2 mutation carriers, younger age at diagnosis of the first breast cancer predicts a higher risk of CBC .	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('CBC', 'Disease', (124, 127))	('CBC', 'cellular_component', 'GO:0005846', ('124', '127'))	('BRCA1/2', 'Gene', (19, 26))	('mutation', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('BRCA1/2', 'Gene', '672;675', (19, 26))	('breast cancer', 'Disease', (84, 97))
12126	20647335	Furthermore, even among women without a recognized genetic predisposition to breast cancer, younger women would still be expected to derive more benefit from CPM owing to their longer life expectancy and subsequently higher expected lifetime risk of developing another primary breast cancer.	('breast cancer', 'Disease', (77, 90))	('CPM', 'Chemical', '-', (158, 161))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('breast cancer', 'Disease', (277, 290))	('CPM', 'Var', (158, 161))	('women', 'Species', '9606', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('women', 'Species', '9606', (100, 105))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
12138	20647335	Indeed, in a previous study, we found that bilateral mastectomy for unilateral cancer conferred a higher risk of complications than unilateral mastectomy, with 8.4% of the complications occurring on the primary side, 6.3% occurring on the contralateral side, and 1.7% occurring bilaterally; thus, CPM does increase the complexity of the surgical procedure and may increase the complications incurred .	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('increase', 'PosReg', (306, 314))	('CPM', 'Chemical', '-', (297, 300))	('unilateral cancer', 'Disease', (68, 85))	('CPM', 'Var', (297, 300))	('increase', 'PosReg', (364, 372))	('unilateral cancer', 'Disease', 'MESH:D000069584', (68, 85))
12139	20647335	Breast cancer patients with deleterious BRCA1/2 mutations have a significantly increased risk of developing CBC .	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('CBC', 'cellular_component', 'GO:0005846', ('108', '111'))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('BRCA1/2', 'Gene', (40, 47))	('BRCA1/2', 'Gene', '672;675', (40, 47))	('Breast cancer', 'Disease', (0, 13))	('mutations', 'Var', (48, 57))	('CBC', 'Disease', (108, 111))	('patients', 'Species', '9606', (14, 22))
12143	20647335	In our study, genetic testing for BRCA1/2 mutations was associated with patients choosing to undergo CPM.	('CPM', 'Disease', (101, 104))	('BRCA1/2', 'Gene', (34, 41))	('BRCA1/2', 'Gene', '672;675', (34, 41))	('associated', 'Reg', (56, 66))	('genetic testing', 'Var', (14, 29))	('CPM', 'Chemical', '-', (101, 104))	('mutations', 'Var', (42, 51))	('patients', 'Species', '9606', (72, 80))
12146	20647335	Although there is evidence that CPM does in fact decrease CBC risk , the impact of CPM on survival has been more controversial.	('decrease', 'NegReg', (49, 57))	('CPM', 'Chemical', '-', (83, 86))	('CBC', 'cellular_component', 'GO:0005846', ('58', '61'))	('CBC', 'Disease', (58, 61))	('CPM', 'Var', (32, 35))	('CPM', 'Chemical', '-', (32, 35))
12147	20647335	If there is indeed a survival benefit from CPM, it could be hypothesized that the benefit would be greatest in patients with early-stage cancer, who have the lowest risk of death from the primary cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CPM', 'Chemical', '-', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('CPM', 'Var', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (196, 202))	('patients', 'Species', '9606', (111, 119))
12148	20647335	reported that in BRCA1/2 mutation carriers, patients with early-stage node-negative breast cancer would be expected to have the greatest gains in life expectancy after CPM .	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('patients', 'Species', '9606', (44, 52))	('BRCA1/2', 'Gene', '672;675', (17, 24))	('CPM', 'Chemical', '-', (168, 171))	('mutation', 'Var', (25, 33))	('life expectancy', 'CPA', (146, 161))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gains', 'PosReg', (137, 142))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('BRCA1/2', 'Gene', (17, 24))	('breast cancer', 'Disease', (84, 97))
12154	20647335	reported that patients who underwent CPM were more likely to undergo breast reconstruction than patients who did not undergo CPM .	('CPM', 'Chemical', '-', (37, 40))	('breast', 'Disease', (69, 75))	('patients', 'Species', '9606', (96, 104))	('CPM', 'Chemical', '-', (125, 128))	('patients', 'Species', '9606', (14, 22))	('CPM', 'Var', (37, 40))
12267	24166728	However, NAC might also induce reactive changes, such as fibrosis and inflammation, and result in non-specific contrast enhancements leading to overestimated tumor size by MRI.	('inflammation', 'Disease', 'MESH:D007249', (70, 82))	('NAC', 'cellular_component', 'GO:0005854', ('9', '12'))	('tumor', 'Disease', (158, 163))	('induce', 'Reg', (24, 30))	('inflammation', 'Disease', (70, 82))	('contrast', 'MPA', (111, 119))	('NAC', 'Var', (9, 12))	('enhancements', 'PosReg', (120, 132))	('NAC', 'Chemical', '-', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('overestimated', 'PosReg', (144, 157))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('inflammation', 'biological_process', 'GO:0006954', ('70', '82'))	('fibrosis', 'Disease', 'MESH:D005355', (57, 65))	('fibrosis', 'Disease', (57, 65))
12332	23181716	It has been described that numerous autologous proteins of tumor cells, generally known as tumor-associated antigens (TAAs), can elicit humoral immune response in cancer patients as a result of their aberrant expression , alternative splicing of pre-messenger RNAs , point mutations , aberrant localization, folding , degradation  and/or post-translation alteration .	('expression', 'MPA', (209, 219))	('tumor', 'Disease', (59, 64))	('localization', 'biological_process', 'GO:0051179', ('294', '306'))	('humoral immune response', 'biological_process', 'GO:0006959', ('136', '159'))	('pre-messenger', 'Protein', (246, 259))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('aberrant', 'Var', (200, 208))	('tumor', 'Disease', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('point mutations', 'Var', (267, 282))	('aberrant', 'Var', (285, 293))	('translation', 'biological_process', 'GO:0006412', ('343', '354'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('elicit', 'PosReg', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('expression', 'Species', '29278', (209, 219))	('patients', 'Species', '9606', (170, 178))	('pre', 'molecular_function', 'GO:0003904', ('246', '249'))	('humoral immune response', 'MPA', (136, 159))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('post-translation', 'MPA', (338, 354))	('folding', 'MPA', (308, 315))	('cancer', 'Disease', (163, 169))	('degradation', 'biological_process', 'GO:0009056', ('318', '329'))	('alternative splicing', 'Var', (222, 242))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('degradation', 'MPA', (318, 329))	('localization', 'MPA', (294, 306))	('splicing', 'biological_process', 'GO:0045292', ('234', '242'))
12360	23181716	Endogenous peroxidase was quenched with H2O2 (3%) in 0.01% PBS.	('H2O2', 'Chemical', 'MESH:D006861', (40, 44))	('H2O2', 'Var', (40, 44))	('quenched', 'NegReg', (26, 34))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('PBS', 'Chemical', '-', (59, 62))
12426	23181716	Notably, LRRFIP1 can be mutated in breast tumors and soft tissue sarcomas , and may be involved in the regulation of cell growth .	('mutated', 'Var', (24, 31))	('breast tumors', 'Disease', (35, 48))	('LRRFIP1', 'Gene', '9208', (9, 16))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (53, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('involved', 'Reg', (87, 95))	('breast tumor', 'Phenotype', 'HP:0100013', (35, 47))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (53, 73))	('breast tumors', 'Phenotype', 'HP:0100013', (35, 48))	('regulation of cell growth', 'biological_process', 'GO:0001558', ('103', '128'))	('LRRFIP1', 'Gene', (9, 16))	('soft tissue sarcomas', 'Disease', (53, 73))	('breast tumors', 'Disease', 'MESH:D001943', (35, 48))
12548	33446123	The reason behind increased risk of breast cancer with first pregnancy at age 35 may be breast tissue which are responsible of carrying cluster of cells with cancer causing mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('breast cancer', 'Disease', (36, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('age', 'Gene', (74, 77))	('age', 'Gene', '5973', (74, 77))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('mutation', 'Var', (173, 181))
12551	33446123	A study done in Bangui of Central Africa showed that lack of education was significantly associated with breast cancer (p-value< 0.001).	('lack of education', 'Var', (53, 70))	('associated', 'Reg', (89, 99))	('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))
12564	33446123	The major reason behind this association might be inherited gene mutation such as Breast Cancer Gene 1 (BRCA1) or Breast Cancer Gene 2 (BRCA2) mutations.	('Breast Cancer', 'Disease', (82, 95))	('Breast Cancer', 'Disease', 'MESH:D001943', (114, 127))	('BRCA1', 'Gene', '672', (104, 109))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Breast Cancer', 'Disease', 'MESH:D001943', (82, 95))	('BRCA1', 'Gene', (104, 109))	('Breast Cancer', 'Phenotype', 'HP:0003002', (114, 127))	('BRCA2', 'Gene', (136, 141))	('Cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Breast Cancer', 'Disease', (114, 127))	('Breast Cancer', 'Phenotype', 'HP:0003002', (82, 95))	('mutations', 'Var', (143, 152))	('BRCA2', 'Gene', '675', (136, 141))
12604	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('114', '129'))	('increased', 'PosReg', (27, 36))	('tyrosine', 'Chemical', 'MESH:D014443', (162, 170))	('Tyr674', 'Chemical', '-', (133, 139))	('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))	('kinase activity', 'molecular_function', 'GO:0016301', ('171', '186'))	('TrkA', 'Gene', '4914', (216, 220))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('phosphorylation', 'MPA', (114, 129))	('pleural effusions', 'Phenotype', 'HP:0002202', (90, 107))
12639	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))	('gene expression', 'biological_process', 'GO:0010467', ('44', '59'))	('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))
12640	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))
12643	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))
12656	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))
12659	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))	('glycosylation', 'biological_process', 'GO:0070085', ('91', '104'))	('SK-BR-3', 'CellLine', 'CVCL:0033', (127, 134))	('~180 kDa', 'Var', (53, 61))
12664	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))
12667	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))	('Ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('Tyr490', 'Var', (21, 27))
12669	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))	('GNF-5837', 'Var', (9, 17))	('Herceptin', 'Chemical', 'MESH:D000068878', (59, 68))	('cytotoxic', 'MPA', (39, 48))
12677	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))
12691	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))	('Erk1', 'molecular_function', 'GO:0004707', ('163', '167'))	('AKT', 'Gene', (179, 182))	('overexpression', 'Var', (70, 84))	('Erk1/2', 'Gene', '5595;5594', (163, 169))	('growth', 'CPA', (94, 100))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('signaling', 'biological_process', 'GO:0023052', ('192', '201'))	('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))	('PI3K', 'molecular_function', 'GO:0016303', ('174', '178'))	('TrkA', 'Gene', '4914', (65, 69))	('activation', 'PosReg', (149, 159))
12795	31608201	The results indicated that the lesions were from two distinct primary tumors with breast cancer cells harboring a TP53 frameshift mutation and the ovarian lesion displaying a distinct TP53 nonsense mutation .	('breast cancer', 'Disease', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('primary tumors', 'Disease', (62, 76))	('ovarian lesion', 'Disease', (147, 161))	('ovarian lesion', 'Phenotype', 'HP:0100615', (147, 161))	('TP53', 'Gene', '7157', (114, 118))	('TP53', 'Gene', '7157', (184, 188))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('TP53', 'Gene', (184, 188))	('ovarian lesion', 'Disease', 'MESH:D010049', (147, 161))	('primary tumors', 'Disease', 'MESH:D001932', (62, 76))	('TP53', 'Gene', (114, 118))	('frameshift mutation', 'Var', (119, 138))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
12796	31608201	Further, the peritoneal lesions harbored the same mutation as the ovarian mass, in addition to a distinct Nuclear Receptor Coactivator 2 (NCOA2) mutation .	('Nuclear Receptor Coactivator 2', 'Gene', (106, 136))	('NCOA2', 'Gene', '10499', (138, 143))	('NCOA2', 'Gene', (138, 143))	('Nuclear Receptor Coactivator 2', 'Gene', '10499', (106, 136))	('harbored', 'Reg', (32, 40))	('mutation', 'Var', (50, 58))	('mutation', 'Var', (145, 153))
12841	30568591	Mutations of CDH1, the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome.	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('E-cadherin', 'Gene', (37, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('cadherin', 'molecular_function', 'GO:0008014', ('39', '47'))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('E-cadherin', 'Gene', '999', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Mutations', 'Var', (0, 9))	('underlie', 'Reg', (119, 127))	('hereditary diffuse gastric cancer (HDGC) syndrome', 'Disease', 'MESH:D013274', (128, 177))	('gastric cancer', 'Disease', (147, 161))	('CDH1', 'Gene', (13, 17))	('gastric cancer', 'Disease', (100, 114))
12843	30568591	Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of CDH1 mutation carriers; these criteria have been proven to have excellent sensitivity and specificity.	('CDH1', 'Gene', (8, 12))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (123, 137))	('mutation', 'Var', (220, 228))	('CDH1', 'Gene', (215, 219))	('mutations', 'Var', (22, 31))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Disease', (131, 137))	('Cancer', 'Disease', 'MESH:D009369', (131, 137))
12848	30568591	This review focuses on molecular and histological findings in HDGC, as opposed to sporadic diffuse gastric cancer, and their implications for the management of CDH1 mutation carriers and the diagnosis and treatment of HDGC.	('HDGC', 'Disease', 'MESH:D013274', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastric cancer', 'Disease', (99, 113))	('mutation', 'Var', (165, 173))	('CDH1', 'Gene', (160, 164))	('HDGC', 'Disease', (62, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('HDGC', 'Disease', 'MESH:D013274', (218, 222))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('HDGC', 'Disease', (218, 222))
12862	30568591	For example, MAP3K6 germline mutations have also been associated with familial gastric cancer, and the gastric cancers associated with MAP3K6 predominantly have a signet ring cell morphology, although a minor glandular component has been described (Gaston et al.,).	('MAP3K6', 'Gene', '9064', (135, 141))	('gastric cancers', 'Disease', (103, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('MAP3K', 'molecular_function', 'GO:0004709', ('135', '140'))	('familial gastric cancer', 'Disease', (70, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MAP3K6', 'Gene', (13, 19))	('germline mutations', 'Var', (20, 38))	('familial gastric cancer', 'Disease', 'MESH:D013274', (70, 93))	('gastric cancers', 'Disease', 'MESH:D013274', (103, 118))	('MAP3K6', 'Gene', '9064', (13, 19))	('MAP3K6', 'Gene', (135, 141))	('gastric cancers', 'Phenotype', 'HP:0012126', (103, 118))	('MAP3K', 'molecular_function', 'GO:0004709', ('13', '18'))	('associated', 'Reg', (54, 64))
12864	30568591	In addition to CDH1, the gene encoding E-cadherin, germline pathogenic variants in PALB2 and other cancer-predisposing genes have been identified by whole-exome sequencing of HDGC families (Fewings et al.,).	('variants', 'Var', (71, 79))	('E-cadherin', 'Gene', (39, 49))	('HDGC', 'Disease', (175, 179))	('E-cadherin', 'Gene', '999', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('PALB2', 'Gene', (83, 88))	('PALB2', 'Gene', '79728', (83, 88))	('HDGC', 'Disease', 'MESH:D013274', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))
12866	30568591	Although CDH1 somatic mutations are present in up to 50% of sporadic diffuse gastric carcinoma (SDGC) (Becker et al.,) and epigenetic inactivation of CDH1 had been detected in several tumor types (Yoshiura et al.,), it was not until 1998 that Guilford (Guilford et al.,) reported the presence of a CDH1 mutation in a large kindred from New Zealand with early-onset diffuse gastric cancer.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (373, 387))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('gastric carcinoma', 'Disease', (77, 94))	('tumor', 'Disease', (184, 189))	('CDH1', 'Gene', (9, 13))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (77, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('gastric cancer', 'Disease', (373, 387))	('mutation', 'Var', (303, 311))	('CDH1', 'Gene', (298, 302))	('gastric cancer', 'Disease', 'MESH:D013274', (373, 387))	('gastric carcinoma', 'Disease', 'MESH:D013274', (77, 94))
12867	30568591	This seminal study, for the first time, established the pathogenic role of CDH1 mutations in HDGC.	('HDGC', 'Disease', (93, 97))	('CDH1', 'Gene', (75, 79))	('HDGC', 'Disease', 'MESH:D013274', (93, 97))	('mutations', 'Var', (80, 89))
12868	30568591	CDH1 germline mutations are detected in approximately 25% of HDGC patients and are inherited in an autosomal-dominant fashion (Caldas et al.,).	('HDGC', 'Disease', (61, 65))	('patients', 'Species', '9606', (66, 74))	('HDGC', 'Disease', 'MESH:D013274', (61, 65))	('mutations', 'Var', (14, 23))	('CDH1', 'Gene', (0, 4))
12870	30568591	In addition to having an increased risk of gastric cancer, CDH1 mutation carriers also have an increased risk of lobular breast carcinoma.	('breast carcinoma', 'Phenotype', 'HP:0003002', (121, 137))	('mutation', 'Var', (64, 72))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (25, 57))	('gastric cancer', 'Disease', 'MESH:D013274', (43, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('gastric cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lobular breast carcinoma', 'Disease', (113, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (43, 57))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (113, 137))	('CDH1', 'Gene', (59, 63))
12872	30568591	HDGC patients with germline CDH1 mutations have lower 1 and 5 years survival rates (36 and 4%, respectively) than HDGC patients without germline CDH1 mutations do (48 and 13%, respectively) (van der Post et al.,), emphasizing the importance of screening for CDH1 germline mutations (Benusiglio et al.,).	('HDGC', 'Disease', 'MESH:D013274', (0, 4))	('CDH1', 'Gene', (28, 32))	('patients', 'Species', '9606', (5, 13))	('HDGC', 'Disease', (0, 4))	('lower', 'NegReg', (48, 53))	('patients', 'Species', '9606', (119, 127))	('HDGC', 'Disease', 'MESH:D013274', (114, 118))	('mutations', 'Var', (33, 42))	('HDGC', 'Disease', (114, 118))
12873	30568591	The International Gastric Cancer Linkage Consortium (IGCLC) defined the clinical criteria to select patients eligible for CDH1 germline mutations: (1) two or more documented cases of gastric cancer in first- or second-degree relatives regardless of age, with at least one confirmed diffuse gastric cancer; (2) diffuse gastric cancer before age 40 years without a family history; or (3) families with diagnoses of both diffuse gastric cancer and lobular breast carcinoma, at least one before age 50 years (van der Post et al.,).	('gastric cancer', 'Disease', (183, 197))	('gastric cancer', 'Phenotype', 'HP:0012126', (426, 440))	('gastric cancer', 'Disease', 'MESH:D013274', (318, 332))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (18, 32))	('patients', 'Species', '9606', (100, 108))	('mutations', 'Var', (136, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('gastric cancer', 'Phenotype', 'HP:0012126', (290, 304))	('gastric cancer', 'Disease', 'MESH:D013274', (183, 197))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (445, 469))	('gastric cancer', 'Phenotype', 'HP:0012126', (318, 332))	('gastric cancer', 'Disease', (426, 440))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Cancer', 'Disease', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('lobular breast carcinoma', 'Disease', (445, 469))	('gastric cancer', 'Phenotype', 'HP:0012126', (183, 197))	('gastric cancer', 'Disease', (290, 304))	('cancer', 'Phenotype', 'HP:0002664', (434, 440))	('gastric cancer', 'Disease', 'MESH:D013274', (426, 440))	('CDH1', 'Gene', (122, 126))	('breast carcinoma', 'Phenotype', 'HP:0003002', (453, 469))	('gastric cancer', 'Disease', (318, 332))	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (290, 304))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
12874	30568591	One study showed that HDGC patients without a known CDH1 mutation diagnosed by multigene cancer panel before surgery were more likely to have metastatic disease and die of their disease than were patients with known CDH1 mutation status (Moslim et al.,), suggesting that genetic counseling and detection of CDH1 mutations in asymptomatic carriers improves HDGC patient survival.	('HDGC', 'Disease', 'MESH:D013274', (356, 360))	('HDGC', 'Disease', (22, 26))	('metastatic disease', 'CPA', (142, 160))	('CDH1', 'Gene', (307, 311))	('HDGC', 'Disease', (356, 360))	('CDH1', 'Gene', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('patient', 'Species', '9606', (196, 203))	('patients', 'Species', '9606', (196, 204))	('patient', 'Species', '9606', (27, 34))	('patients', 'Species', '9606', (27, 35))	('cancer', 'Disease', (89, 95))	('mutations', 'Var', (312, 321))	('improves', 'PosReg', (347, 355))	('HDGC', 'Disease', 'MESH:D013274', (22, 26))	('patient', 'Species', '9606', (361, 368))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
12875	30568591	This review will discuss current molecular and histological findings in HDGC, as opposed to SDGC, and their implications for the management of CDH1 mutation carriers and the diagnosis and treatment of HDGC.	('HDGC', 'Disease', 'MESH:D013274', (201, 205))	('HDGC', 'Disease', 'MESH:D013274', (72, 76))	('HDGC', 'Disease', (72, 76))	('HDGC', 'Disease', (201, 205))	('mutation', 'Var', (148, 156))	('CDH1', 'Gene', (143, 147))
12877	30568591	More than 100 CDH1 pathogenic germline variants have been described in HDGC families (Hansford et al.,), and they are scattered across the entire gene, including introns and each of 16 exons (Corso et al.,; Melo et al.,; Li et al.,).	('CDH1', 'Gene', (14, 18))	('pathogenic', 'Reg', (19, 29))	('HDGC', 'Disease', 'MESH:D013274', (71, 75))	('variants', 'Var', (39, 47))	('HDGC', 'Disease', (71, 75))
12878	30568591	Cases of sporadic gastric cancer with pathologic germline mutations have also been reported (Garziera et al.,).	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (9, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('germline mutations', 'Var', (49, 67))	('sporadic gastric cancer', 'Disease', (9, 32))
12888	30568591	Reduced or absent E-cadherin expression is seen in both the in situ and invasive components of HDGC, suggesting that inactivation of E-cadherin is an early event (Carneiro et al.,).	('absent', 'NegReg', (11, 17))	('HDGC', 'Disease', (95, 99))	('E-cadherin', 'Gene', (133, 143))	('inactivation', 'Var', (117, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('cadherin', 'molecular_function', 'GO:0008014', ('135', '143'))	('absent E-cadherin', 'Phenotype', 'HP:0030117', (11, 28))	('E-cadherin', 'Gene', '999', (133, 143))	('expression', 'MPA', (29, 39))	('HDGC', 'Disease', 'MESH:D013274', (95, 99))	('E-cadherin', 'Gene', (18, 28))	('E-cadherin', 'Gene', '999', (18, 28))
12889	30568591	E-cadherin loss generally correlates with the identification of an alteration of the second CDH1 allele (i.e., a second hit) (Barber et al.,).	('alteration', 'Var', (67, 77))	('loss', 'NegReg', (11, 15))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('CDH1', 'Gene', (92, 96))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', '999', (0, 10))
12896	30568591	Conditional knockout of CDH1 in mouse stomach induces signet ring-like cells in stroma (analogous to intramucosal signet ring cell carcinoma) but not the development of carcinoma invading into submucosa (Mimata et al.,).	('CDH1', 'Gene', (24, 28))	('carcinoma', 'Disease', 'MESH:D002277', (131, 140))	('knockout', 'Var', (12, 20))	('intramucosal signet ring cell carcinoma', 'Disease', 'MESH:D018279', (101, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinoma', 'Disease', 'MESH:D002277', (169, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('intramucosal signet ring cell carcinoma', 'Disease', (101, 140))	('carcinoma', 'Disease', (131, 140))	('carcinoma', 'Disease', (169, 178))	('mouse', 'Species', '10090', (32, 37))	('induces', 'Reg', (46, 53))	('signet ring-like cells in stroma', 'CPA', (54, 86))
12908	30568591	Loss of EGFR inhibition increases the activation of EGFR and its downstream components, such as phosphoinositide 3-kinase and c-Src.	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('inhibition', 'Var', (13, 23))	('activation', 'MPA', (38, 48))	('phosphoinositide 3-kinase', 'MPA', (96, 121))	('EGFR', 'Gene', '1956', (8, 12))	('Loss', 'NegReg', (0, 4))	('c-Src', 'Gene', (126, 131))	('c-Src', 'Gene', '6714', (126, 131))	('EGFR', 'Gene', (8, 12))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
12911	30568591	Association between specific CDH1 polymorphisms with a subset of HER2-positive gastric cancer and possibly favorable prognosis has been described (Caggiari et al.,).	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))	('HER2', 'Gene', '2064', (65, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('Association', 'Interaction', (0, 11))	('polymorphisms', 'Var', (34, 47))	('CDH1', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('gastric cancer', 'Disease', (79, 93))	('HER2', 'Gene', (65, 69))
12926	30568591	Periodic acid-Schiff (PAS) staining is superior to hematoxylin and eosin (HE) staining for screening prophylactic gastrectomy specimens from CDH1 mutation carriers (Lee et al.,).	('Periodic acid-Schiff', 'Chemical', '-', (0, 20))	('CDH1', 'Gene', (141, 145))	('PAS', 'Chemical', '-', (22, 25))	('carriers', 'Reg', (155, 163))	('HE', 'Chemical', '-', (74, 76))	('PAS', 'cellular_component', 'GO:0000407', ('22', '25'))	('eosin', 'Chemical', 'MESH:D004801', (67, 72))	('hematoxylin', 'Chemical', 'MESH:D006416', (51, 62))	('mutation', 'Var', (146, 154))
12934	30568591	The process of basement membrane breakthrough, which is still hypothetical, may be induced by the expression of type IV collagenases, which have been found to be upregulated when E-cadherin is downregulated through the inactivation of the other copy of CDH1 gene (Margulis et al.,).	('downregulated', 'NegReg', (193, 206))	('basement membrane', 'cellular_component', 'GO:0005604', ('15', '32'))	('inactivation', 'Var', (219, 231))	('cadherin', 'molecular_function', 'GO:0008014', ('181', '189'))	('E-cadherin', 'Gene', (179, 189))	('E-cadherin', 'Gene', '999', (179, 189))	('upregulated', 'PosReg', (162, 173))	('CDH1', 'Gene', (253, 257))	('basement membrane breakthrough', 'CPA', (15, 45))
12943	30568591	Despite the seemingly different differentiation, both large and small cells express the epithelial markers cytokeratin 8 and 18 but not markers of epithelial-mesenchymal transition such as vimentin, high Ki67 (Barber et al.,), and c-Src (Humar et al.,).	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('147', '180'))	('vimentin', 'cellular_component', 'GO:0045099', ('189', '197'))	('c-Src', 'Gene', (231, 236))	('vimentin', 'Gene', (189, 197))	('cytokeratin 8', 'Gene', '3856', (107, 120))	('c-Src', 'Gene', '6714', (231, 236))	('vimentin', 'cellular_component', 'GO:0045098', ('189', '197'))	('vimentin', 'Gene', '7431', (189, 197))	('high Ki67', 'Var', (199, 208))	('cytokeratin 8', 'Gene', (107, 120))
12946	30568591	The long and asymptomatic presence of intramucosal carcinoma in CDH1 mutation carriers and the low proliferative index suggest that intramucosal carcinoma has an indolent nature.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('intramucosal carcinoma', 'Disease', 'MESH:D002277', (132, 154))	('intramucosal carcinoma', 'Disease', (132, 154))	('mutation', 'Var', (69, 77))	('carriers', 'Reg', (78, 86))	('intramucosal carcinoma', 'Disease', 'MESH:D002277', (38, 60))	('intramucosal carcinoma', 'Disease', (38, 60))	('CDH1', 'Gene', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
12950	30568591	Several patterns of E-cadherin have been detected immunohistochemically, including complete loss of staining, attenuated staining, and aberrant staining.	('attenuated', 'NegReg', (110, 120))	('E-cadherin', 'Gene', (20, 30))	('E-cadherin', 'Gene', '999', (20, 30))	('loss', 'NegReg', (92, 96))	('staining', 'MPA', (100, 108))	('staining', 'MPA', (121, 129))	('aberrant staining', 'Var', (135, 152))	('cadherin', 'molecular_function', 'GO:0008014', ('22', '30'))
12951	30568591	However, screening by E-cadherin immunohistochemical staining is not feasible, because 60% of gastric cancers without E-cadherin expression and 70% of gastric cancers with aberrant expression are negative for CDH1 alterations (Corso et al.,).	('E-cadherin', 'Gene', (118, 128))	('negative', 'NegReg', (196, 204))	('E-cadherin', 'Gene', '999', (118, 128))	('E-cadherin', 'Gene', (22, 32))	('E-cadherin', 'Gene', '999', (22, 32))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('gastric cancers', 'Disease', 'MESH:D013274', (151, 166))	('gastric cancers', 'Disease', (151, 166))	('gastric cancers', 'Phenotype', 'HP:0012126', (151, 166))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('gastric cancers', 'Disease', 'MESH:D013274', (94, 109))	('cadherin', 'molecular_function', 'GO:0008014', ('24', '32'))	('gastric cancers', 'Disease', (94, 109))	('gastric cancers', 'Phenotype', 'HP:0012126', (94, 109))	('CDH1', 'Gene', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('alterations', 'Var', (214, 225))	('without', 'NegReg', (110, 117))
12953	30568591	Signet ring cell carcinoma in situ, including pagetoid spread of signet ring cells, appears specific to HDGC with CDH1 mutations, as it has not been reported in SDGC (Carneiro et al.,; Fitzgerald et al.,) or HDGC without germline CDH1 mutations (van der Post et al.,).	('HDGC', 'Disease', (208, 212))	('HDGC', 'Disease', 'MESH:D013274', (104, 108))	('ring cell carcinoma', 'Disease', (7, 26))	('ring cell carcinoma', 'Disease', 'MESH:D018279', (7, 26))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (17, 34))	('CDH1', 'Gene', (114, 118))	('HDGC', 'Disease', (104, 108))	('HDGC', 'Disease', 'MESH:D013274', (208, 212))	('carcinoma in situ', 'Disease', 'MESH:D002278', (17, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('mutations', 'Var', (119, 128))	('carcinoma in situ', 'Disease', (17, 34))	('pagetoid spread', 'CPA', (46, 61))
12965	30568591	One recent study showed that up to 8% of patients with bilateral LCIS have germline mutations in CDH1 (Petridis et al.,).	('patients', 'Species', '9606', (41, 49))	('germline mutations', 'Var', (75, 93))	('CDH1', 'Gene', (97, 101))
12966	30568591	Earlier studies showed a lower prevalence of CDH1 germline mutations in patients with no history of gastric carcinoma (Rahman et al.,; Masciari et al.,).	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (100, 117))	('germline mutations', 'Var', (50, 68))	('gastric carcinoma', 'Disease', 'MESH:D013274', (100, 117))	('CDH1', 'Gene', (45, 49))	('gastric carcinoma', 'Disease', (100, 117))	('patients', 'Species', '9606', (72, 80))
12968	30568591	In one study, a CDH1 missense germline mutation co-segregated with colorectal carcinoma; however, the same mutation was also present in the normal population.	('colorectal carcinoma', 'Disease', (67, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (67, 87))	('missense germline', 'Var', (21, 38))	('CDH1', 'Gene', (16, 20))
12971	30568591	CDH1 mutations have also been identified in patients with blepharocheilodontic syndrome, a congenital development disorder causing dysmorphic features, which can be accompanied by imperforate anus, hypothyroidism, and neural tube defect.	('blepharocheilodontic syndrome', 'Disease', 'MESH:C536188', (58, 87))	('patients', 'Species', '9606', (44, 52))	('hypothyroidism', 'Disease', 'MESH:D007037', (198, 212))	('congenital development disorder', 'Disease', 'MESH:D002658', (91, 122))	('neural tube defect', 'Disease', (218, 236))	('neural tube defect', 'Phenotype', 'HP:0045005', (218, 236))	('hypothyroidism', 'Phenotype', 'HP:0000821', (198, 212))	('mutations', 'Var', (5, 14))	('identified', 'Reg', (30, 40))	('hypothyroidism', 'Disease', (198, 212))	('congenital development disorder', 'Disease', (91, 122))	('imperforate anus', 'Phenotype', 'HP:0002023', (180, 196))	('dysmorphic features', 'Disease', 'MESH:D000013', (131, 150))	('blepharocheilodontic syndrome', 'Disease', (58, 87))	('neural tube defect', 'Disease', 'MESH:D009436', (218, 236))	('CDH1', 'Gene', (0, 4))	('dysmorphic features', 'Disease', (131, 150))
12972	30568591	However, the mutations identified in blepharocheilodontic syndrome all occur in extracellular calcium binding repeats and are functionally distinct from those identified in HDGC (Kievit et al.,).	('calcium', 'Chemical', 'MESH:D002118', (94, 101))	('blepharocheilodontic syndrome', 'Disease', (37, 66))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('blepharocheilodontic syndrome', 'Disease', 'MESH:C536188', (37, 66))	('extracellular', 'cellular_component', 'GO:0005576', ('80', '93'))	('HDGC', 'Disease', 'MESH:D013274', (173, 177))	('mutations', 'Var', (13, 22))	('HDGC', 'Disease', (173, 177))	('occur', 'Reg', (71, 76))
12975	30568591	Liquid biopsies based on cell-free circulating DNA have been used to detect CDH1 promoter methylation in the plasma/serum of gastric cancer patients (Tsujiura et al.,).	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('CDH1', 'Gene', (76, 80))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('methylation', 'Var', (90, 101))	('patients', 'Species', '9606', (140, 148))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
12979	30568591	For difficult cases, functional assessment, such as in vitro evaluation of an E-cadherin-induced cell adhesion and invasion assay, may be ultimately needed to ascertain the role of CDH1 missense mutations (Suriano et al.,; Barber et al.,; Corso et al.,).	('E-cadherin', 'Gene', (78, 88))	('E-cadherin', 'Gene', '999', (78, 88))	('missense mutations', 'Var', (186, 204))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('cell adhesion', 'biological_process', 'GO:0007155', ('97', '110'))	('CDH1', 'Gene', (181, 185))
12992	30568591	Using careful white-light examination with targeted biopsies and 24 random biopsies (4 each of the prepylorus, antrum, T zone, body, fundus, and cardia) combined with detailed histopathology, Lim et al (van der Post et al.,) found signet ring cell carcinomas in 14 of 22 patients with, and 2 of 7 patients without, CDH1 mutations fulfilling the 2010 HDGC criteria.	('ring cell carcinomas', 'Disease', (238, 258))	('HDGC', 'Disease', (350, 354))	('mutations', 'Var', (320, 329))	('cardia', 'Disease', (145, 151))	('patients', 'Species', '9606', (297, 305))	('Lim', 'Gene', '10611', (192, 195))	('cardia', 'Disease', 'MESH:D004938', (145, 151))	('ring cell carcinomas', 'Disease', 'MESH:D018279', (238, 258))	('Lim', 'Gene', (192, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (248, 258))	('patients', 'Species', '9606', (271, 279))	('HDGC', 'Disease', 'MESH:D013274', (350, 354))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('CDH1', 'Gene', (315, 319))
12998	30568591	Because of the high lifetime risk of invasive lobular carcinoma, women with CDH1 mutations should undergo annual radiologic surveillance, with bilateral breast magnetic resonance imaging being the preferred modality, along with annual clinical breast examination (van der Post et al.,).	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (37, 63))	('CDH1', 'Gene', (76, 80))	('invasive lobular carcinoma', 'Disease', (37, 63))	('mutations', 'Var', (81, 90))	('women', 'Species', '9606', (65, 70))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (46, 63))
13000	30568591	Contralateral mastectomy for CDH1 mutation carriers diagnosed with invasive lobular carcinoma may be considered on an individual basis (Wright et al.,).	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('mutation', 'Var', (34, 42))	('CDH1', 'Gene', (29, 33))	('invasive lobular carcinoma', 'Disease', (67, 93))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (67, 93))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (76, 93))
13016	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))
13105	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))
13233	32487046	So far, invasive breast cancer has been classified according to histological features and immunohistochemical expression of estrogen receptors (ER), progesterone receptors (PR) and HER2 overexpression and/or HER2 gene amplification.	('gene amplification', 'Var', (213, 231))	('overexpression', 'PosReg', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('HER2', 'Gene', (208, 212))	('HER2', 'Gene', '2064', (208, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('invasive breast cancer', 'Disease', (8, 30))	('HER2', 'Gene', (181, 185))	('HER2', 'Gene', '2064', (181, 185))	('invasive breast cancer', 'Disease', 'MESH:D001943', (8, 30))
13295	32487046	Recently, molecular analyses of invasive lobular carcinomas established that these tumors have a distinct genomic profile compared to IBC-NST, exhibiting a high frequency of CDH1 mutations, loss of PTEN, activation of AKT, and mutations in TBX3 and FOXA1.	('CDH1', 'Gene', '999', (174, 178))	('invasive lobular carcinomas', 'Disease', (32, 59))	('TBX3', 'Gene', '6926', (240, 244))	('AKT', 'Gene', '207', (218, 221))	('PTEN', 'Gene', '5728', (198, 202))	('NST', 'Gene', '25830', (138, 141))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('CDH1', 'Gene', (174, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (41, 58))	('TBX3', 'Gene', (240, 244))	('BC', 'Phenotype', 'HP:0003002', (135, 137))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('FOXA1', 'Gene', '3169', (249, 254))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (179, 188))	('FOXA1', 'Gene', (249, 254))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (41, 59))	('AKT', 'Gene', (218, 221))	('mutations', 'Var', (227, 236))	('activation', 'PosReg', (204, 214))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (32, 59))	('loss', 'NegReg', (190, 194))	('PTEN', 'Gene', (198, 202))	('tumors', 'Disease', (83, 89))	('NST', 'Gene', (138, 141))
13300	32487046	The biological behavior of metaplastic carcinomas might be related to beta-Catenin gene mutations and activation of WNT pathway.	('beta-Catenin', 'Gene', '1499', (70, 82))	('WNT pathway', 'Pathway', (116, 127))	('mutations', 'Var', (88, 97))	('metaplastic carcinoma', 'Disease', (27, 48))	('metaplastic carcinoma', 'Disease', 'MESH:D009369', (27, 48))	('carcinomas', 'Disease', 'MESH:D009369', (39, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('carcinomas', 'Disease', (39, 49))	('beta-Catenin', 'Gene', (70, 82))
13301	32487046	Furthermore, metaplastic tumors were included in mesenchymal-like molecular subtype based on their gene expression profile, characterized by PI3K/mTOR pathway aberrations, downregulation of genes involved in DNA repair and response to chemotherapy.	('genes', 'Gene', (190, 195))	('DNA repair', 'biological_process', 'GO:0006281', ('208', '218'))	('mTOR', 'Gene', '2475', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mTOR', 'Gene', (146, 150))	('tumors', 'Disease', (25, 31))	('aberrations', 'Var', (159, 170))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('downregulation', 'NegReg', (172, 186))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('PI3K', 'molecular_function', 'GO:0016303', ('141', '145'))	('gene expression', 'biological_process', 'GO:0010467', ('99', '114'))
13309	32487046	evaluated the prognostic role of TILs in TNBC patients who did not receive adjuvant chemotherapy, demonstrating that TILs is an independent prognostic factor in early-stage TNBC.	('BC', 'Phenotype', 'HP:0003002', (43, 45))	('patients', 'Species', '9606', (46, 54))	('TILs', 'Var', (117, 121))	('BC', 'Phenotype', 'HP:0003002', (175, 177))	('early-stage TNBC', 'Disease', (161, 177))
13325	32487046	Genetically, MYB-NFIB fusion gene is a prevalent feature of adenoid cystic carcinoma.	('adenoid cystic carcinoma', 'Disease', (60, 84))	('fusion gene', 'Var', (22, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('NFIB', 'Gene', (17, 21))	('MYB', 'Gene', '4602', (13, 16))	('MYB', 'Gene', (13, 16))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (60, 84))	('NFIB', 'Gene', '4781', (17, 21))
13332	32487046	Current clinical data indicate that patients with triple negative lobular or metaplastic carcinoma are less responsive to chemotherapy, contrary to patients affected by other TNBC histologic types, increasing the need to identify unambiguous molecular targets.	('metaplastic carcinoma', 'Disease', (77, 98))	('patients', 'Species', '9606', (148, 156))	('BC', 'Phenotype', 'HP:0003002', (177, 179))	('triple negative', 'Var', (50, 65))	('patients', 'Species', '9606', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('less', 'NegReg', (103, 107))	('metaplastic carcinoma', 'Disease', 'MESH:D009369', (77, 98))
13387	28445295	In our case, GIT recurrence occurred 11 years after treatment of T1N0M0 breast cancer.	('T1N0M0', 'Var', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('GIT', 'Disease', (13, 16))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
13405	27524621	Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients.	('cadherin', 'molecular_function', 'GO:0008014', ('18', '26'))	('patients', 'Species', '9606', (102, 110))	('genetic inactivation', 'Var', (47, 67))	('E-cadherin', 'Protein', (16, 26))	('PTEN', 'Gene', (71, 75))	('loss', 'NegReg', (8, 12))	('ILC', 'Disease', (42, 45))
13406	27524621	Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC), the main histological ILC subtype.	('E-cadherin', 'Protein', (49, 59))	('mouse', 'Species', '10090', (107, 112))	('CLC', 'Gene', (137, 140))	('CLC', 'Gene', '12735', (137, 140))	('PTEN', 'Gene', (64, 68))	('cadherin', 'molecular_function', 'GO:0008014', ('51', '59'))	('inactivation', 'Var', (33, 45))	('classical ILC', 'Disease', (122, 135))
13407	27524621	While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER) status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('cell survival', 'CPA', (105, 118))	('loss', 'Var', (6, 10))	('tumor', 'Disease', (298, 303))	('inactivation', 'Var', (83, 95))	('estrogen receptor', 'Gene', (225, 242))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('ER', 'Gene', '2099', (244, 246))	('human', 'Species', '9606', (324, 329))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('cell dissemination', 'CPA', (33, 51))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('E-cadherin', 'Protein', (14, 24))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('PTEN', 'Gene', (78, 82))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('promoted', 'PosReg', (96, 104))	('CLC', 'Gene', (330, 333))	('CLC', 'Gene', '12735', (330, 333))	('estrogen receptor', 'Gene', '2099', (225, 242))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))
13408	27524621	Combined inactivation of E-cadherin and PTEN is sufficient to cause CLC development.	('CLC', 'Gene', (68, 71))	('PTEN', 'Gene', (40, 44))	('cause', 'Reg', (62, 67))	('CLC', 'Gene', '12735', (68, 71))	('inactivation', 'Var', (9, 21))	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))	('E-cadherin', 'Protein', (25, 35))
13409	27524621	These CLCs showed significant tumor regression upon BEZ235-mediated inhibition of PI3K signaling.	('PI3K signaling', 'Pathway', (82, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('BEZ235', 'Chemical', 'MESH:C531198', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BEZ235-mediated', 'Var', (52, 67))	('PI3K signaling', 'biological_process', 'GO:0014065', ('82', '96'))	('CLC', 'Gene', (6, 9))	('CLC', 'Gene', '12735', (6, 9))	('inhibition', 'NegReg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
13410	27524621	In summary, this mouse model provides important insights into CLC development and suggests inhibition of phosphatidylinositol 3-kinase (PI3K) signaling as a potential therapeutic strategy for targeting CLC.	('PI3K) signaling', 'biological_process', 'GO:0014065', ('136', '151'))	('inhibition', 'Var', (91, 101))	('mouse', 'Species', '10090', (17, 22))	('phosphatidylinositol 3-kinase', 'Gene', (105, 134))	('phosphatidylinositol 3-kinase', 'Gene', '18708', (105, 134))	('PI3K', 'molecular_function', 'GO:0016303', ('136', '140'))	('CLC', 'Gene', (62, 65))	('CLC', 'Gene', (202, 205))	('CLC', 'Gene', '12735', (62, 65))	('CLC', 'Gene', '12735', (202, 205))
13412	27524621	demonstrate that combined inactivation of E-cadherin and PTEN in mouse mammary epithelium results in rapid formation of classical invasive lobular carcinoma (CLC).	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (139, 156))	('inactivation', 'Var', (26, 38))	('mouse', 'Species', '10090', (65, 70))	('CLC', 'Gene', (158, 161))	('CLC', 'Gene', '12735', (158, 161))	('PTEN', 'Gene', (57, 61))	('invasive lobular carcinoma', 'Disease', (130, 156))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (130, 156))	('formation', 'biological_process', 'GO:0009058', ('107', '116'))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('E-cadherin', 'Protein', (42, 52))
13413	27524621	This mouse model provides important insights into CLC development and suggests that inhibition of PI3K signaling is a potential strategy for targeting CLC.	('CLC', 'Gene', (50, 53))	('CLC', 'Gene', '12735', (50, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('98', '102'))	('CLC', 'Gene', (151, 154))	('PI3K signaling', 'biological_process', 'GO:0014065', ('98', '112'))	('CLC', 'Gene', '12735', (151, 154))	('mouse', 'Species', '10090', (5, 10))	('inhibition', 'Var', (84, 94))
13420	27524621	Activation of the phosphatidylinositol 3-kinase (PI3K) pathway, as displayed by either activating PIK3CA mutations or homozygous deletions or inactivating mutations in PTEN, is frequently observed in ILC.	('deletions', 'Var', (129, 138))	('phosphatidylinositol 3-kinase', 'Gene', (18, 47))	('phosphatidylinositol 3-kinase', 'Gene', '18708', (18, 47))	('inactivating mutations', 'Var', (142, 164))	('PTEN', 'Gene', (168, 172))	('ILC', 'Disease', (200, 203))	('PIK3CA', 'Gene', (98, 104))	('activating', 'PosReg', (87, 97))	('mutations', 'Var', (105, 114))	('Activation', 'PosReg', (0, 10))	('PI3K', 'molecular_function', 'GO:0016303', ('49', '53'))	('PIK3CA', 'Gene', '18706', (98, 104))
13422	27524621	To test whether constitutive activation of PI3K signaling can, indeed, drive the formation of ILC, we generated mice with mammary-specific Cre-conditional inactivation of E-cadherin and PTEN.	('cadherin', 'molecular_function', 'GO:0008014', ('173', '181'))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('inactivation', 'Var', (155, 167))	('PTEN', 'Gene', (186, 190))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('E-cadherin', 'Protein', (171, 181))	('PI3K signaling', 'biological_process', 'GO:0014065', ('43', '57'))	('mice', 'Species', '10090', (112, 116))
13426	27524621	Importantly, the phenotype of AdCre-transduced mTmG organoids appeared unaltered as compared to non-transduced organoids from the same mouse, indicating that organoid growth rate and phenotype are not affected by AdCre transduction (Figure S1A).	('organoid growth rate', 'CPA', (158, 178))	('AdCre', 'Var', (213, 218))	('transduction', 'biological_process', 'GO:0009293', ('219', '231'))	('mouse', 'Species', '10090', (135, 140))
13428	27524621	Concurrent inactivation of E-cadherin and PTEN revealed a combined phenotype of Cdh1Delta/Delta and PtenDelta/Delta organoids, as Cdh1Delta/Delta;PtenDelta/Delta organoids were both enlarged and showed discohesive cellular structures (Figure S1B).	('inactivation', 'Var', (11, 23))	('discohesive cellular structures', 'CPA', (202, 233))	('Cdh1', 'Gene', (80, 84))	('Cdh1', 'Gene', '12550', (80, 84))	('cadherin', 'molecular_function', 'GO:0008014', ('29', '37'))	('E-cadherin', 'Protein', (27, 37))	('Cdh1', 'Gene', (130, 134))	('Cdh1', 'Gene', '12550', (130, 134))
13429	27524621	Efficient recombination was confirmed by western blotting and PCR, showing strong reduction of E-cadherin and/or PTEN protein expression and deletion of the Cdh1F and PtenF alleles, respectively (Figures 1A and S1C).	('Cdh1', 'Gene', (157, 161))	('deletion', 'Var', (141, 149))	('PtenF', 'Gene', (167, 172))	('expression', 'MPA', (126, 136))	('PTEN protein', 'Protein', (113, 125))	('reduction', 'NegReg', (82, 91))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('E-cadherin', 'Protein', (95, 105))	('Cdh1', 'Gene', '12550', (157, 161))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
13430	27524621	In addition, AdCre-transduced PtenF/F and Cdh1F/F;PtenF/F organoids showed a strong induction of AKT phosphorylation, indicating activation of PI3K signaling due to PTEN loss (Figure 1A).	('Cdh1', 'Gene', '12550', (42, 46))	('Cdh1', 'Gene', (42, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('143', '147'))	('activation', 'PosReg', (129, 139))	('loss', 'Var', (170, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('101', '116'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('143', '157'))	('induction', 'PosReg', (84, 93))	('PTEN', 'Gene', (165, 169))	('AKT', 'Pathway', (97, 100))
13435	27524621	Consistent with a survival role for the PI3K signaling pathway, both PtenDelta/Delta and Cdh1Delta/Delta;PtenDelta/Delta organoids showed almost no apoptotic cells (Figure 1E), resulting in an increase in organoid size over time (Figures 1B and 1C).	('Cdh1', 'Gene', (89, 93))	('increase', 'PosReg', (193, 201))	('organoid size', 'CPA', (205, 218))	('PI3K signaling', 'biological_process', 'GO:0014065', ('40', '54'))	('PtenDelta/Delta', 'Var', (105, 120))	('signaling pathway', 'biological_process', 'GO:0007165', ('45', '62'))	('PI3K', 'molecular_function', 'GO:0016303', ('40', '44'))	('Cdh1', 'Gene', '12550', (89, 93))
13440	27524621	Histological analysis and immunohistochemistry (IHC) for cytokeratin 8 (CK8; marking luminal mammary epithelial cells) indicated inactivation of E-cadherin to cause hyperplastic and dysplastic ducts, as well as a marked accumulation of dissociated mammary epithelial cells in the lumen of mammary epithelium from 6-week-old Wcre;Cdh1F/F mice (Figure 2A).	('dysplastic', 'Disease', (182, 192))	('E-cadherin', 'Protein', (145, 155))	('accumulation', 'PosReg', (220, 232))	('cadherin', 'molecular_function', 'GO:0008014', ('147', '155'))	('dysplastic', 'Disease', 'MESH:D004416', (182, 192))	('cytokeratin 8', 'Gene', (57, 70))	('mice', 'Species', '10090', (337, 341))	('cause', 'Reg', (159, 164))	('CK8', 'Gene', '16691', (72, 75))	('cytokeratin 8', 'Gene', '16691', (57, 70))	('Cdh1', 'Gene', '12550', (329, 333))	('CK8', 'Gene', (72, 75))	('inactivation', 'Var', (129, 141))	('Cdh1', 'Gene', (329, 333))
13441	27524621	In contrast, mammary epithelium from 6-week-old Wcre;Cdh1F/F;PtenF/F mice displayed multifocal neoplastic lesions infiltrating the surrounding stroma (Figure 2A).	('PtenF/F', 'Var', (61, 68))	('mice', 'Species', '10090', (69, 73))	('multifocal neoplastic lesions', 'Disease', (84, 113))	('Cdh1', 'Gene', (53, 57))	('Cdh1', 'Gene', '12550', (53, 57))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (95, 113))	('multifocal neoplastic lesions', 'Disease', 'None', (84, 113))
13448	27524621	Since inactivation of PTEN rescued apoptosis and promoted survival of E-cadherin-deficient mammary epithelial cells in Cdh1Delta/Delta;PtenDelta/Delta organoids, we analyzed apoptosis by CC3 IF staining in mammary gland sections from 6-week-old Wcre;Cdh1F/F, Wcre;PtenF/F, and Wcre;Cdh1F/F;PtenF/F mice.	('inactivation', 'Var', (6, 18))	('CC3', 'Gene', '12367', (187, 190))	('PTEN', 'Gene', (22, 26))	('Cdh1', 'Gene', '12550', (119, 123))	('mice', 'Species', '10090', (298, 302))	('Cdh1', 'Gene', (282, 286))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('Cdh1', 'Gene', (250, 254))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('CC3', 'Gene', (187, 190))	('apoptosis', 'CPA', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('35', '44'))	('Cdh1', 'Gene', (119, 123))	('apoptosis', 'biological_process', 'GO:0006915', ('35', '44'))	('Cdh1', 'Gene', '12550', (282, 286))	('survival', 'CPA', (58, 66))	('promoted', 'PosReg', (49, 57))	('Cdh1', 'Gene', '12550', (250, 254))
13452	27524621	Whole-mount analysis of mammary glands from 8-week-old Wcre;Cdh1F/F;PtenF/F mice showed, beside neoplastic lesions and hyperplastic ducts, a delay in mammary gland development, as compared to age-matched wild-type mammary glands (Figure S2B).	('neoplastic lesions', 'Disease', 'MESH:D051437', (96, 114))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (96, 114))	('PtenF/F', 'Var', (68, 75))	('mammary gland development', 'biological_process', 'GO:0030879', ('150', '175'))	('delay', 'NegReg', (141, 146))	('mice', 'Species', '10090', (76, 80))	('Cdh1', 'Gene', '12550', (60, 64))	('mammary gland development', 'CPA', (150, 175))	('Cdh1', 'Gene', (60, 64))	('neoplastic lesions', 'Disease', (96, 114))
13453	27524621	Impaired mammary gland maturation was also observed during pregnancy, as pups from five 12-week-old Wcre;Cdh1F/F;PtenF/F mice grew poorly and died 6 days after birth, while littermates fostered onto wild-type dams showed normal weight and survival (Figure S2C).	('mammary gland maturation', 'CPA', (9, 33))	('poorly', 'NegReg', (131, 137))	('PtenF/F', 'Var', (113, 120))	('Cdh1', 'Gene', '12550', (105, 109))	('mice', 'Species', '10090', (121, 125))	('Cdh1', 'Gene', (105, 109))	('grew', 'CPA', (126, 130))
13458	27524621	Additional inactivation of E-cadherin significantly decreased mammary tumor latency to 109 days of age in Wcre;Cdh1F/F;PtenF/F mice, demonstrating strong synergy between E-cadherin and PTEN loss in mammary tumorigenesis (Figure 3A).	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', (70, 75))	('decreased', 'NegReg', (52, 61))	('inactivation', 'Var', (11, 23))	('loss', 'NegReg', (190, 194))	('Cdh1', 'Gene', '12550', (111, 115))	('Cdh1', 'Gene', (111, 115))	('cadherin', 'molecular_function', 'GO:0008014', ('29', '37'))	('cadherin', 'molecular_function', 'GO:0008014', ('172', '180'))	('E-cadherin', 'Protein', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('PTEN', 'Gene', (185, 189))
13462	27524621	Notably, additional inactivation of E-cadherin completely shifted mammary tumor morphology.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inactivation', 'Var', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('E-cadherin', 'Protein', (36, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('tumor', 'Disease', (74, 79))	('shifted', 'Reg', (58, 65))
13465	27524621	Moreover, IHC staining revealed elevated levels of phosphorylated (p)-AKT, p-4ebp1, and p-S6 in tumor cells, confirming the activation of PI3K signaling due to loss of PTEN (Figure S3B).	('PTEN', 'Gene', (168, 172))	('activation', 'PosReg', (124, 134))	('elevated', 'PosReg', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('S3B', 'Gene', '11778', (181, 184))	('loss', 'NegReg', (160, 164))	('phosphorylated', 'MPA', (51, 65))	('tumor', 'Disease', (96, 101))	('PI3K signaling', 'Pathway', (138, 152))	('PI3K', 'molecular_function', 'GO:0016303', ('138', '142'))	('S3B', 'Gene', (181, 184))	('p-S6', 'Var', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('p-4ebp1', 'Var', (75, 82))	('levels', 'MPA', (41, 47))	('PI3K signaling', 'biological_process', 'GO:0014065', ('138', '152'))
13487	27524621	The sudden and stochastic transition from linear to exponential growth kinetics suggests the acquisition of additional mutations in these tumors over time.	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('mutations', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
13488	27524621	Indeed, whole-exome sequencing of seven randomly selected exponentially growing tumors and 14 mCLCs revealed that all exponentially growing tumors harbored mutations in at least one cancer-related gene, while none of the mCLCs showed additional mutations (Figure 4E).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mCLC', 'Gene', (221, 225))	('tumors', 'Disease', (140, 146))	('mCLC', 'Gene', (94, 98))	('mCLC', 'Gene', '12735', (221, 225))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('mCLC', 'Gene', '12735', (94, 98))	('mutations', 'Var', (156, 165))	('harbored', 'Reg', (147, 155))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (80, 86))	('cancer', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
13496	27524621	In contrast, microscopic or macroscopic metastases were observed in 34% and 5% of tumor-bearing Wcre;Cdh1F/F;PtenF/+ and Wcre;Cdh1F/F;PtenF/F mice, respectively (Figure 5C).	('Cdh1', 'Gene', '12550', (126, 130))	('Cdh1', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Cdh1', 'Gene', '12550', (101, 105))	('mice', 'Species', '10090', (142, 146))	('metastases', 'Disease', (40, 50))	('PtenF/+', 'Var', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Cdh1', 'Gene', (101, 105))	('metastases', 'Disease', 'MESH:D009362', (40, 50))	('tumor', 'Disease', (82, 87))	('microscopic', 'CPA', (13, 24))
13519	27524621	Even more profound changes in the microenvironment of mammary ducts were observed in Wcre;Cdh1F/F;PtenF/F mice.	('mice', 'Species', '10090', (106, 110))	('PtenF/F', 'Var', (98, 105))	('changes', 'Reg', (19, 26))	('microenvironment', 'MPA', (34, 50))	('Cdh1', 'Gene', '12550', (90, 94))	('Cdh1', 'Gene', (90, 94))
13520	27524621	Early lesions of 6-week-old Wcre;Cdh1F/F;PtenF/F mice showed a clear increase in collagen and numbers of fibroblasts and displayed increased numbers of infiltrating macrophages and T cells, especially at the periphery (Figure 6A).	('increase', 'PosReg', (69, 77))	('increased', 'PosReg', (131, 140))	('collagen', 'molecular_function', 'GO:0005202', ('81', '89'))	('collagen', 'CPA', (81, 89))	('mice', 'Species', '10090', (49, 53))	('infiltrating macrophages', 'CPA', (152, 176))	('Cdh1', 'Gene', '12550', (33, 37))	('PtenF/F', 'Var', (41, 48))	('T cells', 'CPA', (181, 188))	('Cdh1', 'Gene', (33, 37))
13525	27524621	In summary, both human CLCs and mCLCs arising in Wcre;Cdh1F/F;PtenF/F mice are heterotypic tumors characterized by a rich stromal compartment consisting mainly of collagen and fibroblasts.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('heterotypic tumors', 'Disease', 'MESH:D009369', (79, 97))	('CLC', 'Gene', (33, 36))	('CLC', 'Gene', (23, 26))	('human', 'Species', '9606', (17, 22))	('CLC', 'Gene', '12735', (23, 26))	('mCLC', 'Gene', (32, 36))	('CLC', 'Gene', '12735', (33, 36))	('collagen', 'molecular_function', 'GO:0005202', ('163', '171'))	('mCLC', 'Gene', '12735', (32, 36))	('PtenF/F', 'Var', (62, 69))	('heterotypic tumors', 'Disease', (79, 97))	('mice', 'Species', '10090', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Cdh1', 'Gene', '12550', (54, 58))	('Cdh1', 'Gene', (54, 58))
13531	27524621	Target inhibition of the PI3K signaling pathway by BEZ235 was confirmed by IHC and western blotting, showing decreased phosphorylation of both AKT and S6 in CLCs from mice treated with BEZ235 (Figures 7A and 7B).	('decreased', 'NegReg', (109, 118))	('PI3K signaling pathway', 'Pathway', (25, 47))	('PI3K', 'molecular_function', 'GO:0016303', ('25', '29'))	('phosphorylation', 'MPA', (119, 134))	('BEZ235', 'Var', (185, 191))	('AKT', 'Pathway', (143, 146))	('CLC', 'Gene', (157, 160))	('CLC', 'Gene', '12735', (157, 160))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('BEZ235', 'Chemical', 'MESH:C531198', (51, 57))	('BEZ235', 'Chemical', 'MESH:C531198', (185, 191))	('PI3K signaling', 'biological_process', 'GO:0014065', ('25', '39'))	('mice', 'Species', '10090', (167, 171))	('signaling pathway', 'biological_process', 'GO:0007165', ('30', '47'))
13533	27524621	Significantly fewer and smaller CLC lesions were observed in the mammary glands of BEZ235-treated littermates compared to t = 0 and vehicle-treated Wcre;Cdh1F/F;PtenF/F mice, indicating that this PI3K/mTOR inhibitor strongly inhibited tumor formation in our mCLC model (Figures 7C and 7D).	('fewer', 'NegReg', (14, 19))	('mTOR', 'Gene', (201, 205))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('CLC lesions', 'Disease', 'MESH:D051437', (32, 43))	('BEZ235-treated', 'Var', (83, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('196', '200'))	('smaller', 'NegReg', (24, 31))	('Cdh1', 'Gene', '12550', (153, 157))	('inhibited', 'NegReg', (225, 234))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('CLC lesions', 'Disease', (32, 43))	('mCLC', 'Gene', '12735', (258, 262))	('mTOR', 'Gene', '56717', (201, 205))	('mice', 'Species', '10090', (169, 173))	('Cdh1', 'Gene', (153, 157))	('tumor', 'Disease', (235, 240))	('BEZ235', 'Chemical', 'MESH:C531198', (83, 89))	('formation', 'biological_process', 'GO:0009058', ('241', '250'))	('mCLC', 'Gene', (258, 262))
13535	27524621	In this study, we show that concomitant inactivation of E-cadherin and PTEN leads to rapid formation of mouse mammary tumors that faithfully recapitulate the histopathology, molecular phenotype, ER status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mouse', 'Species', '10090', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('CLC', 'Gene', (280, 283))	('CLC', 'Gene', '12735', (280, 283))	('tumor', 'Disease', (248, 253))	('E-cadherin', 'Protein', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('formation', 'biological_process', 'GO:0009058', ('91', '100'))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumors', 'Disease', (118, 124))	('ER', 'Gene', '2099', (195, 197))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('inactivation', 'Var', (40, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('58', '66'))	('PTEN', 'Gene', (71, 75))	('tumor', 'Disease', (118, 123))	('human', 'Species', '9606', (274, 279))
13536	27524621	Inactivating mutations of E-cadherin and PTEN co-occur in a substantial fraction (13%) of human ILCs.	('Inactivating mutations', 'Var', (0, 22))	('human', 'Species', '9606', (90, 95))	('E-cadherin', 'Protein', (26, 36))	('human ILCs', 'Disease', (90, 100))	('PTEN', 'Gene', (41, 45))	('co-occur', 'Reg', (46, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))
13537	27524621	In line with this, our data revealed potent synergism and causality between E-cadherin and PTEN inactivation in CLC formation.	('CLC', 'Gene', (112, 115))	('E-cadherin', 'Protein', (76, 86))	('inactivation', 'Var', (96, 108))	('CLC', 'Gene', '12735', (112, 115))	('cadherin', 'molecular_function', 'GO:0008014', ('78', '86'))	('synergism', 'Interaction', (44, 53))	('PTEN', 'Gene', (91, 95))	('formation', 'biological_process', 'GO:0009058', ('116', '125'))	('causality', 'Interaction', (58, 67))
13538	27524621	Previously, we reported that inactivation of E-cadherin and P53 in mammary epithelium results in the development of pleomorphic ILC, a relatively rare subtype of ILC.	('P53', 'Gene', (60, 63))	('E-cadherin', 'Protein', (45, 55))	('P53', 'Gene', '22059', (60, 63))	('pleomorphic ILC', 'Disease', (116, 131))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('results in', 'Reg', (86, 96))	('inactivation', 'Var', (29, 41))
13539	27524621	In contrast, inactivation of PTEN alters the tumor outcome of E-cadherin-deficient cells toward CLC, which is the most common subtype of ILC.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('inactivation', 'Var', (13, 25))	('alters', 'Reg', (34, 40))	('PTEN', 'Gene', (29, 33))	('tumor', 'Disease', (45, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('64', '72'))	('CLC', 'Gene', (96, 99))	('CLC', 'Gene', '12735', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
13541	27524621	In apparent contrast to its tumor-suppressor role, E-cadherin inactivation limits mammary epithelial cell survival in vivo as E-cadherin-deficient luminal epithelial cells were found to accumulate in the lumen of mammary ducts and undergo apoptosis, which is most likely due to reduced junctional integrity caused by E-cadherin loss.	('tumor', 'Disease', (28, 33))	('inactivation', 'Var', (62, 74))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('undergo', 'Reg', (231, 238))	('cadherin', 'molecular_function', 'GO:0008014', ('53', '61'))	('E-cadherin-deficient', 'Gene', (126, 146))	('accumulate', 'PosReg', (186, 196))	('loss', 'NegReg', (328, 332))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('239', '248'))	('reduced', 'NegReg', (278, 285))	('E-cadherin', 'Protein', (317, 327))	('mammary epithelial cell survival', 'CPA', (82, 114))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('apoptosis', 'biological_process', 'GO:0006915', ('239', '248'))	('cadherin', 'molecular_function', 'GO:0008014', ('319', '327'))	('limits', 'NegReg', (75, 81))	('apoptosis', 'CPA', (239, 248))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('cadherin', 'molecular_function', 'GO:0008014', ('128', '136'))
13542	27524621	Previously, E-cadherin inactivation in the mammary gland was found to limit the survival of alveolar cells during the onset of lactation, supporting a role for E-cadherin in maintaining the survival of luminal mammary epithelial cells.	('lactation', 'Disease', (127, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('lactation', 'Disease', 'MESH:D007775', (127, 136))	('E-cadherin', 'Protein', (12, 22))	('survival of alveolar cells', 'CPA', (80, 106))	('cadherin', 'molecular_function', 'GO:0008014', ('162', '170'))	('limit', 'NegReg', (70, 75))	('lactation', 'biological_process', 'GO:0007595', ('127', '136'))	('inactivation', 'Var', (23, 35))
13543	27524621	PTEN inactivation also enabled the survival of E-cadherin-deficient mammary epithelial cells in vivo, permitting the formation of CLC.	('cadherin', 'molecular_function', 'GO:0008014', ('49', '57'))	('CLC', 'Gene', (130, 133))	('permitting', 'PosReg', (102, 112))	('CLC', 'Gene', '12735', (130, 133))	('enabled', 'PosReg', (23, 30))	('formation', 'biological_process', 'GO:0009058', ('117', '126'))	('inactivation', 'Var', (5, 17))	('PTEN', 'Gene', (0, 4))
13544	27524621	Importantly, as tumor onset in female Wcre;Cdh1F/F;PtenF/F mice was extremely rapid, and no additional mutations were detected in the ensuing mCLCs, the combined inactivation of E-cadherin and PTEN appears to be sufficient and, thus, causal for CLC formation.	('mCLC', 'Gene', (142, 146))	('mCLC', 'Gene', '12735', (142, 146))	('mice', 'Species', '10090', (59, 63))	('CLC', 'Gene', '12735', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('PTEN', 'Gene', (193, 197))	('cadherin', 'molecular_function', 'GO:0008014', ('180', '188'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('CLC', 'Gene', (143, 146))	('CLC', 'Gene', '12735', (143, 146))	('formation', 'biological_process', 'GO:0009058', ('249', '258'))	('tumor', 'Disease', (16, 21))	('inactivation', 'Var', (162, 174))	('Cdh1', 'Gene', '12550', (43, 47))	('Cdh1', 'Gene', (43, 47))	('E-cadherin', 'Protein', (178, 188))	('CLC', 'Gene', (245, 248))
13545	27524621	It is, therefore, likely that activation of PI3K signaling due to loss of PTEN promotes the survival of E-cadherin-deficient mammary epithelial cells and subsequent formation of CLC.	('survival', 'CPA', (92, 100))	('loss', 'Var', (66, 70))	('formation', 'MPA', (165, 174))	('formation', 'biological_process', 'GO:0009058', ('165', '174'))	('CLC', 'Gene', (178, 181))	('activation', 'PosReg', (30, 40))	('CLC', 'Gene', '12735', (178, 181))	('PTEN', 'Gene', (74, 78))	('E-cadherin-deficient', 'Protein', (104, 124))	('promotes', 'PosReg', (79, 87))	('cadherin', 'molecular_function', 'GO:0008014', ('106', '114'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('44', '58'))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
13546	27524621	Indeed, mCLCs from our Wcre;Cdh1F/F;PtenF/F mouse model showed activated PI3K signaling, as evidenced by expression of p-AKT and p-S6.	('Cdh1', 'Gene', '12550', (28, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('mCLC', 'Gene', (8, 12))	('Cdh1', 'Gene', (28, 32))	('mCLC', 'Gene', '12735', (8, 12))	('PI3K signaling', 'biological_process', 'GO:0014065', ('73', '87'))	('PI3K signaling', 'Pathway', (73, 87))	('p-S6', 'Var', (129, 133))	('activated', 'PosReg', (63, 72))	('p-AKT', 'Pathway', (119, 124))	('mouse', 'Species', '10090', (44, 49))
13547	27524621	Also, human ILCs were found to show frequent activation of PI3K signaling, as evidenced by increased AKT phosphorylation, reduced PTEN expression, and a high incidence of somatic mutations leading to PI3K pathway activation.	('AKT', 'Pathway', (101, 104))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))	('human', 'Species', '9606', (6, 11))	('PI3K signaling', 'biological_process', 'GO:0014065', ('59', '73'))	('PI3K pathway', 'Pathway', (200, 212))	('PTEN', 'Protein', (130, 134))	('PI3K signaling', 'Pathway', (59, 73))	('activation', 'PosReg', (213, 223))	('activation', 'PosReg', (45, 55))	('expression', 'MPA', (135, 145))	('mutations', 'Var', (179, 188))	('increased', 'PosReg', (91, 100))	('reduced', 'NegReg', (122, 129))	('PI3K', 'molecular_function', 'GO:0016303', ('200', '204'))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
13550	27524621	At present, BEZ235 is under evaluation in phase I/II clinical trials, and future studies are needed to investigate its efficacy in patients with CLC.	('patients', 'Species', '9606', (131, 139))	('CLC', 'Gene', '12735', (145, 148))	('BEZ235', 'Var', (12, 18))	('CLC', 'Gene', (145, 148))	('BEZ235', 'Chemical', 'MESH:C531198', (12, 18))
13551	27524621	However, it should be noted that antitumoral efficacy of PI3K pathway inhibitors might be reduced, in case CLCs acquire additional activating mutations in oncoproteins, such as KRAS, or loss-of-function mutations in tumor suppressors, such as PTPN11/SHP2 and p53, which we identified to alter tumor outcome and growth kinetics of mCLCs.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('reduced', 'NegReg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('loss-of-function', 'NegReg', (186, 202))	('SHP2', 'Gene', (250, 254))	('CLC', 'Gene', '12735', (107, 110))	('CLC', 'Gene', (107, 110))	('PTPN11', 'Gene', '19247', (243, 249))	('mCLC', 'Gene', '12735', (330, 334))	('tumor', 'Disease', (216, 221))	('mutations', 'Var', (142, 151))	('alter', 'Reg', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('SHP2', 'Gene', '19247', (250, 254))	('p53', 'Gene', '22059', (259, 262))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('CLC', 'Gene', '12735', (331, 334))	('PTPN11', 'Gene', (243, 249))	('activating', 'PosReg', (131, 141))	('KRAS', 'Gene', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('PI3K', 'molecular_function', 'GO:0016303', ('57', '61'))	('mutations', 'Var', (203, 212))	('mCLC', 'Gene', (330, 334))	('KRAS', 'Gene', '16653', (177, 181))	('tumor', 'Disease', (37, 42))	('p53', 'Gene', (259, 262))	('PI3K pathway', 'Pathway', (57, 69))	('tumor', 'Disease', (293, 298))	('CLC', 'Gene', (331, 334))
13558	27524621	In conclusion, in this study we presented concomitant inactivation of E-cadherin and PTEN in mammary epithelium to drive the formation of mCLC, thus developing a pertinent mouse model for human CLC.	('mCLC', 'Gene', '12735', (138, 142))	('CLC', 'Gene', (194, 197))	('human', 'Species', '9606', (188, 193))	('CLC', 'Gene', (139, 142))	('CLC', 'Gene', '12735', (194, 197))	('CLC', 'Gene', '12735', (139, 142))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('mouse', 'Species', '10090', (172, 177))	('formation', 'biological_process', 'GO:0009058', ('125', '134'))	('PTEN', 'Gene', (85, 89))	('mCLC', 'Gene', (138, 142))	('drive', 'PosReg', (115, 120))	('inactivation', 'Var', (54, 66))	('E-cadherin', 'Protein', (70, 80))
13580	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.	('APBI', 'Chemical', '-', (147, 151))	('T1-T2N0-N1micM0', 'Var', (66, 81))	('ILC', 'Disease', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (91, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('patients', 'Species', '9606', (38, 46))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (82, 107))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('invasive ductal carcinoma', 'Disease', (82, 107))
13601	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))
13716	30153845	In addition, we demonstrated the deleterious mutation C.del866C in CDH1gene, but no mutations in any of the other 33 genes analyzed by next generation sequencing.	('CDH1', 'Gene', (67, 71))	('CDH1', 'Gene', '999', (67, 71))	('C.del866C', 'Var', (54, 63))
13724	30153845	The diagnosis of lobular carcinoma was confirmed by immunohistochemistry (loss of expression of E-cadherin), and by targeted next generation sequencing, which identified a CDH1 mutation.	('mutation', 'Var', (177, 185))	('CDH1', 'Gene', (172, 176))	('lobular carcinoma', 'Disease', 'MESH:D018275', (17, 34))	('CDH1', 'Gene', '999', (172, 176))	('lobular carcinoma', 'Disease', (17, 34))	('cadherin', 'molecular_function', 'GO:0008014', ('98', '106'))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (17, 34))	('E-cadherin', 'Gene', (96, 106))	('loss of expression', 'NegReg', (74, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('E-cadherin', 'Gene', '999', (96, 106))
13744	30153845	We used an in-house panel based on hybrid capture for sequence enrichment including the 34 genes frequently mutated in breast cancer (AKT1, ARID1A, ARID1B, BRCA1, BRCA2, CASP8, CCND1, CDH1, ERBB2, ESR1, FGFR1, GATA3, GRB7, GSDMB, MAP2K4, KRAS, MAP3K1, MLL3, MYC, NCOR1, NF1, PGAP, PIK3CA3, PNMT, PTEN, RB1, SF3B1, STARD3, TBX3, TCAP, TP53, VGLL1, ZNF217, ZNF703) and regions in chromosome 8 (targeting amplification of FGFR1 and MYC), chromosome 11 (targeting amplification of CCND1), chromosome 17 (targeting amplification of ERBB2) and chromosome 20 (targeting amplification of ZNF217).	('AKT1', 'Gene', '207', (134, 138))	('MYC', 'Gene', (258, 261))	('ZNF217', 'Gene', '7764', (347, 353))	('MAP3K', 'molecular_function', 'GO:0004709', ('244', '249'))	('BRCA2', 'Gene', '675', (163, 168))	('FGFR1', 'Gene', '2260', (203, 208))	('MAP2K', 'molecular_function', 'GO:0004708', ('230', '235'))	('MLL3', 'Gene', '58508', (252, 256))	('ERBB2', 'Gene', (190, 195))	('AKT1', 'Gene', (134, 138))	('MYC', 'Gene', '4609', (258, 261))	('CCND1', 'Gene', (477, 482))	('MYC', 'Gene', (429, 432))	('MLL3', 'Gene', (252, 256))	('TP53', 'Gene', (334, 338))	('KRAS', 'Gene', '3845', (238, 242))	('ARID1B', 'Gene', '57492', (148, 154))	('MAP3K1', 'Gene', '4214', (244, 250))	('chromosome', 'cellular_component', 'GO:0005694', ('485', '495'))	('CDH1', 'Gene', (184, 188))	('PNMT', 'Gene', '5409', (290, 294))	('MYC', 'Gene', '4609', (429, 432))	('FGFR1', 'Gene', '2260', (419, 424))	('TP53', 'Gene', '7157', (334, 338))	('ZNF217', 'Gene', (347, 353))	('NF1', 'Gene', (270, 273))	('RB1', 'Gene', (302, 305))	('ERBB2', 'Gene', '2064', (527, 532))	('BRCA1', 'Gene', '672', (156, 161))	('mutated', 'Var', (108, 115))	('chromosome', 'cellular_component', 'GO:0005694', ('538', '548'))	('CCND1', 'Gene', '595', (477, 482))	('RB1', 'Gene', '5925', (302, 305))	('VGLL1', 'Gene', (340, 345))	('ERBB2', 'Gene', '2064', (190, 195))	('PNMT', 'Gene', (290, 294))	('ARID1B', 'Gene', (148, 154))	('CDH1', 'Gene', '999', (184, 188))	('CASP8', 'Gene', '841', (170, 175))	('ZNF217', 'Gene', '7764', (580, 586))	('TCAP', 'Gene', (328, 332))	('PTEN', 'Gene', '5728', (296, 300))	('ARID1A', 'Gene', (140, 146))	('NF1', 'Gene', '4763', (270, 273))	('SF3B1', 'Gene', (307, 312))	('GSDMB', 'Gene', (223, 228))	('ARID1A', 'Gene', '8289', (140, 146))	('TCAP', 'Gene', '8557', (328, 332))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('ESR1', 'Gene', '2099', (197, 201))	('ESR1', 'Gene', (197, 201))	('BRCA1', 'Gene', (156, 161))	('chromosome', 'cellular_component', 'GO:0005694', ('378', '388'))	('MAP2K4', 'Gene', '6416', (230, 236))	('MAP2K4', 'Gene', (230, 236))	('SF3B1', 'Gene', '23451', (307, 312))	('NCOR1', 'Gene', (263, 268))	('breast cancer', 'Disease', (119, 132))	('FGFR1', 'Gene', (419, 424))	('NCOR1', 'Gene', '9611', (263, 268))	('GRB7', 'Gene', (217, 221))	('PTEN', 'Gene', (296, 300))	('FGFR1', 'Gene', (203, 208))	('MAP3K1', 'Gene', (244, 250))	('ZNF217', 'Gene', (580, 586))	('VGLL1', 'Gene', '51442', (340, 345))	('GRB7', 'Gene', '2886', (217, 221))	('ERBB2', 'Gene', (527, 532))	('GATA3', 'Gene', '2625', (210, 215))	('FGFR', 'molecular_function', 'GO:0005007', ('419', '423'))	('FGFR', 'molecular_function', 'GO:0005007', ('203', '207'))	('chromosome', 'cellular_component', 'GO:0005694', ('435', '445'))	('GATA3', 'Gene', (210, 215))	('TBX3', 'Gene', (322, 326))	('ZNF703', 'Gene', (355, 361))	('CCND1', 'Gene', '595', (177, 182))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('CCND1', 'Gene', (177, 182))	('STARD3', 'Gene', (314, 320))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('GSDMB', 'Gene', '55876', (223, 228))	('TBX3', 'Gene', '6926', (322, 326))	('BRCA2', 'Gene', (163, 168))	('ZNF703', 'Gene', '80139', (355, 361))	('STARD3', 'Gene', '10948', (314, 320))	('KRAS', 'Gene', (238, 242))	('CASP8', 'Gene', (170, 175))
13745	30153845	With this technique, we identified a deleterious mutation (C.del866C) in CDH1 (the gene coding for E-cadherin protein) (Fig.	('C.del866C', 'Var', (59, 68))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('CDH1', 'Gene', (73, 77))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('CDH1', 'Gene', '999', (73, 77))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))
13755	30153845	In the best of our knowledge, only 7 previous invasive lobular carcinoma (ILC) with OGCs have been described in literature, but none of these had confirmation of the histological type by E-cadherin immunohistochemistry and/or mutational analysis of CDH1 gene nor were of pleomorphic subtype.	('mutational', 'Var', (226, 236))	('E-cadherin', 'Gene', (187, 197))	('E-cadherin', 'Gene', '999', (187, 197))	('invasive lobular carcinoma', 'Disease', (46, 72))	('CDH1', 'Gene', (249, 253))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (55, 72))	('CDH1', 'Gene', '999', (249, 253))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (46, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('cadherin', 'molecular_function', 'GO:0008014', ('189', '197'))
13758	30153845	In this sense, it has been reported that more than two third of mixed ductal-lobular carcinomas do not have CDH1 mutations and their mutational and transcriptional profiles are suggestive of invasive ductal carcinoma.	('ductal carcinoma', 'Phenotype', 'HP:0030075', (200, 216))	('ductal-lobular carcinomas', 'Disease', (70, 95))	('ductal-lobular carcinomas', 'Disease', 'MESH:D018299', (70, 95))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (77, 94))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (191, 216))	('CDH1', 'Gene', (108, 112))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (77, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('CDH1', 'Gene', '999', (108, 112))	('mutations', 'Var', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('invasive ductal carcinoma', 'Disease', (191, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))
13760	30153845	The World Health Organization (WHO) describes it as a variant of the ILC that retains the distinctive growth pattern of classic lobular carcinoma, but showing a greater degree of cellular atypia and pleomorphism and a higher mitotic rate than classic ILC.	('growth pattern', 'biological_process', 'GO:0007150', ('102', '116'))	('mitotic rate', 'CPA', (225, 237))	('higher', 'PosReg', (218, 224))	('lobular carcinoma', 'Disease', 'MESH:D018275', (128, 145))	('pleomorphism', 'Var', (199, 211))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (128, 145))	('lobular carcinoma', 'Disease', (128, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('growth pattern', 'biological_process', 'GO:0040007', ('102', '116'))
13762	30153845	In addition to the absence of E-Cadherin expression, we demonstrated the CDH1 mutation 866delC by targeted next generation sequencing.	('mutation', 'Var', (78, 86))	('CDH1', 'Gene', (73, 77))	('E-Cadherin', 'Gene', (30, 40))	('866delC', 'Mutation', 'c.866delC', (87, 94))	('Cadherin', 'molecular_function', 'GO:0008014', ('32', '40'))	('CDH1', 'Gene', '999', (73, 77))	('E-Cadherin', 'Gene', '999', (30, 40))
13764	30153845	Although with some differences among studies, some of the most common alterations detected were mutations in CDH1 (42.8% to 65%), PIK3CA (34.8% to 48%), TBX3 (9% to 13.3%), FOXA1 7% to (9%), GATA3 (5% to 7.1%), MAP3K1 (5.1% to 6%), and AKT1 (2.5% to 5.1%).	('PIK3CA', 'Gene', (130, 136))	('MAP3K1', 'Gene', (211, 217))	('TBX3', 'Gene', (153, 157))	('MAP3K1', 'Gene', '4214', (211, 217))	('AKT1', 'Gene', (236, 240))	('GATA3', 'Gene', (191, 196))	('MAP3K', 'molecular_function', 'GO:0004709', ('211', '216'))	('CDH1', 'Gene', (109, 113))	('TBX3', 'Gene', '6926', (153, 157))	('GATA3', 'Gene', '2625', (191, 196))	('FOXA1', 'Gene', (173, 178))	('to 7', 'Species', '1214577', (201, 205))	('AKT1', 'Gene', '207', (236, 240))	('CDH1', 'Gene', '999', (109, 113))	('mutations', 'Var', (96, 105))
13765	30153845	Compared with classical ILC, a higher frequency of HER2 mutations have been identified in PLC (20.8%).	('PLC', 'cellular_component', 'GO:0042824', ('90', '93'))	('mutations', 'Var', (56, 65))	('HER2', 'Gene', '2064', (51, 55))	('HER2', 'Gene', (51, 55))
13800	19664271	NUCKS has been characterized as a cell cycle related protein that is synthesized in the M/G1 phase.	('M/G1', 'SUBSTITUTION', 'None', (88, 92))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('cell cycle', 'biological_process', 'GO:0007049', ('34', '44'))	('M/G1', 'Var', (88, 92))	('G1 phase', 'biological_process', 'GO:0051318', ('90', '98'))	('NUCKS', 'Gene', '64710', (0, 5))	('NUCKS', 'Gene', (0, 5))
13805	19664271	Furthermore, translational modifications of NUCKS revealed acetylation and methylation sites specific for breast cancer, resembling the data from core histones.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('modifications', 'Var', (27, 40))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('core', 'cellular_component', 'GO:0019013', ('146', '150'))	('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))
13851	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))
13873	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))
13875	19664271	NUCKS has been characterized as a cell cycle related protein synthesized during the M/G1 phase.	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('G1 phase', 'biological_process', 'GO:0051318', ('86', '94'))	('M/G1', 'Var', (84, 88))	('cell cycle', 'biological_process', 'GO:0007049', ('34', '44'))	('M/G1', 'SUBSTITUTION', 'None', (84, 88))	('NUCKS', 'Gene', '64710', (0, 5))	('NUCKS', 'Gene', (0, 5))
13918	19664271	The signal was visualized with DAB chromogen (0.05% DAB, 0.024% H2O2 in PBS).	('PBS', 'Chemical', '-', (72, 75))	('0.05', 'Var', (46, 50))	('0.024%', 'Var', (57, 63))	('DAB', 'Chemical', 'MESH:C000469', (31, 34))	('H2O2', 'Chemical', 'MESH:D006861', (64, 68))	('DAB', 'Chemical', 'MESH:C000469', (52, 55))
14066	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))
14087	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))
14090	30337563	Autocrine activation of GFR signalling and its downstream PI3K/Akt hub was independent of oncogenic mutations in PIK3CA, AKT1 or PTEN.	('signalling', 'biological_process', 'GO:0023052', ('28', '38'))	('mutations', 'Var', (100, 109))	('GFR signalling', 'Pathway', (24, 38))	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('PIK3CA', 'Gene', (113, 119))	('PIK3CA', 'Gene', '5290', (113, 119))	('AKT1', 'Gene', '207', (121, 125))	('PTEN', 'Gene', (129, 133))	('PTEN', 'Gene', '5728', (129, 133))	('AKT1', 'Gene', (121, 125))
14092	30337563	Pharmacological inhibition of Akt using AZD5363 or MK2206 resulted in robust inhibition of cell growth and survival of ILC cells, and impeded tumour growth in a mouse ILC model.	('impeded', 'NegReg', (134, 141))	('cell growth', 'CPA', (91, 102))	('AZD5363', 'Chemical', 'MESH:C575618', (40, 47))	('tumour growth', 'Disease', (142, 155))	('MK2206', 'Chemical', 'MESH:C548887', (51, 57))	('AZD5363', 'Var', (40, 47))	('inhibition', 'NegReg', (77, 87))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumour growth', 'Disease', 'MESH:D006130', (142, 155))	('Akt', 'Pathway', (30, 33))	('MK2206', 'Var', (51, 57))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('77', '102'))	('mouse', 'Species', '10090', (161, 166))
14097	30337563	Loss of E-cadherin expression is observed in the vast majority of lobular breast cancers, mostly due to inactivating CDH1 mutations and subsequent loss of heterozygosity, or epigenetic silencing of the E-cadherin promoter.	('expression', 'MPA', (19, 29))	('lobular breast cancers', 'Disease', 'MESH:D013274', (66, 88))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('E-cadherin', 'Protein', (8, 18))	('lobular breast cancers', 'Disease', (66, 88))	('CDH1', 'Gene', (117, 121))	('CDH1', 'Gene', '999', (117, 121))	('Loss', 'NegReg', (0, 4))	('mutations', 'Var', (122, 131))	('inactivating', 'Var', (104, 116))	('cadherin', 'molecular_function', 'GO:0008014', ('204', '212'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (66, 87))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))	('breast cancers', 'Phenotype', 'HP:0003002', (74, 88))	('loss of', 'NegReg', (147, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('epigenetic silencing', 'Var', (174, 194))
14098	30337563	As a result of E-cadherin inactivation, the adherens junction (AJ) is no longer functional, leading to disruption of epithelial integrity and acquisition of tumour-promoting events such as anchorage independence, angiogenesis and tumour cell invasion.	('invasion', 'CPA', (242, 250))	('inactivation', 'Var', (26, 38))	('E-cadherin', 'Protein', (15, 25))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('anchorage independence', 'CPA', (189, 211))	('cadherin', 'molecular_function', 'GO:0008014', ('17', '25'))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('angiogenesis', 'biological_process', 'GO:0001525', ('213', '225'))	('angiogenesis', 'CPA', (213, 225))	('tumour', 'Disease', 'MESH:D009369', (230, 236))	('adherens junction', 'cellular_component', 'GO:0005912', ('44', '61'))	('tumour', 'Disease', (157, 163))	('tumour', 'Disease', (230, 236))	('acquisition', 'PosReg', (142, 153))	('disruption', 'NegReg', (103, 113))	('epithelial integrity', 'CPA', (117, 137))
14099	30337563	Another major driver in breast cancer is the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, which can be activated through loss of phosphatase and tensin homolog (PTEN) function or activating mutations in PI3K subunits or their downstream effectors.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('147', '177'))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('loss', 'NegReg', (139, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('mutations', 'Var', (208, 217))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('breast cancer', 'Disease', (24, 37))	('activating', 'PosReg', (197, 207))	('activated', 'PosReg', (121, 130))	('phosphatase', 'molecular_function', 'GO:0016791', ('147', '158'))	('PTEN', 'Gene', (179, 183))	('phosphatidylinositol-4,5-bisphosphate 3-kinase', 'Gene', '5290', (45, 91))	('PI3K', 'molecular_function', 'GO:0016303', ('221', '225'))	('PTEN', 'Gene', '5728', (179, 183))
14100	30337563	ILCs represent a subgroup of tumours in which the mutation rate of PIK3CA (48%) and genomic loss of PTEN (13%) is higher than in matched IDCs (37% and 11%, respectively).	('PTEN', 'Gene', (100, 104))	('PIK3CA', 'Gene', '5290', (67, 73))	('PTEN', 'Gene', '5728', (100, 104))	('IDC', 'Gene', '4000', (137, 140))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumours', 'Disease', (29, 36))	('IDC', 'Gene', (137, 140))	('loss', 'NegReg', (92, 96))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))	('rat', 'Species', '10116', (59, 62))	('genomic', 'CPA', (84, 91))	('ILCs', 'Disease', (0, 4))	('PIK3CA', 'Gene', (67, 73))	('mutation', 'Var', (50, 58))
14103	30337563	Given the broad occurrence of PI3K/Akt pathway mutations, clinical intervention of this pathway has not been tailored for a specific breast cancer subtype.	('breast cancer', 'Disease', (133, 146))	('PI3K/Akt', 'Gene', (30, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('mutations', 'Var', (47, 56))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
14114	30337563	As reported previously, we noted that expression levels of alpha-catenin, beta-catenin and p120-catenin were decreased in E-cadherin mutant ILC cells (Fig.	('decreased', 'NegReg', (109, 118))	('expression levels', 'MPA', (38, 55))	('cadherin', 'molecular_function', 'GO:0008014', ('124', '132'))	('beta-catenin', 'Gene', '1499', (74, 86))	('p120-catenin', 'Gene', '1500', (91, 103))	('beta-catenin', 'Gene', (74, 86))	('E-cadherin', 'Protein', (122, 132))	('mutant', 'Var', (133, 139))	('p120-catenin', 'Gene', (91, 103))
14118	30337563	Interestingly, PTEN expression was reduced or lost in the majority of ILC samples when compared to E-cadherin-expressing cells (Table 2), suggesting that inactivation of PTEN may be induced during ILC progression.	('expression', 'MPA', (20, 30))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('ILC', 'Disease', (197, 200))	('PTEN', 'Gene', (170, 174))	('inactivation', 'Var', (154, 166))	('reduced', 'NegReg', (35, 42))	('PTEN', 'Gene', '5728', (170, 174))	('PTEN', 'Gene', (15, 19))	('PTEN', 'Gene', '5728', (15, 19))	('lost', 'NegReg', (46, 50))
14121	30337563	To study if Akt pathway activation could be induced by autocrine growth factor-dependent signals, we initially cultured our cell lines without serum and assayed phosphorylation of Akt (at residues Ser473 and Thr308).	('Akt pathway', 'Pathway', (12, 23))	('Thr308', 'Var', (208, 214))	('Akt', 'Protein', (180, 183))	('Ser473', 'Chemical', '-', (197, 203))	('Thr308', 'Chemical', '-', (208, 214))	('phosphorylation', 'biological_process', 'GO:0016310', ('161', '176'))	('Ser', 'cellular_component', 'GO:0005790', ('197', '200'))
14124	30337563	To assess if mutational activation of core PI3K pathway components was underpinning pathway activation, we performed next-generation sequencing on mILC cell lines, which did not reveal somatic mutations in the GFR/PI3K/Akt pathway members Igf1r, Pik3ca, Akt1, Akt2, Akt3, Pten and Mtor (data not shown).	('Akt3', 'Gene', (266, 270))	('Mtor', 'Gene', '2475', (281, 285))	('core', 'cellular_component', 'GO:0019013', ('38', '42'))	('Akt1', 'Gene', (254, 258))	('Igf1r', 'Gene', '3480', (239, 244))	('Pik3ca', 'Gene', '5290', (246, 252))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('Akt2', 'Gene', (260, 264))	('Mtor', 'Gene', (281, 285))	('Akt2', 'Gene', '208', (260, 264))	('rat', 'Species', '10116', (126, 129))	('Pten', 'Gene', '5728', (272, 276))	('Pten', 'Gene', (272, 276))	('Akt3', 'Gene', '10000', (266, 270))	('Akt1', 'Gene', '207', (254, 258))	('Igf1r', 'Gene', (239, 244))	('Pik3ca', 'Gene', (246, 252))	('GFR/PI3K/Akt', 'Gene', (210, 222))	('mutational', 'Var', (13, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('214', '218'))
14125	30337563	In contrast, the human ILC cell line IPH-926 harboured a heterozygous deletion in PTEN (c.950_953delTACT) that probably contributes to the observed Akt activation under serum-free conditions.	('activation', 'PosReg', (152, 162))	('human', 'Species', '9606', (17, 22))	('IPH-926', 'CellLine', 'CVCL:A625', (37, 44))	('Akt', 'Pathway', (148, 151))	('c.950_953delTACT', 'Mutation', 'c.950_953delTACT', (88, 104))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))	('c.950_953delTACT', 'Var', (88, 104))
14127	30337563	These results indicate that loss of E-cadherin promotes constitutive Akt activation, even in the presence of PTEN-inactivating mutations.	('activation', 'PosReg', (73, 83))	('loss', 'Var', (28, 32))	('promotes', 'PosReg', (47, 55))	('constitutive', 'MPA', (56, 68))	('PTEN', 'Gene', (109, 113))	('E-cadherin', 'Protein', (36, 46))	('PTEN', 'Gene', '5728', (109, 113))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))
14132	30337563	Indeed, knock-out of E-cadherin ( Cdh1) in the mouse Trp53 /  cells increased Akt phosphorylation on Thr308 and Ser473 by 8.8- and 4.4-fold, respectively, upon stimulation with IGF (Fig.	('Thr308', 'Chemical', '-', (101, 107))	('Thr308', 'Var', (101, 107))	('Ser473', 'Var', (112, 118))	(' Cdh1', 'Gene', (33, 38))	('Ser473', 'Chemical', '-', (112, 118))	('Ser', 'cellular_component', 'GO:0005790', ('112', '115'))	('Akt', 'Pathway', (78, 81))	('cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('increased', 'PosReg', (68, 77))	('mouse', 'Species', '10090', (47, 52))
14133	30337563	Knock-out of E-cadherin in the MCF7 cells also induced a higher (up to 2.0-fold) activation of Akt after IGF administration (Supplementary Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('MCF7', 'CellLine', 'CVCL:0031', (31, 35))	('rat', 'Species', '10116', (117, 120))	('Knock-out', 'Var', (0, 9))	('activation', 'PosReg', (81, 91))	('Akt', 'Pathway', (95, 98))	('E-cadherin', 'Protein', (13, 23))
14134	30337563	However, because (in contrast to the mouse Trp53 /  cells) MCF7 cells contain an activating PIK3CA mutation and AKT1 amplification, our data suggest that de-repression of GFR signalling upon E-cadherin loss has a modest effect on IGF-induced Akt activation in the presence of oncogenic GFR signalling.	('AKT1', 'Gene', (112, 116))	('cadherin', 'molecular_function', 'GO:0008014', ('193', '201'))	('PIK3CA', 'Gene', (92, 98))	('PIK3CA', 'Gene', '5290', (92, 98))	('de-repression', 'NegReg', (154, 167))	('activation', 'PosReg', (246, 256))	('signalling', 'biological_process', 'GO:0023052', ('290', '300'))	('signalling', 'biological_process', 'GO:0023052', ('175', '185'))	('E-cadherin', 'Protein', (191, 201))	('mutation', 'Var', (99, 107))	('Akt', 'Pathway', (242, 245))	('mouse', 'Species', '10090', (37, 42))	('MCF7', 'CellLine', 'CVCL:0031', (59, 63))	('loss', 'NegReg', (202, 206))	('AKT1', 'Gene', '207', (112, 116))	('activating', 'PosReg', (81, 91))
14135	30337563	Given the ability of IGF-1 to hyperactivate the PI3K/Akt pathway in E-cadherin mutant breast cancer cells, we analysed IGF1 expression in the METABRIC and TCGA (http://cancergenome.nih.gov/) mRNA expression datasets (Fig.	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('cancer', 'Disease', (168, 174))	('IGF-1', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('IGF1', 'Gene', (119, 123))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Disease', (86, 99))	('IGF-1', 'Gene', '3479', (21, 26))	('mutant', 'Var', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('hyperactivate', 'PosReg', (30, 43))	('IGF1', 'Gene', '3479', (119, 123))	('PI3K/Akt pathway', 'Pathway', (48, 64))	('E-cadherin', 'Protein', (68, 78))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))
14153	30337563	Given the increase in Akt activity, we wondered whether E-cadherin mutant breast cancer cells were sensitive to pharmacological inhibition of the PI3K/Akt pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('breast cancer', 'Disease', (74, 87))	('cadherin', 'molecular_function', 'GO:0008014', ('58', '66'))	('E-cadherin', 'Protein', (56, 66))	('increase', 'PosReg', (10, 18))	('Akt', 'CPA', (22, 25))	('mutant', 'Var', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PI3K/Akt pathway', 'Pathway', (146, 162))	('activity', 'MPA', (26, 34))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
14155	30337563	The latter is being used in vitro to target Akt1/2 with high specificity, while AZD5363 and MK2006 are currently being tested in clinical trials.	('Akt1', 'Gene', '207', (44, 48))	('MK2006', 'Var', (92, 98))	('AZD5363', 'Chemical', 'MESH:C575618', (80, 87))	('AZD5363', 'Var', (80, 87))	('MK2006', 'Chemical', '-', (92, 98))	('Akt1', 'Gene', (44, 48))
14156	30337563	Using VIII, AZD5363 or MK2206, we observed a dose-dependent inhibition of growth and survival in adherent and non-adherent conditions (Fig.	('MK2206', 'Chemical', 'MESH:C548887', (23, 29))	('AZD5363', 'Chemical', 'MESH:C575618', (12, 19))	('AZD5363', 'Var', (12, 19))	('VIII', 'Gene', '1351', (6, 10))	('survival', 'CPA', (85, 93))	('MK2206', 'Var', (23, 29))	('inhibition', 'NegReg', (60, 70))	('VIII', 'Gene', (6, 10))	('inhibition of growth', 'biological_process', 'GO:0045926', ('60', '80'))	('growth', 'CPA', (74, 80))
14157	30337563	Although all inhibitors induced a reduction in growth and survival, the strongest reduction in growth and survival was observed for MK2206, with a 50% growth inhibition (GI50) observed at concentrations below 500 nM in all cell types (Fig.	('MK2206', 'Var', (132, 138))	('reduction', 'NegReg', (82, 91))	('survival', 'CPA', (106, 114))	('survival', 'CPA', (58, 66))	('growth', 'MPA', (151, 157))	('reduction', 'NegReg', (34, 43))	('MK2206', 'Chemical', 'MESH:C548887', (132, 138))	('rat', 'Species', '10116', (195, 198))	('growth', 'CPA', (47, 53))	('growth', 'CPA', (95, 101))
14159	30337563	As such, our results show that loss of E-cadherin causes a hypersensitive PI3K/Akt pathway, which sensitises cancer cells to pharmacological inhibition of Akt.	('hypersensitive', 'Disease', (59, 73))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))	('E-cadherin', 'Protein', (39, 49))	('loss', 'Var', (31, 35))	('cancer', 'Disease', (109, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('hypersensitive', 'Disease', 'MESH:D004342', (59, 73))
14163	30337563	Inhibition of Akt using MK2206 led to a significant inhibition of tumour growth during the treatment (Fig.	('MK2206', 'Chemical', 'MESH:C548887', (24, 30))	('Akt', 'Pathway', (14, 17))	('Inhibition', 'NegReg', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumour growth', 'Disease', (66, 79))	('MK2206', 'Var', (24, 30))	('tumour growth', 'Disease', 'MESH:D006130', (66, 79))	('inhibition', 'NegReg', (52, 62))
14176	30337563	However, we have not obtained evidence for PTEN decrease as a direct result of E-cadherin knock-out.	('knock-out', 'Var', (90, 99))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('decrease', 'NegReg', (48, 56))	('E-cadherin', 'Protein', (79, 89))	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))
14177	30337563	Activation of PI3K signalling in cancer is often attributed to activating mutations, which are also frequently observed in ILC.	('cancer', 'Disease', (33, 39))	('PI3K signalling', 'Pathway', (14, 29))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutations', 'Var', (74, 83))	('ILC', 'Disease', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Activation', 'PosReg', (0, 10))	('signalling', 'biological_process', 'GO:0023052', ('19', '29'))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))
14178	30337563	An opportunity to treat primary ILC and its disseminating cancer cells arises from the ability of MK2206 to potently restrain cell survival of ILC cell lines in both adherent and non-adherent settings.	('MK2206', 'Chemical', 'MESH:C548887', (98, 104))	('cell survival', 'CPA', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('restrain', 'NegReg', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('MK2206', 'Var', (98, 104))	('cancer', 'Disease', (58, 64))
14179	30337563	As a mono-therapy, MK2206 had a moderate effect on tumour growth in a breast xenograft model, while combination with paclitaxel further increased this anti-tumour effect.	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('tumour', 'Disease', (156, 162))	('rat', 'Species', '10116', (36, 39))	('MK2206', 'Var', (19, 25))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour growth', 'Disease', (51, 64))	('tumour growth', 'Disease', 'MESH:D006130', (51, 64))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('tumour', 'Disease', (51, 57))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))
14180	30337563	In addition, phase I clinical trials combining MK2206 with paclitaxel, anastrozole or trastuzumab in advanced solid tumours and metastatic breast cancer reported anti-tumour activity with no serious adverse effects.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('solid tumours', 'Disease', 'MESH:D009369', (110, 123))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('anastrozole', 'Chemical', 'MESH:D000077384', (71, 82))	('tumour', 'Disease', (167, 173))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('trastuzumab', 'Chemical', 'MESH:D000068878', (86, 97))	('MK2206', 'Var', (47, 53))	('tumour', 'Disease', (116, 122))	('solid tumours', 'Disease', (110, 123))	('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))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('MK2206', 'Chemical', 'MESH:C548887', (47, 53))
14181	30337563	Although the response to MK2206 in vitro was highly increased in cell lines harbouring PIK3CA or PTEN mutations, tumour responses could not be linked to the presence of mutations in PIK3CA.	('PIK3CA', 'Gene', '5290', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('increased', 'PosReg', (52, 61))	('MK2206', 'Chemical', 'MESH:C548887', (25, 31))	('PTEN', 'Gene', (97, 101))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('PTEN', 'Gene', '5728', (97, 101))	('PIK3CA', 'Gene', (182, 188))	('PIK3CA', 'Gene', '5290', (182, 188))	('response', 'MPA', (13, 21))	('tumour', 'Disease', (113, 119))	('mutations', 'Var', (102, 111))	('PIK3CA', 'Gene', (87, 93))
14183	30337563	These parameters further strengthen our assumption that AJ inactivation promotes PI3K/Akt activation and that hyperactivation through E-cadherin loss evokes differential dependency on PI3K/Akt signals when compared to cancers that are oncogene-addicted due to somatic mutations in GFR pathway effectors.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('activation', 'PosReg', (90, 100))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('inactivation', 'Var', (59, 71))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('loss', 'NegReg', (145, 149))	('cancers', 'Disease', (218, 225))	('PI3K', 'molecular_function', 'GO:0016303', ('184', '188'))	('E-cadherin', 'Protein', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('PI3K/Akt', 'Pathway', (81, 89))	('promotes', 'PosReg', (72, 80))	('dependency', 'MPA', (170, 180))
14198	30337563	Secondary antibodies were swine anti-rabbit-PO (p217, DAKO), goat anti-mouse-PO (170-6516, Bio-Rad), goat anti-rabbit-PO (170-6515, Bio-Rad) and rabbit anti-goat-PO (p160, DAKO).	('p160', 'Gene', '10514', (166, 170))	('rabbit', 'Species', '9986', (145, 151))	('rabbit', 'Species', '9986', (37, 43))	('mouse', 'Species', '10090', (71, 76))	('p160', 'Gene', (166, 170))	('170-6515', 'Var', (122, 130))	('goat', 'Species', '9925', (61, 65))	('Rad', 'Gene', '6236', (95, 98))	('Rad', 'biological_process', 'GO:1990116', ('95', '98'))	('goat', 'Species', '9925', (157, 161))	('Rad', 'Gene', (95, 98))	('swine', 'Species', '9823', (26, 31))	('Rad', 'biological_process', 'GO:1990116', ('136', '139'))	('Rad', 'Gene', '6236', (136, 139))	('170-6516', 'Var', (81, 89))	('goat', 'Species', '9925', (101, 105))	('Rad', 'Gene', (136, 139))	('rabbit', 'Species', '9986', (111, 117))
14223	30337563	Fixed samples were incubated overnight at 4  C with primary antibodies in 1% bovine serum albumin in PBS using the following antibodies: mouse anti-p120-catenin (1:500; 610134, BD Biosciences) and Alexa Fluor 555-conjugated anti-E-cadherin (1:100; 560064, BD Biosciences).	('bovine', 'Species', '9913', (77, 83))	('PBS', 'Chemical', '-', (101, 104))	('mouse', 'Species', '10090', (137, 142))	('p120-catenin', 'Gene', '1500', (148, 160))	('p120-catenin', 'Gene', (148, 160))	('1:500; 610134', 'Var', (162, 175))	('Alexa Fluor 555', 'Chemical', 'MESH:C000608607', (197, 212))	('cadherin', 'molecular_function', 'GO:0008014', ('231', '239'))
14233	30337563	When tumours reached a volume of 100 mm3, mice were sham-treated (30% captisol) or treated with MK2206 (120 mg/kg) three times per week on alternating days for 3 weeks.	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('MK2206', 'Chemical', 'MESH:C548887', (96, 102))	('mice', 'Species', '10090', (42, 46))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumours', 'Disease', (5, 12))	('captisol', 'Chemical', 'MESH:C093196', (70, 78))	('MK2206', 'Var', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
14245	30337563	For mouse variants predicted to have a functional consequence, the corresponding human sequence was analysed for the presence of known somatic mutations in cancer (COSMIC).	('mouse', 'Species', '10090', (4, 9))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('variants', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('human', 'Species', '9606', (81, 86))
14280	29850340	On the other hand, the aberrant expression of E-cadherin observed in lobular carcinomas is associated with the loss of membranous staining for other molecules of the E-cadherin-membrane complex.	('cadherin', 'molecular_function', 'GO:0008014', ('48', '56'))	('lobular carcinomas', 'Disease', (69, 87))	('E-cadherin', 'Gene', (46, 56))	('loss', 'NegReg', (111, 115))	('E-cadherin', 'Gene', (166, 176))	('E-cadherin', 'Gene', '999', (166, 176))	('cadherin', 'molecular_function', 'GO:0008014', ('168', '176'))	('membrane', 'cellular_component', 'GO:0016020', ('177', '185'))	('E-cadherin', 'Gene', '999', (46, 56))	('lobular carcinomas', 'Disease', 'MESH:D018275', (69, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('membranous staining for other', 'MPA', (119, 148))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (69, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('expression', 'MPA', (32, 42))	('aberrant', 'Var', (23, 31))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (69, 87))
14351	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))	('invasive disease', 'Disease', 'MESH:D009362', (66, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('LCIS', 'Phenotype', 'HP:0030076', (29, 33))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (177, 202))	('LCIS', 'Phenotype', 'HP:0030076', (88, 92))
14353	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.	('cadherin', 'molecular_function', 'GO:0008014', ('160', '168'))	('tumors', 'Phenotype', 'HP:0002664', (380, 386))	('cadherin', 'molecular_function', 'GO:0008014', ('226', '234'))	('truncating mutations', 'Var', (130, 150))	('LCIS', 'Phenotype', 'HP:0030076', (367, 371))	('LCIS', 'Disease', (261, 265))	('E-cadherin', 'Gene', (224, 234))	('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))	('LCIS', 'Phenotype', 'HP:0030076', (261, 265))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('LCIS', 'Disease', (367, 371))	('LCIS', 'Phenotype', 'HP:0030076', (116, 120))	('loss', 'NegReg', (178, 182))	('ILC tumors', 'Disease', (376, 386))
14417	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))
14418	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))	('cadherin', 'molecular_function', 'GO:0008014', ('45', '53'))	('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))
14419	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.	('E-cadherin', 'Gene', (205, 215))	('E-cadherin', 'Gene', '999', (205, 215))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('231', '247'))	('growth control', 'CPA', (160, 174))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('found', 'Reg', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('231', '247'))	('cadherin', 'molecular_function', 'GO:0008014', ('129', '137'))	('tumor', 'Disease', (231, 236))	('Mutations', 'Var', (0, 9))	('cadherin', 'molecular_function', 'GO:0008014', ('207', '215'))	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('loss', 'NegReg', (152, 156))	('association', 'Interaction', (107, 118))	('mutations', 'Var', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('E-cadherin', 'Gene', (127, 137))	('E-cadherin', 'Gene', '999', (127, 137))
14420	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))	('cadherin', 'molecular_function', 'GO:0008014', ('57', '65'))	('mutations', 'Var', (42, 51))
14430	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))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('137', '160'))	('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))
14451	30046588	Results of mammography (MRX), ultrasound (US), and MRI examinations of each patient were retrospectively reviewed, identifying areas of multifocal, multicentric, or contralateral disease detected only with MRI and not with standard exams (MRX or US).	('MRX', 'Gene', '1741', (239, 242))	('MRI', 'Var', (206, 209))	('MRX', 'Gene', (239, 242))	('MRX', 'Gene', '1741', (24, 27))	('multicentric', 'Disease', (148, 160))	('MRX', 'Gene', (24, 27))
14454	30046588	Only six patients of the overall population needed a reoperation after the initial surgery: mastectomy was performed in 5 patients because of positive margins after breast-conservative surgery, while one patient required bilateral mastectomy after breast-conservative surgery, due to the presence of BRCA1 mutation.	('BRCA1', 'Gene', '672', (300, 305))	('presence', 'Reg', (288, 296))	('BRCA1', 'Gene', (300, 305))	('mutation', 'Var', (306, 314))
14456	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))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (58, 79))	('E-cadherin', 'Gene', (0, 10))	('loss of heterozygosity', 'Var', (15, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('E-cadherin', 'Gene', '999', (0, 10))
14457	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))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
14458	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))	('cadherin', 'molecular_function', 'GO:0008014', ('102', '110'))
14459	11879552	However, only lobular tumours showed E-cadherin mutations.	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('cadherin', 'molecular_function', 'GO:0008014', ('39', '47'))	('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))
14463	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))	('CDH1', 'Gene', (47, 51))	('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))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('cadherin', 'molecular_function', 'GO:0008014', ('33', '41'))	('lobular breast cancer', 'Disease', 'MESH:D013274', (100, 121))	('reported', 'Reg', (61, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
14466	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))
14470	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))
14475	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))
14478	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', 'cellular_component', 'GO:0003675', ('17', '24'))	('protein', 'MPA', (17, 24))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('mutational inactivation', 'Var', (63, 86))
14482	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))	('cadherin', 'molecular_function', 'GO:0008014', ('5', '13'))	('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))	('cadherin', 'molecular_function', 'GO:0008014', ('141', '149'))
14483	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))	('cadherin', 'molecular_function', 'GO:0008014', ('68', '76'))
14484	11879552	It therefore seems unlikely that LOH at 16q is associated with a decrease in E-cadherin expression in ductal breast cancer.	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('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))
14485	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))	('cadherin', 'molecular_function', 'GO:0008014', ('105', '113'))	('DCIS', 'Phenotype', 'HP:0030075', (35, 39))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (16, 33))	('LOH', 'Var', (74, 77))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (9, 33))	('ductal carcinoma in situ', 'Disease', (9, 33))	('E-cadherin', 'Protein', (103, 113))	('decrease', 'NegReg', (91, 99))
14488	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))	('cadherin', 'molecular_function', 'GO:0008014', ('158', '166'))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))
14489	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))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('lobular carcinoma in situ', 'Disease', (235, 260))	('tumour', 'Disease', (271, 277))	('CDH1', 'Gene', '999', (149, 153))	('LOH', 'Var', (170, 173))
14498	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))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('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))
14502	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))	('breast', 'Disease', (54, 60))	('CDH1', 'Gene', '999', (233, 237))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cadherin', 'molecular_function', 'GO:0008014', ('32', '40'))	('truncating mutations', 'Var', (209, 229))	('gastric cancer', 'Disease', (65, 79))	('gastric cancer', 'Disease', (155, 169))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (155, 169))
14505	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))	('CDH1', 'Gene', '999', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Disease', (68, 82))	('CDH1', 'Gene', (12, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('Loss', 'Var', (0, 4))
14507	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))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
14510	11879552	LOH at chromosome arm 16q in breast cancer is a frequent event, occurring in at least 50% of breast cancer cases.	('chromosome', 'cellular_component', 'GO:0005694', ('7', '17'))	('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))
14518	30744493	Oestrogen and fibronectin treatment was found to promote the colocalization of SGSM2 at the leading edge with phospho-FAK (Y397).	('SGSM2', 'Gene', (79, 84))	('fibronectin', 'Gene', (14, 25))	('Y397', 'Var', (123, 127))	('fibronectin', 'Gene', '2335', (14, 25))	('promote', 'PosReg', (49, 56))	('FAK', 'molecular_function', 'GO:0004717', ('118', '121'))	('colocalization', 'MPA', (61, 75))
14533	30744493	Consistently, knockdown of SGSM2 by small interfering RNA (siRNA) induced the phosphorylation of focal adhesion kinase (FAK; Y576/577), a decrease in the expression of the epithelial markers E-cadherin, beta-catenin, and Paxillin, and an increase in the expression of upstream epithelial markers Snail and Twist-1, which led to a reduction in cell adhesion and the promotion of cancer cell migration.	('cell adhesion', 'CPA', (343, 356))	('focal adhesion', 'cellular_component', 'GO:0005925', ('97', '111'))	('focal adhesion kinase', 'Gene', '5747', (97, 118))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('cell migration', 'biological_process', 'GO:0016477', ('385', '399'))	('Paxillin', 'Gene', (221, 229))	('Twist-1', 'Gene', (306, 313))	('cadherin', 'molecular_function', 'GO:0008014', ('193', '201'))	('reduction', 'NegReg', (330, 339))	('promotion', 'PosReg', (365, 374))	('expression', 'MPA', (254, 264))	('E-cadherin', 'Protein', (191, 201))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('Snail', 'Gene', (296, 301))	('decrease', 'NegReg', (138, 146))	('focal adhesion kinase', 'Gene', (97, 118))	('small', 'Var', (36, 41))	('beta-catenin', 'Protein', (203, 215))	('phosphorylation', 'MPA', (78, 93))	('SGSM2', 'Gene', (27, 32))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('cancer', 'Disease', (378, 384))	('FAK', 'molecular_function', 'GO:0004717', ('120', '123'))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('increase', 'PosReg', (238, 246))	('cell adhesion', 'biological_process', 'GO:0007155', ('343', '356'))	('Snail', 'Gene', '6615', (296, 301))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('Twist-1', 'Gene', '7291', (306, 313))	('knockdown', 'Var', (14, 23))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('Paxillin', 'Gene', '5829', (221, 229))	('expression', 'MPA', (154, 164))
14540	30744493	The mean of the fold difference in the T > N group (8.62-fold) was higher than that in the N > T group (4.57-fold) (Figure 1(a), Chi-square goodness-of-fit test, ***P < 0.001).	('N', 'Chemical', 'MESH:D009584', (43, 44))	('higher', 'PosReg', (67, 73))	('T > N', 'Var', (39, 44))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('fold difference', 'MPA', (16, 31))
14571	30744493	The cell adhesion ability in the calebin A (10 muM) combined with NNK (100 nM) group was significantly suppressed compared with the DMSO group (Figure 4(c), bar 2 vs. 4; **P < 0.01).	('calebin A', 'Chemical', 'MESH:C448819', (33, 42))	('10', 'Var', (44, 46))	('muM', 'Gene', (47, 50))	('suppressed', 'NegReg', (103, 113))	('cell adhesion ability', 'CPA', (4, 25))	('cell adhesion', 'biological_process', 'GO:0007155', ('4', '17'))	('DMSO', 'Chemical', 'MESH:D004121', (132, 136))	('muM', 'Gene', '56925', (47, 50))
14578	30744493	Compared with wild-type and scramble T47D cells, which exhibited a round and aggregate shape (Figure S3(a,b)), cells of the SGSM2 si1 displayed a flattened and more spindle morphology (Figure S3(c)).	('T47D', 'CellLine', 'CVCL:0553', (37, 41))	('more', 'PosReg', (160, 164))	('spindle', 'cellular_component', 'GO:0005819', ('165', '172'))	('SGSM2 si1', 'Var', (124, 133))
14579	30744493	However, si1 SGSM2, with almost complete inhibition of SGSM2 expression, exhibited significantly decreased cell adhesion in the fibronectin group (Figure 5(a), sc vs. si1; **P < 0.01, n > 3).	('cell adhesion', 'CPA', (107, 120))	('expression', 'MPA', (61, 71))	('SGSM2', 'Gene', (55, 60))	('fibronectin', 'Gene', (128, 139))	('decreased', 'NegReg', (97, 106))	('cell adhesion', 'biological_process', 'GO:0007155', ('107', '120'))	('fibronectin', 'Gene', '2335', (128, 139))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (97, 120))	('si1', 'Var', (9, 12))	('inhibition', 'NegReg', (41, 51))
14580	30744493	Certain epithelial markers, such as E-cadherin, beta-catenin, and Paxillin, were decreased in si1 SGSM2 T47D cells.	('decreased', 'NegReg', (81, 90))	('E-cadherin', 'Protein', (36, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('Paxillin', 'Gene', '5829', (66, 74))	('SGSM2 T47D', 'CellLine', 'CVCL:0553', (98, 108))	('si1 SGSM2', 'Var', (94, 103))	('Paxillin', 'Gene', (66, 74))	('beta-catenin', 'Protein', (48, 60))
14581	30744493	Snail and Twist-1 expression was also increased in si1 SGSM2 T47D cells (Figure 5(c)).	('si1 SGSM2 T47D', 'Var', (51, 65))	('Snail', 'Gene', (0, 5))	('Twist-1', 'Gene', '7291', (10, 17))	('Snail', 'Gene', '6615', (0, 5))	('SGSM2 T47D', 'CellLine', 'CVCL:0553', (55, 65))	('Twist-1', 'Gene', (10, 17))	('expression', 'MPA', (18, 28))	('increased', 'PosReg', (38, 47))
14582	30744493	These results revealed that SGSM2-silenced BC cells exhibit a more migratory phenotype, decreased cell adhesion and improved migration abilities, but why SRC protein was dramatically decreased in si1 SGSM2 T47D cells remains unknown.	('improved', 'PosReg', (116, 124))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (88, 111))	('SRC', 'Gene', '20779', (154, 157))	('migratory phenotype', 'CPA', (67, 86))	('SRC', 'Gene', (154, 157))	('si1', 'Var', (196, 199))	('SGSM2 T47D', 'CellLine', 'CVCL:0553', (200, 210))	('decreased', 'NegReg', (183, 192))	('more', 'PosReg', (62, 66))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('decreased', 'NegReg', (88, 97))	('migration abilities', 'CPA', (125, 144))	('cell adhesion', 'biological_process', 'GO:0007155', ('98', '111'))	('cell adhesion', 'CPA', (98, 111))
14584	30744493	EGTA, a Ca+ -specific chelator, can disrupt cadherin-mediated cell-cell adherens junctions, and subsequent restoration of Ca+ ions may re-establish cadherin-mediated cell-cell contacts.	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('cadherin', 'molecular_function', 'GO:0008014', ('148', '156'))	('Ca+ ions', 'MPA', (122, 130))	('restoration', 'Var', (107, 118))	('cadherin-mediated cell-cell contacts', 'CPA', (148, 184))	('disrupt', 'NegReg', (36, 43))	('cadherin-mediated', 'Protein', (44, 61))	('EGTA', 'Chemical', 'MESH:D004533', (0, 4))	('re-establish', 'PosReg', (135, 147))
14599	30744493	Our study verified that inhibition of SGSM2 could reduce cell adhesion and increase cancer cell migration; however, we also found that SGSM2 was involved in modulating E2-induced cell motility.	('cell adhesion', 'biological_process', 'GO:0007155', ('57', '70'))	('reduce', 'NegReg', (50, 56))	('modulating', 'Reg', (157, 167))	('SGSM2', 'Gene', (135, 140))	('increase cancer', 'Disease', 'MESH:D009369', (75, 90))	('cell migration', 'biological_process', 'GO:0016477', ('91', '105'))	('cell motility', 'biological_process', 'GO:0048870', ('179', '192'))	('reduce cell adhesion', 'Phenotype', 'HP:0008352', (50, 70))	('inhibition', 'Var', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('involved', 'Reg', (145, 153))	('cell adhesion', 'CPA', (57, 70))	('increase cancer', 'Disease', (75, 90))	('SGSM2', 'Gene', (38, 43))
14614	30744493	Incidentally, we noticed that during the cell culture process, 21 muM trypsin-EDTA could cleave SGSM2 protein, and we confirmed that SGSM2 protein was cleaved by treatment with trypsin-EDTA at concentrations of 21 nM or higher.	('EDTA', 'Chemical', 'MESH:D004492', (185, 189))	('cleave', 'Var', (89, 95))	('muM', 'Gene', '56925', (66, 69))	('SGSM2', 'Gene', (96, 101))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('muM', 'Gene', (66, 69))	('EDTA', 'Chemical', 'MESH:D004492', (78, 82))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('protein', 'Protein', (102, 109))
14618	30744493	Consistently, the cell adhesion ability of trypsinized T47D cells was significantly decreased compared with non-trypsinized cells on plates coated with different fibronectin concentrations (0.1, 1, and 10 mug/ml), but these results did not occur on type I- and type-II collagen.	('T47D', 'CellLine', 'CVCL:0553', (55, 59))	('fibronectin', 'Gene', (162, 173))	('T47D', 'Var', (55, 59))	('cell adhesion', 'biological_process', 'GO:0007155', ('18', '31'))	('collagen', 'molecular_function', 'GO:0005202', ('269', '277'))	('mug', 'molecular_function', 'GO:0043739', ('205', '208'))	('cell adhesion ability', 'CPA', (18, 39))	('fibronectin', 'Gene', '2335', (162, 173))	('decreased', 'NegReg', (84, 93))
14619	30744493	In addition, trypsinization also inhibited nicotine- and NNK-induced cell adhesion ability on fibronectin.	('trypsinization', 'Var', (13, 27))	('cell adhesion', 'biological_process', 'GO:0007155', ('69', '82'))	('fibronectin', 'Gene', (94, 105))	('nicotine', 'Chemical', 'MESH:D009538', (43, 51))	('nicotine-', 'MPA', (43, 52))	('fibronectin', 'Gene', '2335', (94, 105))	('cell adhesion ability', 'CPA', (69, 90))	('inhibited', 'NegReg', (33, 42))
14623	30744493	We also found that SGSM2 protein was slightly increased by 0.1 muM calebin A treatment but was decreased after 1 and 10 muM calebin A treatment.	('muM', 'Gene', '56925', (120, 123))	('muM', 'Gene', '56925', (63, 66))	('calebin A', 'Chemical', 'MESH:C448819', (67, 76))	('protein', 'Protein', (25, 32))	('increased', 'PosReg', (46, 55))	('muM', 'Gene', (120, 123))	('muM', 'Gene', (63, 66))	('calebin A', 'Var', (67, 76))	('SGSM2', 'Gene', (19, 24))	('calebin A', 'Chemical', 'MESH:C448819', (124, 133))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))
14627	30744493	Additionally, SGSM2 knockdown promoted T47D cell migration, which was associated with the upregulation of p-FAK (Y576/577) and epithelial-associated markers (Snail and Twist) and the downregulation of E-cadherin, beta-catenin, and Paxillin.	('FAK', 'molecular_function', 'GO:0004717', ('108', '111'))	('SGSM2', 'Gene', (14, 19))	('T47D cell migration', 'CPA', (39, 58))	('Paxillin', 'Gene', (231, 239))	('upregulation', 'PosReg', (90, 102))	('p-FAK', 'Protein', (106, 111))	('Snail', 'Gene', '6615', (158, 163))	('E-cadherin', 'Protein', (201, 211))	('Snail', 'Gene', (158, 163))	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('promoted', 'PosReg', (30, 38))	('Paxillin', 'Gene', '5829', (231, 239))	('T47D', 'CellLine', 'CVCL:0553', (39, 43))	('knockdown', 'Var', (20, 29))	('beta-catenin', 'Protein', (213, 225))	('cadherin', 'molecular_function', 'GO:0008014', ('203', '211'))	('downregulation', 'NegReg', (183, 197))
14635	30744493	After seeding MCF-7 cells on fibronectin-coated slides and allowing them to adhere for two hours, slight SGSM2 localization with p-FAK (Y397) was observed at the fibronectin-induced focal adhesion position, and this phenomenon became more apparent at the sixth hour.	('fibronectin', 'Gene', '2335', (29, 40))	('MCF-7', 'CellLine', 'CVCL:0031', (14, 19))	('fibronectin', 'Gene', (162, 173))	('FAK', 'molecular_function', 'GO:0004717', ('131', '134'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('182', '196'))	('fibronectin', 'Gene', (29, 40))	('localization', 'biological_process', 'GO:0051179', ('111', '123'))	('fibronectin', 'Gene', '2335', (162, 173))	('p-FAK (Y397', 'Var', (129, 140))
14637	30744493	Oestrogen has been reported to promote BC cell motility and invasion via FAK phosphorylation, and FAK recruits the small GTPase cdc42, which induces N-WASP phosphorylation.	('cdc42', 'Gene', (128, 133))	('BC cell motility', 'CPA', (39, 55))	('invasion', 'CPA', (60, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('cell motility', 'biological_process', 'GO:0048870', ('42', '55'))	('FAK', 'molecular_function', 'GO:0004717', ('73', '76'))	('FAK', 'molecular_function', 'GO:0004717', ('98', '101'))	('promote', 'PosReg', (31, 38))	('GTP', 'Chemical', 'MESH:D006160', (121, 124))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('N', 'Chemical', 'MESH:D009584', (149, 150))	('cdc42', 'Gene', '998', (128, 133))	('FAK', 'Var', (98, 101))
14639	30744493	Three components of the cytoskeleton (microfilaments, microtubules, and intermediate filaments) are required for regulating blebbing, and myosin II contraction in the actin cortex, which is regulated by the small GTPase RhoA, leads to membrane detachment and bleb inflation.	('GTP', 'Chemical', 'MESH:D006160', (213, 216))	('leads to', 'Reg', (226, 234))	('RhoA', 'Gene', '387', (220, 224))	('membrane', 'cellular_component', 'GO:0016020', ('235', '243'))	('myosin', 'Var', (138, 144))	('bleb inflation', 'Disease', 'MESH:D001768', (259, 273))	('RhoA', 'Gene', (220, 224))	('bleb', 'cellular_component', 'GO:0032059', ('259', '263'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('24', '36'))	('blebbing', 'biological_process', 'GO:0032060', ('124', '132'))	('bleb inflation', 'Disease', (259, 273))	('membrane detachment', 'CPA', (235, 254))
14640	30744493	In the dynamic changes in motility induced by E2, abundant SGSM2 was observed to accumulate with beta-tubulin at the plasma membrane blebs at the 30-minute mark; moreover, colocalization of SGSM2 and p-FAK (Y397) was found not only in focal adhesions but also at the leading edge of ruffling and lamellipodia.	('SGSM2', 'Var', (190, 195))	('plasma membrane', 'cellular_component', 'GO:0005886', ('117', '132'))	('FAK', 'molecular_function', 'GO:0004717', ('202', '205'))	('ruffling and lamellipodia', 'Disease', 'MESH:C566651', (283, 308))	('accumulate', 'PosReg', (81, 91))	('p-FAK', 'Var', (200, 205))	('motility', 'CPA', (26, 34))	('colocalization', 'Interaction', (172, 186))
14646	30744493	Although fibroadenoma might have the potential to develop into invasive in situ carcinoma in women with the BRCA1 gene mutation, the overall risk of fibroadenoma progression to breast carcinoma is very low.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('mutation', 'Var', (119, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('breast carcinoma', 'Disease', 'MESH:D001943', (177, 193))	('situ carcinoma', 'Disease', (75, 89))	('BRCA1', 'Gene', '672', (108, 113))	('fibroadenoma', 'Disease', 'MESH:D018226', (9, 21))	('breast carcinoma', 'Phenotype', 'HP:0003002', (177, 193))	('BRCA1', 'Gene', (108, 113))	('develop', 'PosReg', (50, 57))	('fibroadenoma', 'Disease', 'MESH:D018226', (149, 161))	('women', 'Species', '9606', (93, 98))	('fibroadenoma', 'Disease', (9, 21))	('situ carcinoma', 'Disease', 'MESH:D002278', (75, 89))	('fibroadenoma', 'Disease', (149, 161))	('breast carcinoma', 'Disease', (177, 193))
14655	30744493	Because BC is a heterogeneous disease that is caused by DNA mutations or epigenetic changes, we conjectured that these phenomena could disrupt the connection between SGSM2 and other genes in breast tumours, especially the ERBB2 gene.	('N', 'Chemical', 'MESH:D009584', (57, 58))	('ERBB2', 'Gene', (222, 227))	('DNA mutations', 'Var', (56, 69))	('breast tumours', 'Disease', 'MESH:D001943', (191, 205))	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('SGSM2', 'Gene', (166, 171))	('caused', 'Reg', (46, 52))	('connection', 'Interaction', (147, 157))	('breast tumour', 'Phenotype', 'HP:0100013', (191, 204))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('disrupt', 'NegReg', (135, 142))	('epigenetic changes', 'Var', (73, 91))	('ERBB2', 'Gene', '2064', (222, 227))	('breast tumours', 'Disease', (191, 205))
14660	30744493	Additionally, a functional assay revealed that loss of SGSM2 could enhance cancer cell migration.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cell migration', 'biological_process', 'GO:0016477', ('82', '96'))	('SGSM2', 'Gene', (55, 60))	('cancer', 'Disease', (75, 81))	('loss', 'Var', (47, 51))	('enhance', 'PosReg', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
14697	30744493	A culture insert (Ibidi GmbH) was used to generate a 500 +- 50-mum gap and placed in each well of 12-well plates; then, 3.5 x 10 T47D cells stably expressing SGSM2 si1, si2 or scramble vectors were seeded into both sides of each insert.	('mum', 'Gene', (63, 66))	('10 T47D', 'CellLine', 'CVCL:0553', (126, 133))	('SGSM2 si1', 'Var', (158, 167))	('mum', 'Gene', '56925', (63, 66))
14788	19200374	The tumor cells were diffusely positive for Cytokeratin 8 (Figure 3) ER H-score 80, PR H-score 50, HER-2/neu negative, Ki 67 1, 5%.	('tumor', 'Disease', (4, 9))	('HER-2/neu', 'Gene', (99, 108))	('Cytokeratin 8', 'Gene', (44, 57))	('PR H-score 50', 'Var', (84, 97))	('positive', 'Reg', (31, 39))	('HER-2/neu', 'Gene', '2064', (99, 108))	('Cytokeratin 8', 'Gene', '3856', (44, 57))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('ER H-score 80', 'Var', (69, 82))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
14869	27078887	Amplification of three genes (CCND1, FADD, ORAOV1) at 11q13.3 was present in 2/11 patients in both foci.	('FADD', 'Gene', '8772', (37, 41))	('Amplification', 'Var', (0, 13))	('ORAOV1', 'Gene', '220064', (43, 49))	('patients', 'Species', '9606', (82, 90))	('ORAOV1', 'Gene', (43, 49))	('CCND1', 'Gene', (30, 35))	('CCND1', 'Gene', '595', (30, 35))	('FADD', 'Gene', (37, 41))
14880	27078887	Stratification by intrinsic molecular subtyping in a study of 444 consecutive invasive breast cancer patients, showed that within the luminal A subtype (associated with higher survival rates), multifocal luminal A patients (n = 79) had significantly worse survival than unifocal luminal A (n = 212) patients and multifocal luminal B patients (n = 13) had significantly worse survival than unifocal luminal B patients (n = 29).	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (214, 222))	('multifocal luminal', 'Var', (193, 211))	('worse', 'NegReg', (250, 255))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('patients', 'Species', '9606', (408, 416))	('patients', 'Species', '9606', (333, 341))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('patients', 'Species', '9606', (299, 307))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('survival', 'MPA', (256, 264))
14901	27078887	Reactions were performed in duplicate with 20ng gDNA, TaqMan Universal PCR master mix, RNase P primer/ probe (4403328), and the CCND1 primer/probe set (Life Technologies).	('CCND1', 'Gene', '595', (128, 133))	('4403328', 'Var', (110, 117))	('RNase P', 'molecular_function', 'GO:0004526', ('87', '94'))	('CCND1', 'Gene', (128, 133))
14924	27078887	The strongest associated pathways on both measures of association were PI3K and cell cycle, closely followed by DNA repair, TGFbeta, RAS, Wnt and MAPK.	('TGFbeta', 'Gene', '7040', (124, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('146', '150'))	('cell cycle', 'CPA', (80, 90))	('cell cycle', 'biological_process', 'GO:0007049', ('80', '90'))	('TGFbeta', 'Gene', (124, 131))	('PI3K', 'Var', (71, 75))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('DNA repair', 'biological_process', 'GO:0006281', ('112', '122'))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
14929	27078887	11q13.3 amplification has been previously described in breast cancer, specifically ILC, and in oral squamous carcinoma where it was reported as prognostic of metastasis.	('ILC', 'Disease', (83, 86))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (95, 118))	('described', 'Reg', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('amplification', 'Var', (8, 21))	('oral squamous carcinoma', 'Disease', (95, 118))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('breast cancer', 'Disease', (55, 68))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (100, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
14930	27078887	Within our dataset, amplifications were identified in CCND1, FADD and ORAOV1 in all three punches from both foci.	('FADD', 'Gene', (61, 65))	('FADD', 'Gene', '8772', (61, 65))	('amplifications', 'Var', (20, 34))	('CCND1', 'Gene', (54, 59))	('ORAOV1', 'Gene', '220064', (70, 76))	('CCND1', 'Gene', '595', (54, 59))	('ORAOV1', 'Gene', (70, 76))
14934	27078887	A third patient (patient 8) showed some evidence of deletion at the CCND1, FADD and ORAOV1 genes in either one or both foci and consistent low level amplification across all three punches in each focus for AKT3 mapping to 1q43, copy number ranging 2.68-3.16 (mean 2.88, SD = 0.19) and MET mapping to 7q31.2, copy number ranging 2.52-3.93 (mean 3.24, SD = 0.53).	('to 7', 'Species', '1214577', (297, 301))	('CCND1', 'Gene', '595', (68, 73))	('FADD', 'Gene', (75, 79))	('ORAOV1', 'Gene', (84, 90))	('AKT3', 'Gene', '10000', (206, 210))	('FADD', 'Gene', '8772', (75, 79))	('patient', 'Species', '9606', (17, 24))	('patient', 'Species', '9606', (8, 15))	('CCND1', 'Gene', (68, 73))	('deletion', 'Var', (52, 60))	('ORAOV1', 'Gene', '220064', (84, 90))	('AKT3', 'Gene', (206, 210))
14938	27078887	CCND1 gene expression was significantly correlated with copy number, Spearman r = 0.57, p<0.0001 when measured across the full sample of eleven patients.	('expression', 'MPA', (11, 21))	('gene expression', 'biological_process', 'GO:0010467', ('6', '21'))	('patients', 'Species', '9606', (144, 152))	('correlated', 'Interaction', (40, 50))	('CCND1', 'Gene', (0, 5))	('CCND1', 'Gene', '595', (0, 5))	('copy number', 'Var', (56, 67))
14956	27078887	Loss of CDH1 (E-cadherin) is an important diagnostic feature of ILC.	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('E-cadherin', 'Gene', '999', (14, 24))	('ILC', 'Disease', (64, 67))	('CDH1', 'Gene', (8, 12))	('E-cadherin', 'Gene', (14, 24))	('CDH1', 'Gene', '999', (8, 12))	('Loss', 'Var', (0, 4))
14990	27078887	The most significant pathways were PI3K and cell cycle, although DNA repair, TGFbeta, RAS, Wnt and MAP kinase were also highly significant, with PI3K and RAS showing the largest fold change.	('TGFbeta', 'Gene', (77, 84))	('MAP', 'molecular_function', 'GO:0004239', ('99', '102'))	('cell cycle', 'biological_process', 'GO:0007049', ('44', '54'))	('RAS', 'Gene', (86, 89))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('TGFbeta', 'Gene', '7040', (77, 84))	('PI3K', 'Var', (35, 39))	('DNA repair', 'biological_process', 'GO:0006281', ('65', '75'))	('PI3K', 'Var', (145, 149))	('PI3K', 'molecular_function', 'GO:0016303', ('145', '149'))	('cell cycle', 'CPA', (44, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
14991	27078887	These data are also in agreement with current thinking that E-Cadherin-mediated adhesion inhibits tyrosine kinase receptor signaling; whereas loss of E-Cadherin, a salient feature of ILC, results in activation of receptor tyrosine kinase signaling pathways.	('receptor tyrosine kinase', 'Gene', (213, 237))	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('tyrosine kinase receptor signaling', 'MPA', (98, 132))	('E-Cadherin', 'Gene', (150, 160))	('inhibits', 'NegReg', (89, 97))	('receptor tyrosine kinase', 'Gene', '5979', (213, 237))	('loss', 'Var', (142, 146))	('signaling', 'biological_process', 'GO:0023052', ('238', '247'))	('E-Cadherin', 'Gene', (60, 70))	('Cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('E-Cadherin', 'Gene', '999', (150, 160))	('activation', 'PosReg', (199, 209))	('tyrosine', 'Chemical', 'MESH:D014443', (98, 106))	('E-Cadherin', 'Gene', '999', (60, 70))	('tyrosine', 'Chemical', 'MESH:D014443', (222, 230))	('Cadherin', 'molecular_function', 'GO:0008014', ('62', '70'))
15000	27078887	We also observed some evidence for deletion of the same region in a single patient in either one or both foci, although given the difficulty in reliably estimating small copy number changes (particularly in samples from FFPE material), this could be due to artifact, and to our knowledge, deletion of CCND1 has not previously been reported.	('CCND1', 'Gene', (301, 306))	('deletion', 'Var', (35, 43))	('CCND1', 'Gene', '595', (301, 306))	('patient', 'Species', '9606', (75, 82))	('deletion', 'Var', (289, 297))
15011	27078887	Current literature suggests loss of CDH1 and other genes that potentially differentiate between ILC and IDC, promote epithelial to mesenchymal transition and activation of receptor tyrosine signaling pathways.	('loss', 'Var', (28, 32))	('IDC', 'Disease', (104, 107))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('promote', 'PosReg', (109, 116))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('117', '153'))	('CDH1', 'Gene', (36, 40))	('activation', 'PosReg', (158, 168))	('epithelial to mesenchymal transition', 'CPA', (117, 153))	('CDH1', 'Gene', '999', (36, 40))	('receptor tyrosine signaling pathways', 'Pathway', (172, 208))	('ILC', 'Disease', (96, 99))	('tyrosine', 'Chemical', 'MESH:D014443', (181, 189))
15013	27078887	The main limitations of these observations are the limited sample size (eleven patients), and lack of point mutation analysis, as heterogeneity of driver mutations between foci would suggest a source of metastatic potential in MF ILC, that we were unable to address by gene expression analyses.	('gene expression', 'biological_process', 'GO:0010467', ('269', '284'))	('metastatic potential', 'CPA', (203, 223))	('patients', 'Species', '9606', (79, 87))	('mutations', 'Var', (154, 163))
15029	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))	('reduced', 'NegReg', (341, 348))	('correlated', 'Reg', (193, 203))	('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))
15087	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))
15116	28779344	The percentage of lobular component was significantly increased in cases with aberrant E-cadherin or p120 expression (both p = <0.001).	('p120', 'Gene', (101, 105))	('aberrant', 'Var', (78, 86))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('lobular component', 'CPA', (18, 35))	('increased', 'PosReg', (54, 63))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('p120', 'Gene', '1500', (101, 105))
15125	28779344	E-cadherin is the main cell-to-cell-adhesion molecule in the adherens junction of epithelial cells and its expression is very often lost in ILC by somatic mutations, deletions or promoter methylation.	('cell-adhesion molecule', 'molecular_function', 'GO:0098631', ('31', '53'))	('adherens junction', 'cellular_component', 'GO:0005912', ('61', '78'))	('methylation', 'biological_process', 'GO:0032259', ('188', '199'))	('E-cadherin', 'Gene', '999', (0, 10))	('expression', 'MPA', (107, 117))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('lost', 'NegReg', (132, 136))	('E-cadherin', 'Gene', (0, 10))	('deletions', 'Var', (166, 175))	('cell-adhesion', 'biological_process', 'GO:0007155', ('31', '44'))	('promoter methylation', 'Var', (179, 199))
15138	28779344	An experienced observer (PJvD) scored E-cadherin membrane staining as normal, reduced or negative, and p120 was scored as normal (membrane staining comparable to normal breast tissue), reduced or aberrant (cytoplasmic/negative) staining.	('aberrant', 'Var', (196, 204))	('membrane', 'cellular_component', 'GO:0016020', ('49', '57'))	('membrane', 'cellular_component', 'GO:0016020', ('130', '138'))	('p120', 'Gene', '1500', (103, 107))	('E-cadherin', 'Gene', (38, 48))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))	('p120', 'Gene', (103, 107))	('E-cadherin', 'Gene', '999', (38, 48))
15169	28779344	Nevertheless, the percentage of the lobular component was significantly higher for cases with aberrant E-cadherin or p120 expression, consistent with previous research where both are biomarkers of lobular differentiation.	('higher', 'PosReg', (72, 78))	('p120', 'Gene', '1500', (117, 121))	('aberrant', 'Var', (94, 102))	('E-cadherin', 'Gene', (103, 113))	('E-cadherin', 'Gene', '999', (103, 113))	('cadherin', 'molecular_function', 'GO:0008014', ('105', '113'))	('p120', 'Gene', (117, 121))
15253	28583188	The analysis of HNF4A in conjunction with the previous panel clearly increased the diagnostic value and supported the literature data.	('diagnostic value', 'MPA', (83, 99))	('increased', 'PosReg', (69, 78))	('analysis', 'Var', (4, 12))	('HNF4A', 'Gene', '3172', (16, 21))	('HNF4A', 'Gene', (16, 21))
15264	27411687	p120-Catenin Is Critical for the Development of Invasive Lobular Carcinoma in Mice Loss of E-cadherin expression is causal to the development of invasive lobular breast carcinoma (ILC).	('breast carcinoma', 'Phenotype', 'HP:0003002', (162, 178))	('E-cadherin', 'Gene', '12550', (91, 101))	('Lobular Carcinoma', 'Phenotype', 'HP:0030076', (57, 74))	('expression', 'MPA', (102, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('E-cadherin', 'Gene', (91, 101))	('Invasive Lobular Carcinoma', 'Disease', (48, 74))	('invasive lobular breast carcinoma', 'Disease', (145, 178))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (145, 178))	('Carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('p120-Catenin', 'Gene', (0, 12))	('Loss', 'Var', (83, 87))	('Invasive Lobular Carcinoma', 'Disease', 'MESH:D018275', (48, 74))	('p120-Catenin', 'Gene', '12388', (0, 12))
15266	27411687	Although p120 is critical for the metastatic potential of ILC through the regulation of Rock-dependent anoikis resistance, it remains unknown whether p120 also contributes to ILC development.	('p120', 'Var', (150, 154))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('ILC', 'Disease', (175, 178))	('Rock', 'Gene', '19877', (88, 92))	('Rock', 'Gene', (88, 92))	('contributes', 'Reg', (160, 171))	('anoikis', 'biological_process', 'GO:0043276', ('103', '110'))
15267	27411687	Using genetically engineered mouse models with mammary gland-specific inactivation of E-cadherin, p120 and p53, we demonstrate that ILC formation induced by E-cadherin and p53 loss is severely impaired upon concomitant inactivation of p120.	('p120', 'Var', (235, 239))	('p53', 'Gene', (107, 110))	('inactivation', 'Var', (70, 82))	('E-cadherin', 'Gene', (157, 167))	('E-cadherin', 'Gene', '12550', (86, 96))	('p53', 'Gene', '22059', (172, 175))	('impaired', 'NegReg', (193, 201))	('inactivation', 'Var', (219, 231))	('E-cadherin', 'Gene', '12550', (157, 167))	('cadherin', 'molecular_function', 'GO:0008014', ('88', '96'))	('mouse', 'Species', '10090', (29, 34))	('loss', 'NegReg', (176, 180))	('p53', 'Gene', '22059', (107, 110))	('ILC formation', 'CPA', (132, 145))	('p53', 'Gene', (172, 175))	('rat', 'Species', '10116', (122, 125))	('formation', 'biological_process', 'GO:0009058', ('136', '145'))	('E-cadherin', 'Gene', (86, 96))	('cadherin', 'molecular_function', 'GO:0008014', ('159', '167'))
15270	27411687	In conclusion, we show that loss of p120 in the context of the p53-deficient mouse models is dominant over E-cadherin inactivation and its inactivation promotes the development of basal, epithelial-to-mesenchymal-transition (EMT)-type invasive mammary tumors.	('loss', 'Var', (28, 32))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '22059', (63, 66))	('p120', 'Var', (36, 40))	('cadherin', 'molecular_function', 'GO:0008014', ('109', '117'))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('basal', 'CPA', (180, 185))	('epithelial-to-mesenchymal-transition', 'biological_process', 'GO:0001837', ('187', '223'))	('EMT', 'biological_process', 'GO:0001837', ('225', '228'))	('E-cadherin', 'Gene', (107, 117))	('E-cadherin', 'Gene', '12550', (107, 117))	('promotes', 'PosReg', (152, 160))	('inactivation', 'Var', (139, 151))	('mouse', 'Species', '10090', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('tumors', 'Disease', (252, 258))
15272	27411687	In breast cancer, mode and timing of E-cadherin inactivation appears to determine tumor type and etiology.	('E-cadherin', 'Gene', (37, 47))	('E-cadherin', 'Gene', '12550', (37, 47))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cadherin', 'molecular_function', 'GO:0008014', ('39', '47'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('determine', 'Reg', (72, 81))	('breast cancer', 'Disease', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('inactivation', 'Var', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
15274	27411687	Cre-lox based conditional mouse models have demonstrated that mutational inactivation of E-cadherin in the mammary gland is not tolerated, leading to clearance of E-cadherin negative cells.	('cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('rat', 'Species', '10116', (132, 135))	('lox', 'Gene', (4, 7))	('rat', 'Species', '10116', (51, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('165', '173'))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '12550', (89, 99))	('mouse', 'Species', '10090', (26, 31))	('lox', 'Gene', '16948', (4, 7))	('mutational inactivation', 'Var', (62, 85))	('clearance', 'CPA', (150, 159))	('E-cadherin', 'Gene', (163, 173))	('E-cadherin', 'Gene', '12550', (163, 173))
15275	27411687	However, in the context of p53 deficiency, E-cadherin loss induces the formation and progression of mouse ILC (mILC), which mimics its human counterpart in phenotype and metastatic dissemination.	('E-cadherin', 'Gene', (43, 53))	('progression', 'CPA', (85, 96))	('E-cadherin', 'Gene', '12550', (43, 53))	('mouse ILC', 'Disease', (100, 109))	('mouse', 'Species', '10090', (100, 105))	('induces', 'Reg', (59, 66))	('loss', 'NegReg', (54, 58))	('human', 'Species', '9606', (135, 140))	('cadherin', 'molecular_function', 'GO:0008014', ('45', '53'))	('deficiency', 'Var', (31, 41))	('formation', 'biological_process', 'GO:0009058', ('71', '80'))	('p53', 'Gene', '22059', (27, 30))	('p53', 'Gene', (27, 30))
15277	27411687	E-cadherin stability and turnover is regulated by p120-catenin (p120), an armadillo-repeat containing molecule that binds directly to the E-cadherin juxtamembrane domain at the cell cortex.	('juxtamembrane', 'cellular_component', 'GO:0009897', ('149', '162'))	('p120-catenin', 'Gene', (50, 62))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('149', '162'))	('turnover', 'MPA', (25, 33))	('regulated', 'Reg', (37, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('140', '148'))	('stability', 'MPA', (11, 20))	('p120-catenin', 'Gene', '12388', (50, 62))	('p120', 'Var', (64, 68))	('cell cortex', 'cellular_component', 'GO:0005938', ('177', '188'))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', '12550', (0, 10))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('149', '162'))	('armadillo-repeat', 'Chemical', '-', (74, 90))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('149', '162'))	('E-cadherin', 'Gene', (138, 148))	('E-cadherin', 'Gene', '12550', (138, 148))
15279	27411687	In contrast, p120 expression patterns in ductal breast cancers are not related to E-cadherin expression.	('breast cancers', 'Phenotype', 'HP:0003002', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('84', '92'))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('p120', 'Var', (13, 17))	('E-cadherin', 'Gene', '12550', (82, 92))	('ductal breast cancers', 'Disease', (41, 62))	('E-cadherin', 'Gene', (82, 92))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('ductal breast cancers', 'Disease', 'MESH:D001943', (41, 62))
15280	27411687	Localization of p120 can therefore be used to aid differential diagnosis between ductal and lobular breast cancer.	('Localization', 'biological_process', 'GO:0051179', ('0', '12'))	('lobular breast cancer', 'Disease', 'MESH:D013274', (92, 113))	('lobular breast cancer', 'Disease', (92, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (92, 113))	('p120', 'Var', (16, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('ductal', 'Disease', (81, 87))
15283	27411687	Of note, p120 appears to have evolved together with the non-neural classical cadherins, separately from ARVCF, delta-catenin and p0071, suggesting different functional roles.	('ARVCF', 'Gene', '11877', (104, 109))	('p0071', 'Gene', '227937', (129, 134))	('p120', 'Var', (9, 13))	('p0071', 'Gene', (129, 134))	('rat', 'Species', '10116', (92, 95))	('ARVCF', 'Gene', (104, 109))
15284	27411687	Although loss of p120 leads to a dissociation of the AJ, conditional loss of p120 in the mouse mammary gland in combination with p53 does not lead to ILC formation but instead induces the formation of high-grade metaplastic-type ductal tumors that metastasize to lungs and lymph nodes.	('ductal tumors', 'Disease', 'MESH:D044584', (229, 242))	('metastasize', 'CPA', (248, 259))	('formation', 'biological_process', 'GO:0009058', ('154', '163'))	('ductal tumors', 'Disease', (229, 242))	('formation', 'biological_process', 'GO:0009058', ('188', '197'))	('dissociation', 'MPA', (33, 45))	('loss', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '22059', (129, 132))	('induces', 'Reg', (176, 183))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('loss of p120', 'Var', (69, 81))	('mouse', 'Species', '10090', (89, 94))
15285	27411687	These observations showed that, although the effect of AJ inactivation is the acquisition of tumor invasion and metastasis, the phenotypical outcome of the resulting tumor is determined by the AJ member that is inactivated.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('acquisition', 'PosReg', (78, 89))	('inactivation', 'Var', (58, 70))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
15286	27411687	To study the contribution of p120 to the development of ILC we introduced a p120 conditional allele into the mILC mouse model, and observed that concomitant loss of p120 at the early stages of tumor development largely prevents the formation of mouse ILC (mILC).	('mouse', 'CPA', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('formation', 'biological_process', 'GO:0009058', ('232', '241'))	('mouse', 'Species', '10090', (114, 119))	('mouse', 'Species', '10090', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('prevents', 'NegReg', (219, 227))	('p120', 'Var', (165, 169))	('loss', 'Var', (157, 161))	('tumor', 'Disease', (193, 198))	('formation', 'CPA', (232, 241))
15289	27411687	Although heterozygous inactivation of p120 in the mILC model influenced the median tumor-free survival (T50; 214 versus 178 days, p = 0,0146), TKO female mice showed similar T50 values when compared to Wcre;Cdh1 F/F;Trp53 F/F mice (188 versus 187 days; p = 0.6627) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mice', 'Species', '10090', (226, 230))	('mice', 'Species', '10090', (154, 158))	('tumor', 'Disease', (83, 88))	('Trp53', 'Gene', '22059', (216, 221))	('Cdh1', 'Gene', '12550', (207, 211))	('Cdh1', 'Gene', (207, 211))	('p120', 'Var', (38, 42))	('heterozygous', 'Var', (9, 21))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('Trp53', 'Gene', (216, 221))
15290	27411687	We also observed no significant T50 differences when comparing Wcre;Ctnnd1 F/+;Cdh1 F/F;Trp53 F/F versus TKO female mice (Fig.	('mice', 'Species', '10090', (116, 120))	('Ctnnd1', 'Gene', (68, 74))	('Trp53', 'Gene', '22059', (88, 93))	('Cdh1', 'Gene', (79, 83))	('Cdh1', 'Gene', '12550', (79, 83))	('F/F', 'Var', (94, 97))	('Ctnnd1', 'Gene', '12388', (68, 74))	('Trp53', 'Gene', (88, 93))
15292	27411687	Interestingly, heterozygous deletion of p120 in Wcre;Ctnnd1 F/+;Cdh1 F/F;Trp53 F/F female mice resulted in a marked increase in the incidence of solid ILC compared to Wcre;Cdh1 F/F;Trp53 F/F control mice (47.1 % versus 4.3 %; p = 0.02, Supplementary Table 1 and).	('solid ILC', 'Disease', (145, 154))	('Cdh1', 'Gene', '12550', (172, 176))	('mice', 'Species', '10090', (199, 203))	('p120', 'Var', (40, 44))	('Cdh1', 'Gene', (172, 176))	('Ctnnd1', 'Gene', '12388', (53, 59))	('Trp53', 'Gene', (73, 78))	('Trp53', 'Gene', '22059', (181, 186))	('mice', 'Species', '10090', (90, 94))	('increase', 'PosReg', (116, 124))	('Cdh1', 'Gene', (64, 68))	('Cdh1', 'Gene', '12550', (64, 68))	('Ctnnd1', 'Gene', (53, 59))	('Trp53', 'Gene', '22059', (73, 78))	('Trp53', 'Gene', (181, 186))
15295	27411687	Furthermore, the percentage of invasive tumors or tumor dissemination (lungs or lymph nodes) did not change upon heterozygous deletion of p120 (Table 1).	('invasive tumors or tumor dissemination', 'Disease', (31, 69))	('deletion', 'Var', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('invasive tumors or tumor dissemination', 'Disease', 'MESH:D009369', (31, 69))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('p120', 'Var', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
15297	27411687	Homozygous deletion of p120 in TKO female mice resulted in a tumor spectrum of mainly SC/CS lesions (p = 0.0094 compared to Wcre;Cdh1 F/F;Trp53 F/F mice; Table 1 and Fig.	('Trp53', 'Gene', (138, 143))	('mice', 'Species', '10090', (42, 46))	('resulted in', 'Reg', (47, 58))	('SC/CS', 'Disease', (86, 91))	('p120', 'Var', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Trp53', 'Gene', '22059', (138, 143))	('mice', 'Species', '10090', (148, 152))	('CS', 'Chemical', 'MESH:D002586', (89, 91))	('Cdh1', 'Gene', '12550', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Cdh1', 'Gene', (129, 133))	('tumor', 'Disease', (61, 66))
15298	27411687	Interestingly, formation of mouse ILC was nearly absent upon homozygous p120 loss (p < 0.0001 compared to Wcre;Cdh1 F/F;Trp53 F/F mice; Table 1).	('mice', 'Species', '10090', (130, 134))	('mouse', 'Species', '10090', (28, 33))	('p120 loss', 'Var', (72, 81))	('Trp53', 'Gene', '22059', (120, 125))	('absent', 'NegReg', (49, 55))	('Cdh1', 'Gene', '12550', (111, 115))	('Cdh1', 'Gene', (111, 115))	('formation', 'biological_process', 'GO:0009058', ('15', '24'))	('Trp53', 'Gene', (120, 125))	('formation', 'MPA', (15, 24))
15300	27411687	In contrast, all tumors from the heterozygous Wcre;Ctnnd1 F/+;Cdh1 F/F;Trp53 F/F mice expressed cytoplasmic and nuclear p120, identical to the expression pattern of p120 in Wcre;Cdh1 F/F;Trp53 F/F mice (Fig.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mice', 'Species', '10090', (81, 85))	('Cdh1', 'Gene', '12550', (178, 182))	('Trp53', 'Gene', '22059', (71, 76))	('Cdh1', 'Gene', '12550', (62, 66))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Cdh1', 'Gene', (178, 182))	('Cdh1', 'Gene', (62, 66))	('Ctnnd1', 'Gene', (51, 57))	('Trp53', 'Gene', (187, 192))	('p120', 'Var', (120, 124))	('Trp53', 'Gene', (71, 76))	('mice', 'Species', '10090', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('Trp53', 'Gene', '22059', (187, 192))	('Ctnnd1', 'Gene', '12388', (51, 57))
15304	27411687	The metastases that formed in Wcre;Ctnnd1 F/+;Cdh1 F/F;Trp53 F/F and TKO displayed marker expression patterns similar to the primary tumors (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('Ctnnd1', 'Gene', '12388', (35, 41))	('metastases', 'Disease', 'MESH:D009362', (4, 14))	('F/F', 'Var', (61, 64))	('Trp53', 'Gene', (55, 60))	('primary tumors', 'Disease', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Cdh1', 'Gene', '12550', (46, 50))	('Ctnnd1', 'Gene', (35, 41))	('primary tumors', 'Disease', 'MESH:D009369', (125, 139))	('Cdh1', 'Gene', (46, 50))	('Trp53', 'Gene', '22059', (55, 60))	('metastases', 'Disease', (4, 14))
15305	27411687	Taken together, our data show that early inactivation of p120 in the context of combined E-cadherin and p53 loss largely prevents formation of mouse ILC, and leads to the formation of high-grade basal mammary tumors that are characterized by a more prominent expression of the basal markers CK14 and vimentin, metaplastic and sarcomatoid histology and strong nuclear atypia.	('formation', 'MPA', (130, 139))	('loss', 'NegReg', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('CK14', 'Gene', '16664', (291, 295))	('p53', 'Gene', (104, 107))	('cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('mouse', 'Species', '10090', (143, 148))	('sarcomatoid', 'Disease', 'MESH:C538614', (326, 337))	('vimentin', 'cellular_component', 'GO:0045099', ('300', '308'))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('leads to', 'Reg', (158, 166))	('inactivation', 'Var', (41, 53))	('E-cadherin', 'Gene', (89, 99))	('p120', 'Var', (57, 61))	('CK14', 'Gene', (291, 295))	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (326, 347))	('prevents', 'NegReg', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('p53', 'Gene', '22059', (104, 107))	('vimentin', 'Gene', (300, 308))	('E-cadherin', 'Gene', '12550', (89, 99))	('sarcomatoid', 'Disease', (326, 337))	('vimentin', 'cellular_component', 'GO:0045098', ('300', '308'))	('vimentin', 'Gene', '22352', (300, 308))
15307	27411687	Given that ARVCF, delta-catenin and p0071 are structurally related to p120 and share several functions at the membrane and in the cytosol, we investigated the effects of p120 loss on the expression and localization of these family members in mILC.	('p120', 'Var', (170, 174))	('localization', 'biological_process', 'GO:0051179', ('202', '214'))	('p0071', 'Gene', '227937', (36, 41))	('p0071', 'Gene', (36, 41))	('membrane', 'cellular_component', 'GO:0016020', ('110', '118'))	('cytosol', 'cellular_component', 'GO:0005829', ('130', '137'))	('ARVCF', 'Gene', (11, 16))	('loss', 'NegReg', (175, 179))	('ARVCF', 'Gene', '11877', (11, 16))
15311	27411687	In accordance with previous findings we observed cytosolic and nuclear p120 expression in mILC and SC/CS tumors from Wcre;Cdh1 F/F;Trp53 F/F mice (Fig.	('mILC', 'Disease', (90, 94))	('CS tumors', 'Disease', (102, 111))	('F/F', 'Var', (137, 140))	('F/F', 'Var', (127, 130))	('Trp53', 'Gene', (131, 136))	('p120', 'Var', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mice', 'Species', '10090', (141, 145))	('CS tumors', 'Disease', 'MESH:D006223', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('Trp53', 'Gene', '22059', (131, 136))	('Cdh1', 'Gene', (122, 126))	('Cdh1', 'Gene', '12550', (122, 126))
15315	27411687	Cytoplasmic p120 is a hallmark of lobular breast cancer.	('hallmark of lobular breast cancer', 'Disease', (22, 55))	('hallmark of lobular breast cancer', 'Disease', 'MESH:D013274', (22, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('Cytoplasmic p120', 'Var', (0, 16))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (34, 55))
15316	27411687	Here we examined the contribution of p120 to ILC development in mice, and demonstrate that p120 is critical for the development of invasive lobular carcinoma in mice.	('mice', 'Species', '10090', (161, 165))	('invasive lobular carcinoma', 'Disease', (131, 157))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (140, 157))	('rat', 'Species', '10116', (81, 84))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (131, 157))	('p120', 'Var', (91, 95))	('mice', 'Species', '10090', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
15317	27411687	Previous data demonstrated that dual inactivation of p120 and p53 in the mouse mammary gland leads to sarcomatoid, epithelial-to-mesenchymal-transition (EMT)-like mammary carcinomas.	('epithelial-to-mesenchymal-transition', 'biological_process', 'GO:0001837', ('115', '151'))	('EMT', 'biological_process', 'GO:0001837', ('153', '156'))	('sarcomatoid', 'Disease', 'MESH:C538614', (102, 113))	('p120', 'Var', (53, 57))	('leads to', 'Reg', (93, 101))	('mouse', 'Species', '10090', (73, 78))	('rat', 'Species', '10116', (21, 24))	('p53', 'Gene', '22059', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('carcinomas', 'Disease', 'MESH:D002277', (171, 181))	('p53', 'Gene', (62, 65))	('sarcomatoid', 'Disease', (102, 113))	('inactivation', 'Var', (37, 49))	('carcinomas', 'Disease', (171, 181))
15318	27411687	These p120 negative mammary tumors presented with anaplastic histological features and expression of basal markers such as CK14 and/or vimentin.	('vimentin', 'Gene', '22352', (135, 143))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('vimentin', 'Gene', (135, 143))	('expression', 'MPA', (87, 97))	('p120 negative', 'Var', (6, 19))	('CK14', 'Gene', (123, 127))	('vimentin', 'cellular_component', 'GO:0045099', ('135', '143'))	('CK14', 'Gene', '16664', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('vimentin', 'cellular_component', 'GO:0045098', ('135', '143'))
15322	27411687	In contrast, poorly differentiated basal tumors, which we also observe in tumors lacking p120, are usually devoid of ER expression.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('basal tumor', 'Phenotype', 'HP:0002671', (35, 46))	('basal tumors', 'Disease', (35, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('basal tumors', 'Phenotype', 'HP:0002671', (35, 47))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('p120', 'Var', (89, 93))	('basal tumors', 'Disease', 'MESH:D002280', (35, 47))	('tumors', 'Disease', (74, 80))
15324	27411687	Because Cre expression is already evident in virgin Wcre;Cdh1 F/F;Trp53 F/F female mice, and tumor incidence occurrs independent of parity, tumorigenesis in these models is most likely instigated in a mammary progenitor cell type.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Trp53', 'Gene', (66, 71))	('tumor', 'Disease', (93, 98))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Trp53', 'Gene', '22059', (66, 71))	('Cdh1', 'Gene', '12550', (57, 61))	('F/F', 'Var', (72, 75))	('Cdh1', 'Gene', (57, 61))	('tumor', 'Disease', (140, 145))
15325	27411687	Because of these data and the fact that most mILC in Wcre;Cdh1 F/F;Trp53 F/F female mice predominantly expressed CK8, we assume that p120 could play a role in the progression of a luminal-type cancer-initiating cell.	('CK8', 'Gene', '16691', (113, 116))	('Trp53', 'Gene', '22059', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('Cdh1', 'Gene', '12550', (58, 62))	('CK8', 'Gene', (113, 116))	('cancer', 'Disease', (193, 199))	('Cdh1', 'Gene', (58, 62))	('role', 'Reg', (151, 155))	('p120', 'Var', (133, 137))	('play', 'Reg', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('Trp53', 'Gene', (67, 72))	('mice', 'Species', '10090', (84, 88))
15326	27411687	Indeed, we show that early dual loss of E-cadherin and p120 almost completely prevents development of mILC.	('loss', 'NegReg', (32, 36))	('E-cadherin', 'Gene', (40, 50))	('prevents', 'NegReg', (78, 86))	('E-cadherin', 'Gene', '12550', (40, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('development of', 'CPA', (87, 101))	('p120', 'Var', (55, 59))
15328	27411687	Finally, all other tumors that developed in p120 knockout mice were diagnosed as basal-type invasive carcinosarcomas, indicating that loss of p120 predisposes mammary progenitors to a basal lineage commitment and prevents the formation of luminal type ILC.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('formation', 'CPA', (226, 235))	('formation', 'biological_process', 'GO:0009058', ('226', '235'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mice', 'Species', '10090', (58, 62))	('prevents', 'NegReg', (213, 221))	('invasive carcinosarcomas', 'Disease', (92, 116))	('invasive carcinosarcomas', 'Disease', 'MESH:D002296', (92, 116))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('loss', 'Var', (134, 138))	('p120', 'Gene', (142, 146))	('basal lineage commitment', 'CPA', (184, 208))
15330	27411687	TKO mILC expressed the luminal CK8 marker, which might be a result of p120 deletion in a luminal-type committed progenitor.	('CK8', 'Gene', '16691', (31, 34))	('p120 deletion', 'Var', (70, 83))	('CK8', 'Gene', (31, 34))
15331	27411687	We studied expression of ARVCF, p0071 and delta-catenin in TKO mILC lesions, which yielded no indication that p120 loss induced a change in expression levels or localization of these proteins.	('localization', 'MPA', (161, 173))	('p0071', 'Gene', '227937', (32, 37))	('p120 loss', 'Var', (110, 119))	('p0071', 'Gene', (32, 37))	('ARVCF', 'Gene', '11877', (25, 30))	('ARVCF', 'Gene', (25, 30))	('localization', 'biological_process', 'GO:0051179', ('161', '173'))	('expression levels', 'MPA', (140, 157))
15333	27411687	Also the fact that inactivation of p120 in the context of p53 loss leads to basal-type invasive and metastatic mammary tumors, renders a redundant role for these p120 family members highly unlikely.	('loss', 'NegReg', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('p120', 'Var', (35, 39))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('p53', 'Gene', (58, 61))	('inactivation', 'Var', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('leads to', 'Reg', (67, 75))	('p53', 'Gene', '22059', (58, 61))
15334	27411687	Forced dual inactivation of p120 and p53 at the early stages of tumor development might induce two scenarios.	('tumor', 'Disease', (64, 69))	('p53', 'Gene', '22059', (37, 40))	('p53', 'Gene', (37, 40))	('induce', 'Reg', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('p120', 'Var', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
15335	27411687	First, p120 loss induces an EMT leading to high-grade, basal-type tumors that show a large degree of nuclear atypia and metastasize to lungs and lymph nodes.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('high-grade', 'Disease', (43, 53))	('induces', 'Reg', (17, 24))	('p120 loss', 'Var', (7, 16))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('EMT', 'biological_process', 'GO:0001837', ('28', '31'))	('basal-type tumors', 'Disease', (55, 72))	('basal-type tumors', 'Disease', 'MESH:D002280', (55, 72))
15338	27411687	Concomitant inactivation would then remove p120 from the ILC-initiating cells and enforce a p120-negative basal breast cancer phenotype.	('remove', 'NegReg', (36, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('p120', 'Var', (43, 47))	('basal breast cancer', 'Disease', (106, 125))	('inactivation', 'Var', (12, 24))	('basal breast cancer', 'Disease', 'MESH:D001943', (106, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
15340	27411687	In human breast cancer, loss of p120 is observed in approximately 15-20 % of invasive ductal carcinomas, with a marked complete loss of p120 expression in metaplastic breast cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('breast cancer', 'Disease', (167, 180))	('loss', 'NegReg', (128, 132))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (77, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('human', 'Species', '9606', (3, 8))	('p120', 'Var', (32, 36))	('invasive ductal carcinomas', 'Disease', (77, 103))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('p120', 'Var', (136, 140))	('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))	('loss', 'NegReg', (24, 28))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
15341	27411687	Despite the fact that conditional p120 inactivation in the mouse mammary gland induces invasive mammary carcinomas, human p120-negative breast cancers are mostly devoid of inactivating CTNND1 mutations and do not show silencing through promotor methylation.	('CTNND1', 'Gene', (185, 191))	('breast cancers', 'Disease', 'MESH:D001943', (136, 150))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancers', 'Disease', (136, 150))	('methylation', 'biological_process', 'GO:0032259', ('245', '256'))	('mouse', 'Species', '10090', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('carcinomas', 'Disease', 'MESH:D002277', (104, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('carcinomas', 'Disease', (104, 114))	('induces', 'Reg', (79, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (136, 150))	('CTNND1', 'Gene', '1500', (185, 191))	('p120 inactivation', 'Var', (34, 51))	('human', 'Species', '9606', (116, 121))
15342	27411687	Moreover, p120 is mostly lost focally in human IDC, indicating that p120 inactivation is a late event in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('human', 'Species', '9606', (41, 46))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('p120 inactivation', 'Var', (68, 85))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
15343	27411687	This notion is supported by the fact that (i) p120 loss in the absence of additional oncogenic mutations will negatively impact both luminal and myoepithelial cells of the mammary gland through destabilization of all classical cadherins, and (ii) p120 controls key biological processes such as activation of Rho-dependent actomyosin contractility and distinct transcriptional programs through Kaiso.	('classical cadherins', 'Protein', (217, 236))	('transcriptional programs', 'CPA', (360, 384))	('Rho-dependent actomyosin contractility', 'CPA', (308, 346))	('actomyosin', 'cellular_component', 'GO:0042641', ('322', '332'))	('negatively', 'NegReg', (110, 120))	('p120', 'Var', (46, 50))	('controls', 'Reg', (252, 260))	('p120', 'Var', (247, 251))	('activation', 'PosReg', (294, 304))	('destabilization', 'NegReg', (194, 209))	('Kaiso', 'Gene', '56805', (393, 398))	('impact', 'Reg', (121, 127))	('loss', 'NegReg', (51, 55))	('luminal', 'CPA', (133, 140))	('Kaiso', 'Gene', (393, 398))
15344	27411687	Thus, although p120 loss can propel tumor progression in both cell lineages, this probably only occurs during later stages of human breast cancer progression.	('human', 'Species', '9606', (126, 131))	('propel', 'Reg', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('p120 loss', 'Var', (15, 24))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('tumor', 'Disease', (36, 41))
15345	27411687	In sum, we show that loss of p120 promotes the development of EMT-type basal invasive mammary tumors.	('loss', 'Var', (21, 25))	('EMT-type basal invasive mammary tumors', 'Disease', (62, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('p120', 'Gene', (29, 33))	('promotes', 'PosReg', (34, 42))	('EMT', 'biological_process', 'GO:0001837', ('62', '65'))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('EMT-type basal invasive mammary tumors', 'Disease', 'MESH:D015674', (62, 100))
15346	27411687	In a p53-deficient context, p120 loss is dominant over E-cadherin inactivation in driving mammary tumorigenesis, thus largely preventing the formation of ILC.	('E-cadherin', 'Gene', (55, 65))	('p120 loss', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('driving', 'CPA', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ILC', 'Disease', (154, 157))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '22059', (5, 8))	('preventing', 'NegReg', (126, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('57', '65'))	('tumor', 'Disease', (98, 103))	('E-cadherin', 'Gene', '12550', (55, 65))
15347	27411687	Conversely, in the context of early mutational E-cadherin activation, p120 will take center stage to unveil its oncogenic role to drive anchorage-independence and metastatic ILC.	('p120', 'Var', (70, 74))	('cadherin', 'molecular_function', 'GO:0008014', ('49', '57'))	('E-cadherin', 'Gene', (47, 57))	('E-cadherin', 'Gene', '12550', (47, 57))	('drive', 'PosReg', (130, 135))	('anchorage-independence', 'CPA', (136, 158))	('metastatic ILC', 'CPA', (163, 177))
15357	27411687	Depending on the primary antibody used, antigen retrieval was performed either by proteinase K (DAKO) treatment for 5 min (for vimentin and CK8) or by boiling of the slides in 10 mM citrate buffer (pH 6.0) for 20 min (for E-cadherin and p120).	('p120', 'Var', (237, 241))	('vimentin', 'cellular_component', 'GO:0045098', ('127', '135'))	('E-cadherin', 'Gene', (222, 232))	('E-cadherin', 'Gene', '12550', (222, 232))	('antibody', 'cellular_component', 'GO:0019815', ('25', '33'))	('CK8', 'Gene', '16691', (140, 143))	('antibody', 'cellular_component', 'GO:0042571', ('25', '33'))	('cadherin', 'molecular_function', 'GO:0008014', ('224', '232'))	('CK8', 'Gene', (140, 143))	('vimentin', 'Gene', '22352', (127, 135))	('antibody', 'cellular_component', 'GO:0019814', ('25', '33'))	('antibody', 'molecular_function', 'GO:0003823', ('25', '33'))	('vimentin', 'cellular_component', 'GO:0045099', ('127', '135'))	('proteinase', 'molecular_function', 'GO:0004175', ('82', '92'))	('citrate', 'Chemical', 'MESH:D019343', (182, 189))	('vimentin', 'Gene', (127, 135))	('boiling', 'Phenotype', 'HP:0020083', (151, 158))
15554	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))	('ADH', 'molecular_function', 'GO:0047636', ('67', '70'))	('proliferative growth advantage', 'CPA', (2, 32))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('DCIS', 'Phenotype', 'HP:0030075', (186, 190))	('ADH', 'molecular_function', 'GO:0004022', ('67', '70'))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))
15594	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))
15595	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))
15600	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.	('cancer', 'Disease', (200, 206))	('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))	('ADH', 'molecular_function', 'GO:0047636', ('166', '169'))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('LOH', 'Var', (111, 114))	('ADH', 'molecular_function', 'GO:0004022', ('166', '169'))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
15621	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))	('gene-expression', 'biological_process', 'GO:0010467', ('57', '72'))	('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))	('gene-expression', 'biological_process', 'GO:0010467', ('176', '191'))	('alterations', 'Var', (192, 203))	('associated', 'Reg', (214, 224))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
15630	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))
15631	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))
15640	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))	('chromosome', 'cellular_component', 'GO:0005694', ('246', '256'))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (122, 143))	('gene-expression', 'biological_process', 'GO:0010467', ('43', '58'))	('loss', 'Var', (238, 242))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
15666	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))
15672	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', 'biological_process', 'GO:0010467', ('12', '27'))	('gene-expression', 'MPA', (12, 27))	('myoepithelial', 'Disease', 'MESH:D009208', (65, 78))	('epigenetic modifications', 'Var', (136, 160))	('changes', 'Reg', (28, 35))
15673	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))	('gene-expression', 'biological_process', 'GO:0010467', ('84', '99'))
15676	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))	('observed', 'Reg', (181, 189))	('DCIS', 'Phenotype', 'HP:0030075', (193, 197))	('myoepithelial', 'Disease', (209, 222))	('invasive breast cancer', 'Disease', (102, 124))
15677	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))
15691	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))
15699	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))	('basement membrane', 'cellular_component', 'GO:0005604', ('275', '292'))	('invade', 'CPA', (310, 316))	('basement membrane of the duct', 'CPA', (275, 304))	('myoepithelial', 'Disease', 'MESH:D009208', (242, 255))	('DCIS', 'Phenotype', 'HP:0030075', (68, 72))
15700	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))	('degradation', 'biological_process', 'GO:0009056', ('243', '254'))	('myoepithelial', 'Disease', 'MESH:D009208', (138, 151))	('invasion of the neoplastic epithelial cells', 'CPA', (296, 339))	('basement membrane', 'cellular_component', 'GO:0005604', ('262', '279'))	('degradation', 'MPA', (243, 254))
15701	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))	('signaling', 'biological_process', 'GO:0023052', ('207', '216'))	('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))
15712	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))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('high', 'Var', (55, 59))	('DCIS', 'Phenotype', 'HP:0030075', (29, 33))
15713	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))
15730	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))	('gene-expression', 'biological_process', 'GO:0010467', ('33', '48'))	('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))
15756	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))
15852	24206539	CAIX, GLUT1, and CXCR4 prevalence rates significantly increased with histological grade, which is consistent with the hypothesis that high grade tumors have a higher proliferation rate, causing neo-angiogenesis to lag behind tumor growth.	('CXCR4', 'Gene', (17, 22))	('histological grade', 'Var', (69, 87))	('tumor', 'Disease', (225, 230))	('CAIX', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('angiogenesis', 'biological_process', 'GO:0001525', ('198', '210'))	('CAIX', 'Gene', '768', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', (145, 150))	('GLUT1', 'Gene', '6513', (6, 11))	('neo-angiogenesis', 'CPA', (194, 210))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('CXCR4', 'molecular_function', 'GO:0038147', ('17', '22'))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('GLUT1', 'Gene', (6, 11))	('increased', 'PosReg', (54, 63))	('tumors', 'Disease', (145, 151))	('CXCR4', 'Gene', '7852', (17, 22))	('higher', 'PosReg', (159, 165))
15883	24206539	Vascular Endothelial Growth Factor (VEGF)), or less tumor-specific targets such as Mucin 1 (MUC1), Mammaglobin, or CD44v6.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Vascular Endothelial Growth Factor', 'Gene', '7422', (0, 34))	('CD44v6', 'Var', (115, 121))	('Vascular Endothelial Growth Factor', 'molecular_function', 'GO:0005172', ('0', '34'))	('tumor', 'Disease', (52, 57))	('VEGF', 'Gene', (36, 40))	('Mucin 1', 'Gene', '4582', (83, 90))	('MUC1', 'Gene', (92, 96))	('MUC1', 'Gene', '4582', (92, 96))	('Vascular Endothelial Growth Factor', 'Gene', (0, 34))	('VEGF', 'Gene', '7422', (36, 40))	('Mucin 1', 'Gene', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
15910	30918738	The positivity for these markers indicated us and supported the diagnosis of lobular breast carcinoma metastasis to endometrium.	('indicated', 'Reg', (33, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('positivity', 'Var', (4, 14))	('breast carcinoma', 'Phenotype', 'HP:0003002', (85, 101))	('lobular breast carcinoma metastasis', 'Disease', 'MESH:D009362', (77, 112))	('lobular breast carcinoma metastasis', 'Disease', (77, 112))
16004	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))	('muM', 'Gene', (78, 81))	('42.70', 'Var', (72, 77))	('muM', 'Gene', '56925', (121, 124))	('malignant', 'Var', (55, 64))	('THb', 'Chemical', '-', (14, 17))	('MAD', 'biological_process', 'GO:0072671', ('133', '136'))	('muM', 'Gene', (121, 124))	('MAD', 'biological_process', 'GO:0072671', ('90', '93'))	('muM', 'Gene', '56925', (78, 81))	('[THb]', 'MPA', (13, 18))
16016	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.	('DCIS', 'Var', (109, 113))	('beta-carotene', 'Chemical', 'MESH:D019207', (135, 148))	('[beta-carotene]', 'MPA', (134, 149))	('increased', 'PosReg', (124, 133))
16021	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))	('MAD', 'biological_process', 'GO:0072671', ('270', '273'))	('MAD', 'biological_process', 'GO:0072671', ('219', '222'))	('malignancy', 'Disease', 'MESH:D009369', (85, 95))	('muM', 'Gene', (208, 211))	('muM', 'Gene', '56925', (208, 211))	('muM', 'Gene', '56925', (259, 262))	('1+ to 2', 'Var', (128, 135))	('muM', 'Gene', (259, 262))	('muM', 'Gene', '56925', (147, 150))	('MAD', 'biological_process', 'GO:0072671', ('158', '161'))
16062	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))
16107	20565965	Its characteristics have been well described, including average age of onset, its rate of hormone receptor and erbB2 positivity, frequency of nodal involvement, rates of metastatic spread, and overall survival.	('hormone receptor', 'Gene', '3164', (90, 106))	('metastatic spread', 'CPA', (170, 187))	('positivity', 'Var', (117, 127))	('hormone receptor', 'Gene', (90, 106))	('erbB2', 'Gene', '2064', (111, 116))	('erbB2', 'Gene', (111, 116))
16252	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))	('Her1', 'Gene', (283, 287))	('Her2', 'Gene', (235, 239))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('290', '294'))	('ER', 'Gene', '2099', (225, 227))	('EGFR', 'Gene', (290, 294))	('ER', 'Gene', '2099', (199, 201))	('Her2', 'Gene', '2064', (55, 59))
16266	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', (239, 243))	('CK5/6+', 'Gene', '3852', (250, 256))	('ER', 'Gene', '2099', (134, 136))	('ER', 'Gene', '2099', (229, 231))	('CK14', 'Gene', '3861', (258, 262))	('Her2', 'Gene', '2064', (197, 201))	('Her2', 'Gene', '2064', (151, 155))	('CK14', 'Gene', (258, 262))
16298	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', 'molecular_function', 'GO:0015283', ('167', '171'))	('BCL2', 'Gene', (167, 171))	('p53', 'Gene', '7157', (192, 195))
16301	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))	('BCL2', 'molecular_function', 'GO:0015283', ('131', '135'))	('HR-positive tumours', 'Disease', (3, 22))	('aggressiveness of the tumour', 'Disease', 'MESH:D001523', (28, 56))	('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))
16315	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))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('HER2', 'Gene', (58, 62))	('patients', 'Species', '9606', (166, 174))	('HER2', 'Gene', '2064', (58, 62))
16324	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))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('mutations', 'Var', (10, 19))	('EGFR', 'Gene', '1956', (0, 4))
16325	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))	('EGFR', 'molecular_function', 'GO:0005006', ('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))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('breast cancers', 'Disease', 'MESH:D001943', (118, 132))	('breast cancers', 'Disease', (118, 132))	('EGFR', 'Gene', '1956', (20, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
4041	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))
16342	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))
16405	22805492	As for HER2/neu amplification status, ILCs were much more likely to be negative (P = 0.001).	('HER2/neu', 'Gene', (7, 15))	('HER2/neu', 'Gene', '2064', (7, 15))	('amplification status', 'Var', (16, 36))	('ILCs', 'Disease', (38, 42))
16435	22805492	In the current study, MRI test was used to evaluate every ILC patient receiving BCS, and no one had received re-excision due to a positive incised margin.	('patient', 'Species', '9606', (62, 69))	('BCS', 'Var', (80, 83))	('ILC', 'Disease', (58, 61))
16457	31263748	FGFR4 overexpression and hotspot mutations in metastatic ER+ breast cancer are enriched in the lobular subtype Invasive lobular carcinoma (ILC) is an understudied subtype of breast cancer that requires novel therapies in the advanced setting.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('breast cancer', 'Disease', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('lobular carcinoma', 'Disease', (120, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (120, 137))	('mutations', 'Var', (33, 42))	('overexpression', 'PosReg', (6, 20))	('lobular carcinoma', 'Disease', 'MESH:D018275', (120, 137))	('FGFR4', 'Gene', '2264', (0, 5))	('FGFR4', 'Gene', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
16460	31263748	In addition, we now report that FGFR4 hotspot mutations are enriched in metastatic breast cancer, with an additional enrichment for ILC, suggesting a multimodal selection of FGFR4 activation.	('FGFR', 'molecular_function', 'GO:0005007', ('174', '178'))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('ILC', 'Disease', (132, 135))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('hotspot', 'PosReg', (38, 45))	('FGFR4', 'Gene', '2264', (32, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('FGFR4', 'Gene', (32, 37))	('FGFR4', 'Gene', '2264', (174, 179))	('FGFR4', 'Gene', (174, 179))
16461	31263748	These data collectively support the notion that FGFR4 is an important mediator of endocrine resistance in ILC, warranting future mechanistic studies on downstream signaling of overexpressed wild-type and mutant FGFR4.	('FGFR4', 'Gene', (48, 53))	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('FGFR', 'molecular_function', 'GO:0005007', ('211', '215'))	('FGFR4', 'Gene', (211, 216))	('mutant', 'Var', (204, 210))	('FGFR4', 'Gene', '2264', (211, 216))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('FGFR4', 'Gene', '2264', (48, 53))
16467	31263748	To model acquired resistance to endocrine therapy in the laboratory, we and others have recently performed RNA-Sequencing on long-term estrogen deprived (LTED) cell lines (GSE116744 and GSE75971) or microarray analysis on tamoxifen resistant cell lines (GSE12708).	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('GSE116744', 'Var', (172, 181))	('tamoxifen', 'Chemical', 'MESH:D013629', (222, 231))	('GSE75971', 'Var', (186, 194))
16478	31263748	Next, the rate of FGFR4 mutations in metastatic cancer was examined in all patients from three recent sequencing studies: MSK-IMPACT, MET500, and Lefebvre et al., as well as from sequencing data from Foundation Medicine.	('FGFR4', 'Gene', '2264', (18, 23))	('FGFR4', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('mutations', 'Var', (24, 33))
16479	31263748	Figure 2a shows the distribution of FGFR4 mutations in these studies, with the most frequently mutated sites being the FGFR4 hotspot mutations previously identified in rhabdomyosarcomas (N535 and V550).	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (168, 185))	('rhabdomyosarcomas', 'Disease', (168, 185))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))	('N535', 'Var', (187, 191))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (168, 185))	('FGFR4', 'Gene', '2264', (119, 124))	('FGFR4', 'Gene', '2264', (36, 41))	('FGFR4', 'Gene', (36, 41))	('mutations', 'Var', (42, 51))	('FGFR4', 'Gene', (119, 124))	('V550', 'Var', (196, 200))
16480	31263748	Although FGFR4 hotspot mutations are rarely detected in primary tumors (<0.05%), they are present in ~0.5-1% of breast metastases, significantly enriched relative to nonbreast metastases (~0.02%) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('FGFR4', 'Gene', '2264', (9, 14))	('primary tumors', 'Disease', (56, 70))	('breast metastases', 'Disease', (169, 186))	('FGFR4', 'Gene', (9, 14))	('breast metastases', 'Disease', (112, 129))	('mutations', 'Var', (23, 32))	('breast metastases', 'Disease', 'MESH:D009362', (169, 186))	('primary tumors', 'Disease', 'MESH:D009369', (56, 70))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('breast metastases', 'Disease', 'MESH:D009362', (112, 129))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
16481	31263748	Treatment data is only available for the MSK-IMPACT data, which shows that 8/9 patients with FGFR4 hotspot mutations were previously treated with endocrine therapy (Supplementary Data 2).	('mutations', 'Var', (107, 116))	('FGFR4', 'Gene', '2264', (93, 98))	('FGFR4', 'Gene', (93, 98))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('patients', 'Species', '9606', (79, 87))
16482	31263748	The total rate of FGFR4 hotspot mutations in patients with endocrine-treated metastases is 3.5% for ILC versus 0.5% for IDC (Fig.	('FGFR4', 'Gene', '2264', (18, 23))	('FGFR4', 'Gene', (18, 23))	('metastases', 'Disease', (77, 87))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (45, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('ILC', 'Disease', (100, 103))
16483	31263748	There are no mutations or copy-number alterations that significantly co-occur or are mutually exclusive with the FGFR4 hotspot mutations in patients with endocrine-treated metastases (q > 0.1).	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('metastases', 'Disease', 'MESH:D009362', (172, 182))	('patients', 'Species', '9606', (140, 148))	('mutations', 'Var', (127, 136))	('metastases', 'Disease', (172, 182))	('FGFR4', 'Gene', '2264', (113, 118))	('FGFR4', 'Gene', (113, 118))
16495	31263748	Additional studies that contain both DNA and RNA analysis will be needed to assess if mutated FGFR4 is overexpressed.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('mutated', 'Var', (86, 93))	('RNA', 'cellular_component', 'GO:0005562', ('45', '48'))	('FGFR4', 'Gene', '2264', (94, 99))	('FGFR4', 'Gene', (94, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('94', '98'))
16497	31263748	However, there are clinical trials with novel pan-FGFR inhibitors that have high potency for wild-type and/or mutated FGFR4 (NCT03238196), as well as at least four ongoing clinical trials with FGFR4-specific small molecules (NCT02325739, NCT02834780, NCT03144661, and NCT02508467).	('NCT02834780', 'Var', (238, 249))	('NCT02325739', 'Var', (225, 236))	('clinical', 'Species', '191496', (172, 180))	('potency', 'MPA', (81, 88))	('NCT03144661', 'Var', (251, 262))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('mutated', 'Var', (110, 117))	('FGFR4', 'Gene', '2264', (118, 123))	('FGFR4', 'Gene', (118, 123))	('clinical', 'Species', '191496', (19, 27))	('FGFR4', 'Gene', '2264', (193, 198))	('FGFR', 'molecular_function', 'GO:0005007', ('50', '54'))	('FGFR4', 'Gene', (193, 198))	('NCT03238196', 'Var', (125, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('193', '197'))	('NCT02508467', 'Var', (268, 279))
16498	31263748	These FGFR4-specific inhibitors exhibit their specificity by interacting with a cysteine residue near the hotspot mutations, suggesting that although they are appropriate for wild-type overexpression of FGFR4, modifications would likely be needed to treat patients with hotspot mutations.	('FGFR4', 'Gene', '2264', (203, 208))	('mutations', 'Var', (114, 123))	('interacting', 'Interaction', (61, 72))	('patients', 'Species', '9606', (256, 264))	('cysteine', 'Chemical', 'MESH:D003545', (80, 88))	('FGFR4', 'Gene', '2264', (6, 11))	('FGFR4', 'Gene', (6, 11))	('FGFR', 'molecular_function', 'GO:0005007', ('203', '207'))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('FGFR4', 'Gene', (203, 208))
16499	31263748	Recent studies show that FGFR1 amplification may play a role in endocrine resistance, and that combined FGFR1 and CDK4/6 inhibition can reverse this phenotype.	('CDK4/6', 'Gene', (114, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('FGFR1', 'Gene', (25, 30))	('CDK4/6', 'Gene', '1019;1021', (114, 120))	('endocrine resistance', 'MPA', (64, 84))	('CDK', 'molecular_function', 'GO:0004693', ('114', '117'))	('play', 'Reg', (49, 53))	('FGFR1', 'Gene', '2260', (25, 30))	('FGFR1', 'Gene', (104, 109))	('FGFR1', 'Gene', '2260', (104, 109))	('amplification', 'Var', (31, 44))
16500	31263748	Future studies of resistance to combined endocrine therapy and CDK4/6 inhibition would benefit from evaluating FGFR4 overexpression and mutations as potential resistance factors, particularly for patients with lobular carcinoma.	('FGFR4', 'Gene', '2264', (111, 116))	('FGFR4', 'Gene', (111, 116))	('lobular carcinoma', 'Disease', 'MESH:D018275', (210, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('patients', 'Species', '9606', (196, 204))	('CDK4/6', 'Gene', '1019;1021', (63, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('mutations', 'Var', (136, 145))	('overexpression', 'PosReg', (117, 131))	('CDK', 'molecular_function', 'GO:0004693', ('63', '66'))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (210, 227))	('lobular carcinoma', 'Disease', (210, 227))	('CDK4/6', 'Gene', (63, 69))
16515	31263748	The FGFR4 hotspots (N535 and V550) were queried in MSK-IMPACT and the Lefebvre et al.	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('V550', 'Var', (29, 33))	('N535', 'Var', (20, 24))	('FGFR4', 'Gene', '2264', (4, 9))	('FGFR4', 'Gene', (4, 9))
16518	31263748	studies, tumors of unspecified histology with a CDH1 mutation or homozygous deletion in CDH1 were classified as ILC.	('mutation', 'Var', (53, 61))	('CDH1', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('ILC', 'Disease', (112, 115))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('CDH1', 'Gene', (88, 92))	('tumors', 'Disease', (9, 15))	('unspecified', 'Species', '32644', (19, 30))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
16520	31263748	Fisher's exact tests were used to quantify odds-ratios and significance for enrichment of FGFR4 hotspot mutations.	('FGFR4', 'Gene', (90, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('mutations', 'Var', (104, 113))	('FGFR4', 'Gene', '2264', (90, 95))
16574	22961065	For I-SPY 1 patients, centrally trained breast radiologists at each site read all MRIs and assigned an imaging phenotype for the pre-treatment MRI based on five previously described imaging patterns: 1) well defined, unicentric mass; 2) well defined, multilobulated mass; 3) area enhancement with nodularity; 4) area enhancement without nodularity; and 5) septal spreading.	('patients', 'Species', '9606', (12, 20))	('nodularity', 'Var', (297, 307))	('pre', 'molecular_function', 'GO:0003904', ('129', '132'))	('enhancement', 'PosReg', (280, 291))	('SPY 1', 'Gene', (6, 11))	('area', 'MPA', (275, 279))	('SPY 1', 'Gene', '245711', (6, 11))	('septal spreading', 'CPA', (356, 372))
16635	33053661	In this context, WNT4 knockdown led to decreased ATP production and increased mitochondrial fragmentation.	('mitochondrial fragmentation', 'CPA', (78, 105))	('ATP production', 'MPA', (49, 63))	('ATP', 'Chemical', 'MESH:D000255', (49, 52))	('knockdown', 'Var', (22, 31))	('WNT4', 'Gene', (17, 21))	('decreased', 'NegReg', (39, 48))	('increased', 'PosReg', (68, 77))
16636	33053661	We identified that high WNT4 expression is associated with similar mTOR pathway activation in ILC and serous ovarian cancer tumors, suggesting that WNT4 signaling is active in multiple tumor types.	('tumor', 'Disease', (185, 190))	('mTOR pathway', 'Pathway', (67, 79))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('high', 'Var', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('ILC and serous ovarian cancer tumors', 'Disease', 'MESH:D018284', (94, 130))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))	('expression', 'MPA', (29, 39))	('WNT4', 'Gene', (24, 28))	('activation', 'PosReg', (80, 90))
16667	33053661	Other shared ER targets included activation of PI3K pathway proteins (e.g., phospho-S6 Kinase/p70S6K, phospho-S6-S235/S236) and suppression of caspase 7 cleavage.	('activation', 'PosReg', (33, 43))	('suppression', 'NegReg', (128, 139))	('caspase 7', 'Gene', (143, 152))	('caspase 7', 'Gene', '840', (143, 152))	('PI3K pathway proteins', 'Pathway', (47, 68))	('phospho-S6-S235/S236', 'Var', (102, 122))	('p70S6K', 'Gene', '6198', (94, 100))	('p70S6K', 'Gene', (94, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('ER', 'Gene', '2099', (13, 15))
16669	33053661	Consistent with the latter, we identified 18 proteins regulated by ER in MM134 and 44PE, but not in MCF-7 (ILC-specific ER targets, Figure 1C).	('MM134', 'Chemical', '-', (73, 78))	('proteins', 'Protein', (45, 53))	('MCF-7', 'CellLine', 'CVCL:0031', (100, 105))	('MM134', 'Var', (73, 78))	('ER', 'Gene', '2099', (120, 122))	('ER', 'Gene', '2099', (67, 69))
16670	33053661	These mainly represent PI3K-related signaling (e.g., phospho-S6-S240/S244, phospho-mTOR, total MCL-1) or transcriptional control (e.g., NOTCH, SNAI1; we reported the latter previously).	('NOTCH', 'Disease', (136, 141))	('phospho-S6-S240/S244', 'Var', (53, 73))	('represent', 'Reg', (13, 22))	('transcriptional control', 'biological_process', 'GO:0006355', ('105', '128'))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('SNAI1', 'Gene', '6615', (143, 148))	('SNAI1', 'Gene', (143, 148))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))
16671	33053661	The differential activation of PI3K-related signaling targets in MCF-7 vs. the ILC models (Figure 1C) may be related to PIK3CA mutational status (MCF-7 are mutant, both ILC models are wild-type).	('PIK3CA', 'Gene', (120, 126))	('MCF-7', 'CellLine', 'CVCL:0031', (65, 70))	('PIK3CA', 'Gene', '5290', (120, 126))	('MCF-7', 'CellLine', 'CVCL:0031', (146, 151))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('activation', 'PosReg', (17, 27))	('mutant', 'Var', (156, 162))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))
16677	33053661	We next used RPPA analyses to profile WNT4 signaling and compared hormone-deprived ILC cells treated with estrogen (as above) transfected with either non-targeting siRNA or WNT4-targeting siRNA (E2 + siNT vs. E2 + siWNT4, respectively).	('E2 + siNT', 'Var', (195, 204))	('E2 + siWNT4', 'Var', (209, 220))	('E2', 'Chemical', 'MESH:D004958', (195, 197))	('E2', 'Chemical', 'MESH:D004958', (209, 211))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))
16678	33053661	Consistent with the critical role of WNT4 in ILC cell proliferation and survival, siWNT4 impacted signaling related to cell cycle progression and checkpoints, and growth factor signaling via PI3K-mTOR, in MM134 and 44PE (Figure S2A-C).	('growth factor signaling', 'MPA', (163, 186))	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('impacted', 'Reg', (89, 97))	('cell cycle', 'biological_process', 'GO:0007049', ('119', '129'))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('MM134', 'Chemical', '-', (205, 210))	('signaling related', 'MPA', (98, 115))	('MM134', 'Var', (205, 210))	('rat', 'Species', '10116', (61, 64))	('PI3K', 'molecular_function', 'GO:0016303', ('191', '195'))	('checkpoints', 'MPA', (146, 157))	('siWNT4', 'Gene', (82, 88))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('cell cycle progression', 'MPA', (119, 141))
16681	33053661	Using a reciprocal approach to the hormone-deprived setting used for RPPA analyses, we confirmed that siWNT4 suppressed ER signaling in full serum (i.e., hormone-replete conditions) and mimicked ER inhibition with fulvestrant (Figure 2C, Figure S2D).	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('suppressed', 'NegReg', (109, 119))	('ER', 'Gene', '2099', (120, 122))	('siWNT4', 'Var', (102, 108))	('fulvestrant', 'Chemical', 'MESH:D000077267', (214, 225))	('ER', 'Gene', '2099', (195, 197))
16682	33053661	This approach confirmed that FOXM1, MCL-1, and pS6 are regulated by ER:WNT4 in MM134 and 44PE (pS6-S235/S236 was modestly regulated in 44PE, leading us to focus on S240/S244).	('pS6', 'Gene', '338413', (95, 98))	('FOXM1', 'Gene', (29, 34))	('S240/S244', 'Var', (164, 173))	('pS6', 'Gene', '338413', (47, 50))	('FOXM1', 'Gene', '2305', (29, 34))	('pS6', 'Gene', (95, 98))	('MM134', 'Chemical', '-', (79, 84))	('pS6', 'Gene', (47, 50))	('ER', 'Gene', '2099', (68, 70))
16690	33053661	RPPA showed that siWNT4 reduced phosphorylation of S6 but not other E2-induced mTOR targets.	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('reduced', 'NegReg', (24, 31))	('E2', 'Chemical', 'MESH:D004958', (68, 70))	('siWNT4', 'Var', (17, 23))	('phosphorylation', 'MPA', (32, 47))
16692	33053661	Based on this, we hypothesized that WNT4 may promote S6K activity during mTOR inhibition, and assessed signaling responses to the mTOR inhibitor everolimus or S6K inhibitor PF-4708671 (PF,) in WNT4 over-expressing MM134 cells (MM134:W4; described previously).	('everolimus', 'Chemical', 'MESH:D000068338', (145, 155))	('S6K', 'Enzyme', (53, 56))	('MM134', 'Chemical', '-', (227, 232))	('over-expressing', 'PosReg', (198, 213))	('mTOR inhibition', 'MPA', (73, 88))	('MM134', 'Chemical', '-', (214, 219))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('promote', 'PosReg', (45, 52))	('activity', 'MPA', (57, 65))	('PF-4708671', 'Chemical', 'MESH:C552719', (173, 183))	('PF-4708671', 'Var', (173, 183))
16699	33053661	Based on this, we hypothesized that ER:WNT4 control of MCL-1 indicates a role for WNT4 in mitochondrial dynamics and cellular metabolism in ILC cells, and found siWNT4 caused a decrease in total ATP content per cell (Figure 4A).	('cellular metabolism', 'biological_process', 'GO:0044237', ('117', '136'))	('decrease', 'NegReg', (177, 185))	('cellular metabolism', 'MPA', (117, 136))	('MCL-1', 'Gene', (55, 60))	('mitochondrial dynamics', 'MPA', (90, 112))	('ATP', 'Chemical', 'MESH:D000255', (195, 198))	('ER', 'Gene', '2099', (36, 38))	('siWNT4', 'Var', (161, 167))	('total ATP content per cell', 'MPA', (189, 215))
16700	33053661	The decrease in cellular ATP levels was progressive over a 1-4d time course after siWNT4 (Figure 4B).	('cellular ATP levels', 'MPA', (16, 35))	('ATP', 'Chemical', 'MESH:D000255', (25, 28))	('siWNT4', 'Var', (82, 88))	('decrease', 'NegReg', (4, 12))
16701	33053661	ER knockdown did not produce a similar decrease in ATP levels, which parallels our prior observations that WNT4 knockdown, but not ER inhibition, induces cell death in ILC cells.	('WNT4', 'Gene', (107, 111))	('ER', 'Gene', '2099', (0, 2))	('ER', 'Gene', '2099', (131, 133))	('ATP', 'Chemical', 'MESH:D000255', (51, 54))	('ATP levels', 'MPA', (51, 61))	('knockdown', 'Var', (112, 121))	('death', 'Disease', 'MESH:D003643', (159, 164))	('cell death', 'biological_process', 'GO:0008219', ('154', '164'))	('death', 'Disease', (159, 164))
16702	33053661	This suggests that continued ER signaling may allow mitochondrial dysfunction to manifest upon WNT4 knockdown, while suppressing ER reduces cell growth and metabolic demand, effectively protecting cells from loss of ER-driven WNT4 expression.	('knockdown', 'Var', (100, 109))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (52, 77))	('ER', 'Gene', '2099', (216, 218))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (52, 77))	('mitochondrial dysfunction', 'Disease', (52, 77))	('cell growth', 'biological_process', 'GO:0016049', ('140', '151'))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('suppressing', 'NegReg', (117, 128))	('ER', 'Gene', '2099', (29, 31))	('ER', 'Gene', '2099', (129, 131))
16703	33053661	The decreased ATP levels and increased MCL-1 observed after WNT4 knockdown is consistent with mitochondrial fission or fragmentation, so we used transmission electron microscopy to investigate mitochondrial phenotype after WNT4 knockdown.	('increased MCL', 'Phenotype', 'HP:0005518', (29, 42))	('decreased', 'NegReg', (4, 13))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('94', '115'))	('MCL-1', 'MPA', (39, 44))	('WNT4', 'Gene', (60, 64))	('increased', 'PosReg', (29, 38))	('ATP', 'Chemical', 'MESH:D000255', (14, 17))	('ATP levels', 'MPA', (14, 24))	('knockdown', 'Var', (65, 74))
16705	33053661	Cells with control siRNA had a mean (+-SD) of 17.4 +- 9.24 mitochondria per cell with a mean area of 0.329 +- 0.233 mum2, siWNT4 caused a >65% increase in mitochondria per cell (mean = 28.9 +- 12.3) while decreasing area by ~45% (mean = 0.184 +- 0.135 mum2) (Figure 4D).	('mitochondria', 'cellular_component', 'GO:0005739', ('155', '167'))	('mitochondria per', 'MPA', (155, 171))	('mum2', 'Gene', (116, 120))	('decreasing', 'NegReg', (205, 215))	('mum2', 'Gene', '58485', (252, 256))	('mum2', 'Gene', '58485', (116, 120))	('mitochondria', 'cellular_component', 'GO:0005739', ('59', '71'))	('area', 'MPA', (216, 220))	('siWNT4', 'Var', (122, 128))	('increase', 'PosReg', (143, 151))	('mum2', 'Gene', (252, 256))
16711	33053661	We further examined whether ER:WNT4 regulated mTOR signaling controlled cellular metabolism, and found that treatment of MM134 cells with either everolimus or PF-4708671 (S6K inhibitor) decreased cellular ATP levels (Figure 4F).	('cellular ATP levels', 'MPA', (196, 215))	('everolimus', 'Chemical', 'MESH:D000068338', (145, 155))	('cellular metabolism', 'MPA', (72, 91))	('MM134', 'Chemical', '-', (121, 126))	('ER', 'Gene', '2099', (28, 30))	('decreased', 'NegReg', (186, 195))	('cellular metabolism', 'biological_process', 'GO:0044237', ('72', '91'))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('PF-4708671', 'Chemical', 'MESH:C552719', (159, 169))	('PF-4708671', 'Var', (159, 169))	('ATP', 'Chemical', 'MESH:D000255', (205, 208))
16724	33053661	Phospho-S6 (S240/244) and phospho-S6K (T389) were also elevated in WNT4-high OvCa but did not reach statistical significance (pS6K-T421/S424 is not available by RPPA).	('Phospho-S6 (S240/244', 'Var', (0, 20))	('phospho-S6K (T389', 'Var', (26, 43))	('WNT4-high OvCa', 'Disease', (67, 81))	('elevated', 'PosReg', (55, 63))	('pS6K', 'Gene', '6198', (126, 130))	('pS6K', 'Gene', (126, 130))
16731	33053661	Our study found that in ILC cells, ER:WNT4 signaling mediates downstream activity of mTOR signaling via p70-S6K, as WNT4 is required for p70-S6K phosphorylation (T421/S424) and downstream S6 phosphorylation.	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('phosphorylation', 'biological_process', 'GO:0016310', ('191', '206'))	('T421/S424', 'Var', (162, 171))	('ER', 'Gene', '2099', (35, 37))	('p70-S6K', 'Gene', '6198', (137, 144))	('phosphorylation', 'biological_process', 'GO:0016310', ('145', '160'))	('p70-S6K', 'Gene', '6198', (104, 111))	('p70-S6K', 'Gene', (137, 144))	('p70-S6K', 'Gene', (104, 111))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))
16738	33053661	T421/S424 are part of a cluster of phosphorylation sites in the C-terminal auto-inhibitory domain of p70-S6K (pseudo-substrate inhibition), and their phosphorylation is necessary for S6K activation.	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('rat', 'Species', '10116', (122, 125))	('T421/S424', 'Var', (0, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('p70-S6K', 'Gene', '6198', (101, 108))	('p70-S6K', 'Gene', (101, 108))
16740	33053661	Neither JNK nor ERK1/2 were regulated by WNT4 knockdown in our RPPA, and we previously showed JNK is not a target of non-canonical paracrine WNT4 signaling in MM134 cells.	('ERK1', 'molecular_function', 'GO:0004707', ('16', '20'))	('MM134', 'Chemical', '-', (159, 164))	('JNK', 'molecular_function', 'GO:0004705', ('8', '11'))	('JNK', 'Gene', (8, 11))	('knockdown', 'Var', (46, 55))	('JNK', 'Gene', '5599', (8, 11))	('JNK', 'Gene', '5599', (94, 97))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))	('ERK1/2', 'Gene', (16, 22))	('JNK', 'molecular_function', 'GO:0004705', ('94', '97'))	('ERK1/2', 'Gene', '5595;5594', (16, 22))	('JNK', 'Gene', (94, 97))
16749	33053661	Importantly, in considering differences in how estrogen drives PI3K/Akt/mTOR signaling in ILC vs. IDC, our RPPA studies included two ILC models (MM134, 44PE) and one IDC model (MCF-7).	('MM134', 'Chemical', '-', (145, 150))	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('Akt', 'Gene', '207', (68, 71))	('MM134', 'Var', (145, 150))	('Akt', 'Gene', (68, 71))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('MCF-7', 'CellLine', 'CVCL:0031', (177, 182))
16751	33053661	We observed that WNT4 knockdown leads to impaired ATP production and mitochondrial fragmentation, and both of these phenotypes precede the induction of cell death (~4d post-siWNT4 transfection).	('death', 'Disease', 'MESH:D003643', (157, 162))	('death', 'Disease', (157, 162))	('mitochondrial fragmentation', 'CPA', (69, 96))	('knockdown', 'Var', (22, 31))	('WNT4', 'Gene', (17, 21))	('cell death', 'biological_process', 'GO:0008219', ('152', '162'))	('impaired', 'NegReg', (41, 49))	('ATP production', 'MPA', (50, 64))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))
16753	33053661	However, one recent study demonstrated that Wnt4 over-expression could rescue a defect in mitochondrial function and dynamics caused by deletion of PTEN-inducible kinase 1 (PINK1) in Drosophila.	('Wnt4', 'Gene', '34007', (44, 48))	('Drosophila', 'Species', '7227', (183, 193))	('defect in mitochondrial function', 'Phenotype', 'HP:0003287', (80, 112))	('defect', 'NegReg', (80, 86))	('PINK1', 'Gene', '31607', (173, 178))	('rat', 'Species', '10116', (33, 36))	('PTEN-inducible kinase 1', 'Gene', (148, 171))	('deletion', 'Var', (136, 144))	('dynamics', 'MPA', (117, 125))	('Wnt4', 'Gene', (44, 48))	('mitochondrial function', 'MPA', (90, 112))	('PINK1', 'Gene', (173, 178))	('PTEN-inducible kinase 1', 'Gene', '31607', (148, 171))
16772	33053661	Everolimus (evero; cat#11597), PF-4708671 (PF; cat#15018), ABT199 (cat#16233), ABT263 (cat#11500), WEHI539 (WEHI; cat#21478), and A1210477 (A121; cat#21113) were obtained from Cayman Chemical (Ann Arbor, MI, USA) and dissolved in DMSO.	('cat#11500', 'Var', (87, 96))	('cat', 'molecular_function', 'GO:0004096', ('146', '149'))	('cat', 'molecular_function', 'GO:0004096', ('67', '70'))	('evero', 'Chemical', 'MESH:D000068338', (12, 17))	('DMSO', 'Chemical', 'MESH:D004121', (230, 234))	('cat', 'molecular_function', 'GO:0004096', ('114', '117'))	('PF-4708671', 'Chemical', 'MESH:C552719', (31, 41))	('cat', 'molecular_function', 'GO:0004096', ('19', '22'))	('PF-4708671', 'Var', (31, 41))	('cat', 'molecular_function', 'GO:0004096', ('47', '50'))	('Everolimus', 'Chemical', 'MESH:D000068338', (0, 10))	('cat', 'molecular_function', 'GO:0004096', ('87', '90'))
16782	33053661	Antibodies were used according to manufacturer's recommendations: WNT4 (R&D, MAB4751, cat# 55025, also see specific immunoblot considerations); ERalpha (Leica, Buffalo Grove, IL, USA; 6F11, cat# ER-6F11-L-F); pER-S118 (Cell Signaling, Danvers, MA, USA; 16J4, cat#2511); FOXM1 (Cell Signaling, D12D5, cat#5436); total S6 (Cell Signaling, 54D2, cat#2317); pS6-S235/236 (Cell Signaling, cat#2211); pS6-S240/244 (Cell Signaling, cat#2215); p70-S6K (Cell Signaling, 49D7, cat#2708); p-p70-S6K-T389 (Cell Signaling, 108D2, cat#9234); p-p70-S6K-T421/S424 (Cell Signaling, cat#9204); total mTOR (Cell Signaling, 7C10, cat#2983); p-mTOR-S2448 (Cell Signaling, D9C2, cat#5536); MCL-1 (Cell Signaling, D35A5, cat#5453); 4E-BP1 (Cell Signaling, cat#9452); p4E-BP1-S65 (Cell Signaling, 174A9, cat#9456); histone H3 (Abcam, Cambridge, MA, USA; cat#ab1791).	('ER', 'Gene', '2099', (144, 146))	('Signaling', 'biological_process', 'GO:0023052', ('554', '563'))	('cat', 'molecular_function', 'GO:0004096', ('657', '660'))	('p70-S6K', 'Gene', '6198', (436, 443))	('Signaling', 'biological_process', 'GO:0023052', ('762', '771'))	('p70-S6K', 'Gene', '6198', (530, 537))	('4E-BP1', 'Gene', (709, 715))	('4E-BP1', 'Gene', '1978', (745, 751))	('cat', 'molecular_function', 'GO:0004096', ('610', '613'))	('Signaling', 'biological_process', 'GO:0023052', ('722', '731'))	('cat', 'molecular_function', 'GO:0004096', ('780', '783'))	('cat', 'molecular_function', 'GO:0004096', ('830', '833'))	('pS6', 'Gene', (395, 398))	('cat', 'molecular_function', 'GO:0004096', ('384', '387'))	('Signaling', 'biological_process', 'GO:0023052', ('499', '508'))	('pS6', 'Gene', (354, 357))	('ERalpha', 'Gene', (144, 151))	('cat', 'molecular_function', 'GO:0004096', ('698', '701'))	('; cat#ab1791', 'Var', (828, 840))	('p70-S6K', 'Gene', (436, 443))	('FOXM1', 'Gene', '2305', (270, 275))	('cat', 'molecular_function', 'GO:0004096', ('467', '470'))	('cat', 'molecular_function', 'GO:0004096', ('343', '346'))	('rat', 'Species', '10116', (134, 137))	('p70-S6K', 'Gene', (530, 537))	('Signaling', 'biological_process', 'GO:0023052', ('450', '459'))	('ER', 'Gene', '2099', (195, 197))	('p70-S6K', 'Gene', '6198', (480, 487))	('cat', 'molecular_function', 'GO:0004096', ('425', '428'))	('cat', 'molecular_function', 'GO:0004096', ('259', '262'))	('4E-BP1', 'Gene', (745, 751))	('cat', 'molecular_function', 'GO:0004096', ('565', '568'))	('pS6', 'Gene', '338413', (395, 398))	('Signaling', 'biological_process', 'GO:0023052', ('414', '423'))	('cat', 'molecular_function', 'GO:0004096', ('86', '89'))	('ERalpha', 'Gene', '2099', (144, 151))	('pS6', 'Gene', '338413', (354, 357))	('cat', 'molecular_function', 'GO:0004096', ('190', '193'))	('Signaling', 'biological_process', 'GO:0023052', ('326', '335'))	('cat', 'molecular_function', 'GO:0004096', ('300', '303'))	('cat', 'molecular_function', 'GO:0004096', ('733', '736'))	('4E-BP1', 'Gene', '1978', (709, 715))	('Signaling', 'biological_process', 'GO:0023052', ('640', '649'))	('Signaling', 'biological_process', 'GO:0023052', ('282', '291'))	('p70-S6K', 'Gene', (480, 487))	('Signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('Signaling', 'biological_process', 'GO:0023052', ('680', '689'))	('ER', 'Gene', '2099', (210, 212))	('Signaling', 'biological_process', 'GO:0023052', ('593', '602'))	('cat', 'molecular_function', 'GO:0004096', ('517', '520'))	('FOXM1', 'Gene', (270, 275))	('; histone', 'Protein', (789, 798))	('Signaling', 'biological_process', 'GO:0023052', ('373', '382'))
16783	33053661	Secondary antibodies were used according to manufacturer's instruction and were obtained from Jackson ImmunoResearch Laboratories (West Grove, PA, USA), goat anti-mouse IgG (cat# 115-035-068), goat anti-rabbit IgG (cat# 111-035-045) and goat anti-rat IgG (cat# 112-035-062).	('cat', 'molecular_function', 'GO:0004096', ('256', '259'))	('cat', 'molecular_function', 'GO:0004096', ('174', '177'))	('cat', 'molecular_function', 'GO:0004096', ('215', '218'))	('rat', 'Species', '10116', (247, 250))	('mouse', 'Species', '10090', (163, 168))	('cat# 115-035-068', 'Var', (174, 190))	('cat# 111-035-045', 'Var', (215, 231))	('cat# 112-035-062', 'Var', (256, 272))	('rat', 'Species', '10116', (121, 124))
16786	33053661	RNA extractions were performed using the RNeasy Mini kit (Qiagen, Germantown, MD, USA), mRNA was converted to cDNA on an Eppendorf Mastercycler Pro (Eppendorf, Hamburg, Germany) and using Promega (Madison, WI, USA) reagents: oligo (dT)15 primer (cat# C110A), random primers (cat# C118A), GoScript 5x reaction buffer (cat# A500D), 25mM MgCl2 (cat# A351H), 10mM dNTPs (cat# U1511), RNasin plus RNase inhibitor (cat# N261B) and GoScript reverse transcriptase (cat# A501D).	('C110A', 'Mutation', 'c.110C>A', (251, 256))	('C118A', 'Mutation', 'c.118C>A', (280, 285))	('cat# C118A', 'Var', (275, 285))	('cat# C110A', 'Var', (246, 256))	('MgCl2', 'Chemical', 'MESH:D015636', (335, 340))	('N261B', 'CellLine', 'CVCL:2133', (414, 419))	('transcriptase', 'molecular_function', 'GO:0003899', ('442', '455'))	('cat', 'molecular_function', 'GO:0004096', ('409', '412'))	('cat', 'molecular_function', 'GO:0004096', ('246', '249'))	('cat', 'molecular_function', 'GO:0004096', ('275', '278'))	('A500D', 'Mutation', 'p.A500D', (322, 327))	('A351H', 'Mutation', 'p.A351H', (347, 352))	('A501D', 'Mutation', 'p.A501D', (462, 467))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('cat', 'molecular_function', 'GO:0004096', ('317', '320'))	('cat', 'molecular_function', 'GO:0004096', ('457', '460'))	('cat', 'molecular_function', 'GO:0004096', ('367', '370'))	('cat# U1511', 'Var', (367, 377))	('transcriptase', 'molecular_function', 'GO:0003968', ('442', '455'))	('cat', 'molecular_function', 'GO:0004096', ('342', '345'))	('transcriptase', 'molecular_function', 'GO:0034062', ('442', '455'))	('cat#', 'Var', (409, 413))
16802	33053661	The following are available online at : Figure S1: The decrease in soluble histone H3 upon estrogen treatment is a subset of total H3 protein, Figure S2: WNT4 knockdown in ILC cells dysregulates cell proliferation and PI3K-mTOR networks, Figure S3: WNT4 regulates S6K activity via T421/S424 phosphorylation.	('knockdown', 'Var', (159, 168))	('rat', 'Species', '10116', (207, 210))	('cell proliferation', 'CPA', (195, 213))	('activity', 'MPA', (268, 276))	('PI3K-mTOR networks', 'Pathway', (218, 236))	('phosphorylation', 'biological_process', 'GO:0016310', ('291', '306'))	('cell proliferation', 'biological_process', 'GO:0008283', ('195', '213'))	('soluble', 'cellular_component', 'GO:0005625', ('67', '74'))	('regulates', 'Reg', (254, 263))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('decrease', 'NegReg', (55, 63))	('S6K', 'Enzyme', (264, 267))	('dysregulates', 'Reg', (182, 194))	('PI3K', 'molecular_function', 'GO:0016303', ('218', '222'))	('T421/S424 phosphorylation', 'MPA', (281, 306))
16854	30581581	Looking at the status of resection margins, assessed via paraffin embedding histopathological exam, it was noted that 6 of recurrences were associated with positive resection margins, 5 recurrences appeared following initial negative resection margins whilst one case occured following a primary tumor with unknown status of resection margins.	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('primary tumor', 'Disease', (288, 301))	('positive', 'Var', (156, 164))	('primary tumor', 'Disease', 'MESH:D009369', (288, 301))	('paraffin', 'Chemical', 'MESH:D010232', (57, 65))
16861	30581581	Thus, breast carcinoma relapses were more commonly seen in patients aged <= 40 years compared to those over 40 years, the difference being of high statistically significance (p <0.01).	('breast carcinoma relapses', 'Disease', (6, 31))	('<= 40 years', 'Var', (73, 84))	('breast carcinoma relapses', 'Disease', 'None', (6, 31))	('patients', 'Species', '9606', (59, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('breast carcinoma', 'Phenotype', 'HP:0003002', (6, 22))
16863	30581581	This histopathological study was conducted on a sample of 303 patients, diagnosed with breast cancer, stages 0-IIIB, TNM stages T1-T2 and T4b, measuring less than 5 cm, treated with breast conserving surgery.	('TNM', 'Gene', '10178', (117, 120))	('TNM', 'Gene', (117, 120))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('T4b', 'Var', (138, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('patients', 'Species', '9606', (62, 70))	('T1-T2', 'Var', (128, 133))
16919	30581581	According to nuclear grade, Komoike et al showed in a 2006 study that ipsilateral local recurrences are more common in patients with nuclear grade 3 carcinomas compared to those with grade 1 and 2 carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('carcinomas', 'Disease', (149, 159))	('patients', 'Species', '9606', (119, 127))	('carcinomas', 'Disease', 'MESH:D002277', (149, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('nuclear grade 3', 'Var', (133, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('carcinomas', 'Disease', 'MESH:D002277', (197, 207))	('ipsilateral local recurrences', 'CPA', (70, 99))	('carcinomas', 'Disease', (197, 207))
16942	21212063	Relationship between Menopausal Symptoms and Risk of Postmenopausal Breast Cancer Prior studies indicate that women with menopausal symptoms have lower estrogen levels as they go through menopause compared to women who do not experience them.	('go through menopause', 'Phenotype', 'HP:0008209', (176, 196))	('Breast Cancer', 'Phenotype', 'HP:0003002', (68, 81))	('menopausal symptom', 'Phenotype', 'HP:0000132', (121, 139))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('menopausal', 'Var', (121, 131))	('women', 'Species', '9606', (209, 214))	('Breast Cancer', 'Disease', (68, 81))	('lower', 'NegReg', (146, 151))	('menopause', 'biological_process', 'GO:0042697', ('187', '196'))	('Breast Cancer', 'Disease', 'MESH:D001943', (68, 81))	('Postmenopausal Breast Cancer', 'Phenotype', 'HP:0008209', (53, 81))	('estrogen levels', 'MPA', (152, 167))	('women', 'Species', '9606', (110, 115))
17040	24530008	We defined genetic-familial risk of breast cancer as any BRCA mutation or a first-degree relative diagnosed with premenopausal breast cancer (diagnosed at or before age 50) or with ovarian cancer at any age.	('premenopausal breast cancer', 'Disease', 'MESH:D001943', (113, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('ovarian cancer', 'Phenotype', 'HP:0100615', (181, 195))	('ovarian cancer', 'Disease', 'MESH:D010051', (181, 195))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('premenopausal breast cancer', 'Disease', (113, 140))	('premenopausal breast cancer', 'Phenotype', 'HP:0008209', (113, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('mutation', 'Var', (62, 70))	('ovarian cancer', 'Disease', (181, 195))	('BRCA', 'Gene', '672', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('BRCA', 'Gene', (57, 61))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
17068	26215581	A totally different peculiar feature of lobular breast cancer is the near universal loss of the cell adhesion protein E-cadherin due to deletion, mutation or hypermethylation of the CDH1 gene promoter.	('hypermethylation', 'Var', (158, 174))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('E-cadherin', 'Gene', (118, 128))	('E-cadherin', 'Gene', '999', (118, 128))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('lobular breast cancer', 'Disease', (40, 61))	('CDH1', 'Gene', (182, 186))	('cell adhesion', 'biological_process', 'GO:0007155', ('96', '109'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('CDH1', 'Gene', '999', (182, 186))	('loss', 'NegReg', (84, 88))	('lobular breast cancer', 'Disease', 'MESH:D013274', (40, 61))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (40, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('deletion', 'Var', (136, 144))	('mutation', 'Var', (146, 154))
17074	26215581	These discussions and decisions about surgical intervention, radiation protocols and systemic therapy are also influenced and informed by our growing knowledge about the relationship between early changes in morphology ('lobular neoplasia', 'lobular intraepithelial neoplasia', 'lobular carcinoma in situ' and so on) and overt invasive malignancy and the underlying driver mutations (see Logan and colleagues in this series).	('malignancy', 'Disease', 'MESH:D009369', (336, 346))	("'lobular carcinoma in situ", 'Phenotype', 'HP:0030076', (278, 304))	('malignancy', 'Disease', (336, 346))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (250, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('neoplasia', 'Phenotype', 'HP:0002664', (229, 238))	('neoplasia', 'Phenotype', 'HP:0002664', (266, 275))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (287, 304))	("'lobular neoplasia', 'lobular intraepithelial neoplasia', 'lobular carcinoma", 'Disease', 'MESH:D018275', (220, 296))	('mutations', 'Var', (373, 382))
17075	26215581	Despite the very strong, albeit not 100 % perfect, correlation between loss of E-cadherin protein expression and the lobular subtype, the relationship between CDH1 germline mutations and the risk of lobular breast cancer development is much more complex (see Dossus and Benusiglio in this series).	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('CDH1', 'Gene', (159, 163))	('lobular breast cancer', 'Disease', (199, 220))	('mutations', 'Var', (173, 182))	('E-cadherin', 'Gene', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lobular breast cancer', 'Disease', 'MESH:D013274', (199, 220))	('loss', 'NegReg', (71, 75))	('CDH1', 'Gene', '999', (159, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('E-cadherin', 'Gene', '999', (79, 89))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (199, 220))	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))	('expression', 'MPA', (98, 108))
17077	26215581	Comprehensive sequence analyses of the estrogen receptor gene and genes encoding ER pathway components in appropriately sized patient cohorts might contribute to the identification of clinically relevant mutations conferring endocrine resistance while still providing proper immunohistochemical staining scored as 'ER positive' ( and references therein).	('mutations', 'Var', (204, 213))	('patient', 'Species', '9606', (126, 133))	('ER', 'Gene', '2099', (81, 83))	('conferring', 'Reg', (214, 224))	('endocrine resistance', 'MPA', (225, 245))	('estrogen receptor', 'Gene', (39, 56))	('ER', 'Gene', '2099', (315, 317))	('estrogen receptor', 'Gene', '2099', (39, 56))
17164	24425047	However, MM134-specific ER binding sites (n=1172) were not enriched in these regions, trending toward depletion (5.3%; Figure 3D, top left).	('binding', 'molecular_function', 'GO:0005488', ('27', '34'))	('MM134', 'Chemical', '-', (9, 14))	('ER', 'Gene', '2099', (24, 26))	('MM134-specific', 'Var', (9, 23))	('depletion', 'MPA', (102, 111))
17188	24425047	However, 4OHT only partially reverses E2-induced growth, and induces ~30% growth itself as a partial agonist (Figure 5C).	('4OHT', 'Chemical', 'MESH:C032278', (9, 13))	('E2', 'Gene', '106478911', (38, 40))	('induces', 'Reg', (61, 68))	('growth', 'MPA', (74, 80))	('reverses', 'NegReg', (29, 37))	('growth', 'MPA', (49, 55))	('4OHT', 'Var', (9, 13))
17193	24425047	However, in MM134, E2, tamoxifen, 4OHT, and endoxifen all induced growth that was reversed by ICI (Figure 5D, right), demonstrating that tamoxifen-induced growth is via activation of ER.	('tamoxifen', 'Chemical', 'MESH:D013629', (23, 32))	('tamoxifen', 'Chemical', 'MESH:D013629', (137, 146))	('MM134', 'Chemical', '-', (12, 17))	('ICI', 'Chemical', '-', (94, 97))	('ER', 'Gene', '2099', (183, 185))	('MM134', 'Var', (12, 17))	('endoxifen', 'Chemical', 'MESH:C055492', (44, 53))	('4OHT', 'Chemical', 'MESH:C032278', (34, 38))	('growth', 'MPA', (66, 72))	('E2', 'Gene', '106478911', (19, 21))
17198	24425047	Conversely, the ICI analog RU 58668 completely reversed E2-induced growth and had no agonist activity (data not shown).	('growth', 'MPA', (67, 73))	('agonist', 'MPA', (85, 92))	('reversed', 'NegReg', (47, 55))	('E2', 'Gene', '106478911', (56, 58))	('RU 58668', 'Chemical', 'MESH:C086511', (27, 35))	('RU 58668', 'Var', (27, 35))	('ICI', 'Chemical', '-', (16, 19))
17217	24425047	These data are consistent with the agonist activity of 4OHT being specific to MM134 versus MCF-7.	('MM134', 'Chemical', '-', (78, 83))	('MM134', 'Var', (78, 83))	('agonist activity', 'MPA', (35, 51))	('4OHT', 'Chemical', 'MESH:C032278', (55, 59))	('MCF-7', 'CellLine', 'CVCL:0031', (91, 96))
17218	24425047	Over-expression of FGFR1 has been implicated in endocrine-resistance and sensitivity to FGFR inhibitors.	('endocrine-resistance', 'MPA', (48, 68))	('FGFR', 'Gene', '2260', (88, 92))	('FGFR1', 'Gene', '2260', (19, 24))	('FGFR', 'Gene', '2260', (19, 23))	('FGFR1', 'Gene', (19, 24))	('implicated', 'Reg', (34, 44))	('Over-expression', 'Var', (0, 15))	('FGFR', 'Gene', (19, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('FGFR', 'Gene', (88, 92))
17220	24425047	MM134 cell growth was assessed following treatment with the FGFR1 inhibitor PD173074 in the absence of E2 (-E2), or presence of 4OHT (+4OHT) or E2 (+E2).	('E2', 'Gene', '106478911', (144, 146))	('4OHT', 'Chemical', 'MESH:C032278', (135, 139))	('E2', 'Gene', '106478911', (103, 105))	('FGFR1', 'Gene', (60, 65))	('FGFR1', 'Gene', '2260', (60, 65))	('E2', 'Gene', '106478911', (108, 110))	('cell growth', 'biological_process', 'GO:0016049', ('6', '17'))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('E2', 'Gene', '106478911', (149, 151))	('MM134', 'Chemical', '-', (0, 5))	('PD173074', 'Var', (76, 84))	('4OHT', 'Chemical', 'MESH:C032278', (128, 132))	('PD173074', 'Chemical', 'MESH:C115711', (76, 84))
17221	24425047	PD173074 reduced cell growth +E2, however, growth was reduced below control -E2 or +4OHT (Figure 7A).	('growth', 'MPA', (43, 49))	('4OHT', 'Chemical', 'MESH:C032278', (84, 88))	('PD173074', 'Var', (0, 8))	('cell growth', 'biological_process', 'GO:0016049', ('17', '28'))	('PD173074', 'Chemical', 'MESH:C115711', (0, 8))	('reduced', 'NegReg', (9, 16))	('reduced', 'NegReg', (54, 61))	('E2', 'Gene', '106478911', (77, 79))	('E2', 'Gene', '106478911', (30, 32))
17222	24425047	Similar results were observed using LY294002, which inhibits PI3K, a downstream FGFR1 effector (Figure 7B), as well as FGFR1 inhibitor SU5402 (Supplemental Figure 4B).	('FGFR1', 'Gene', '2260', (80, 85))	('LY294002', 'Chemical', 'MESH:C085911', (36, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('61', '65'))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('PI3K', 'Gene', (61, 65))	('FGFR1', 'Gene', (119, 124))	('SU5402', 'Chemical', 'MESH:C105686', (135, 141))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('inhibits', 'NegReg', (52, 60))	('LY294002', 'Var', (36, 44))	('FGFR1', 'Gene', '2260', (119, 124))	('FGFR1', 'Gene', (80, 85))
17224	24425047	Reduction of growth below controls suggests that FGFR1 inhibition induces cell death specifically -E2 or +4OHT, but not +E2.	('cell death', 'CPA', (74, 84))	('cell death', 'biological_process', 'GO:0008219', ('74', '84'))	('E2', 'Gene', '106478911', (121, 123))	('FGFR1', 'Gene', (49, 54))	('4OHT', 'Chemical', 'MESH:C032278', (106, 110))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('+4OHT', 'Var', (105, 110))	('inhibition', 'Var', (55, 65))	('E2', 'Gene', '106478911', (99, 101))	('FGFR1', 'Gene', '2260', (49, 54))
17227	24425047	In +E2, PD173074 induced a moderate amount of cell death, however, in -E2 or +4OHT cell death was comparable to STS-induced death.	('cell death', 'biological_process', 'GO:0008219', ('83', '93'))	('cell death', 'CPA', (46, 56))	('4OHT', 'Chemical', 'MESH:C032278', (78, 82))	('E2', 'Gene', '106478911', (4, 6))	('STS', 'Chemical', 'MESH:D019311', (112, 115))	('PD173074', 'Var', (8, 16))	('E2', 'Gene', '106478911', (71, 73))	('PD173074', 'Chemical', 'MESH:C115711', (8, 16))	('cell death', 'biological_process', 'GO:0008219', ('46', '56'))
17228	24425047	Though LY294002 was less effective than PD173074, +E2 cells were similarly resistant to LY294002, but were sensitive -E2 or +4OHT (Figure 7D).	('PD173074', 'Chemical', 'MESH:C115711', (40, 48))	('LY294002', 'Chemical', 'MESH:C085911', (88, 96))	('LY294002', 'Var', (7, 15))	('E2', 'Gene', '106478911', (51, 53))	('E2', 'Gene', '106478911', (118, 120))	('LY294002', 'Var', (88, 96))	('LY294002', 'Chemical', 'MESH:C085911', (7, 15))	('4OHT', 'Chemical', 'MESH:C032278', (125, 129))
17239	24425047	We abrogated E-cadherin in MCF-7 using antibodies or siRNA-mediated knockdown, but these preliminary experiments did not induce endocrine resistance (data not shown).	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('MCF-7', 'CellLine', 'CVCL:0031', (27, 32))	('E-cadherin', 'Gene', (13, 23))	('knockdown', 'Var', (68, 77))	('E-cadherin', 'Gene', '999', (13, 23))	('abrogated', 'NegReg', (3, 12))
17249	24425047	While the expression of tamoxifen-regulated genes may help identify these tumors, FGFR1 amplification or over-expression may also identify these tumors.	('FGFR1', 'Gene', (82, 87))	('over-expression', 'Var', (105, 120))	('amplification', 'Var', (88, 101))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('FGFR1', 'Gene', '2260', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (145, 151))	('tamoxifen', 'Chemical', 'MESH:D013629', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
17252	24425047	FGFR1 amplification may be a common event in primary ILC; however, public data from the Cancer Genome Atlas suggests that FGFR family amplification occurs in ~10% of both ILC and IDC (data not shown).	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'Gene', (122, 126))	('FGFR', 'Gene', (0, 4))	('FGFR', 'Gene', '2260', (122, 126))	('FGFR1', 'Gene', (0, 5))	('FGFR', 'Gene', '2260', (0, 4))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (134, 147))	('ILC', 'Disease', (171, 174))	('IDC', 'Disease', (179, 182))	('FGFR', 'molecular_function', 'GO:0005007', ('122', '126'))
17255	24425047	Another report also observed that several metastatic ILC gained FGFR1 amplifications versus matched primaries.	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('amplifications', 'Var', (70, 84))	('FGFR1', 'Gene', (64, 69))	('FGFR1', 'Gene', '2260', (64, 69))
17256	24425047	Thus, FGFR1 amplification may be may be enriched in recurrent or metastatic ILC.	('metastatic ILC', 'Disease', (65, 79))	('amplification', 'Var', (12, 25))	('FGFR1', 'Gene', (6, 11))	('FGFR1', 'Gene', '2260', (6, 11))	('recurrent', 'Disease', (52, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))
17257	24425047	Both MM134 and SUM44 have FGFR1 amplification and were derived from metastatic pleural effusions.	('amplification', 'MPA', (32, 45))	('pleural effusions', 'Disease', (79, 96))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('pleural effusion', 'Phenotype', 'HP:0002202', (79, 95))	('MM134', 'Chemical', '-', (5, 10))	('MM134', 'Var', (5, 10))	('pleural effusions', 'Disease', 'MESH:D010996', (79, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('pleural effusions', 'Phenotype', 'HP:0002202', (79, 96))
17265	24425047	Consistent with this, an ER binding site near the WNT4 promoter is MM134-specific, and is not observed in IDC cells.	('ER', 'Gene', '2099', (25, 27))	('WNT4', 'Gene', (50, 54))	('WNT4', 'Gene', '54361', (50, 54))	('binding', 'Interaction', (28, 35))	('MM134-specific', 'Var', (67, 81))	('MM134', 'Chemical', '-', (67, 72))	('binding', 'molecular_function', 'GO:0005488', ('28', '35'))
17272	24425047	Though not representative of distal sites, MM134 ER-binding sites within 20kb of an ILC-specific gene were weakly enriched for PAX4 motifs (Supplemental Figure 2C), consistent with the hypothesis that novel co-factors regulate ER binding in ILC.	('PAX4', 'Gene', (127, 131))	('PAX4', 'Gene', '5078', (127, 131))	('binding', 'Interaction', (230, 237))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('ER', 'Gene', '2099', (227, 229))	('ER', 'Gene', '2099', (49, 51))	('MM134', 'Chemical', '-', (43, 48))	('MM134', 'Var', (43, 48))	('ILC-specific', 'Gene', (84, 96))	('binding', 'molecular_function', 'GO:0005488', ('230', '237'))
17273	24425047	Of note, Hsu et al characterized distal EREs in MCF-7; amplification of distal EREs was associated with clinical tamoxifen resistance.	('amplification', 'Var', (55, 68))	('MCF-7', 'CellLine', 'CVCL:0031', (48, 53))	('tamoxifen', 'Chemical', 'MESH:D013629', (113, 122))	('ER', 'Gene', '2099', (79, 81))	('clinical tamoxifen resistance', 'MPA', (104, 133))	('ER', 'Gene', '2099', (40, 42))	('associated', 'Reg', (88, 98))
17280	22354696	p53 mutations in classic and pleomorphic invasive lobular carcinoma of the breast p53 is a tumor suppressor that is frequently mutated in human cancers.	('p53', 'Gene', (82, 85))	('tumor', 'Disease', (91, 96))	('classic', 'Disease', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('p53', 'Gene', '7157', (0, 3))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (50, 67))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (58, 81))	('pleomorphic invasive lobular carcinoma', 'Disease', (29, 67))	('pleomorphic invasive lobular carcinoma', 'Disease', 'MESH:D018275', (29, 67))	('p53', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutations', 'Var', (4, 13))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('human', 'Species', '9606', (138, 143))	('p53', 'Gene', '7157', (82, 85))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))
17281	22354696	Although alterations in p53 are common in breast cancer, few studies have specifically investigated TP53 mutations in the breast cancer subtype invasive lobular carcinoma (ILC).	('TP53', 'Gene', '7157', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (153, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('TP53', 'Gene', (100, 104))	('breast cancer subtype invasive lobular carcinoma', 'Disease', (122, 170))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('alterations', 'Var', (9, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('breast cancer subtype invasive lobular carcinoma', 'Disease', 'MESH:D013274', (122, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
17282	22354696	Recently reported conditional mouse models have indicated that functional p53 inactivation may play a role in ILC development and progression.	('inactivation', 'Var', (78, 90))	('progression', 'CPA', (130, 141))	('play', 'Reg', (95, 99))	('p53', 'Gene', (74, 77))	('mouse', 'Species', '10090', (30, 35))	('ILC', 'Disease', (110, 113))
17283	22354696	Since reports on the detection of TP53 mutations in the relatively favorable classic and more aggressive pleomorphic variants of ILC (PILC) are rare and ambiguous, we performed a comprehensive analysis to determine the mutation status of TP53 in these breast cancer subtypes.	('breast cancer', 'Disease', (252, 265))	('ILC', 'Gene', (129, 132))	('TP53', 'Gene', (34, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('mutations', 'Var', (39, 48))	('TP53', 'Gene', '7157', (238, 242))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('TP53', 'Gene', (238, 242))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('TP53', 'Gene', '7157', (34, 38))
17284	22354696	To increase our understanding of p53-mediated pathways and the roles they may play in the etiology of classic ILC and PILC, we investigated TP53 mutations and p53 accumulation in a cohort of 22 cases of classic and 19 cases of PILC by direct DNA sequencing and immunohistochemistry.	('mutations', 'Var', (145, 154))	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('TP53', 'Gene', '7157', (140, 144))	('TP53', 'Gene', (140, 144))
17285	22354696	We observed 11 potentially pathogenic TP53 mutations, of which three were detected in classic ILC (13.6%) and 8 in PILC (42.1%; p = 0.04).	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('classic ILC', 'Disease', (86, 97))	('pathogenic', 'Reg', (27, 37))	('TP53', 'Gene', '7157', (38, 42))
17286	22354696	TP53 mutations occur more frequently in PILC than classic ILC.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PILC', 'Disease', (40, 44))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (15, 20))
17288	22354696	Inactivating alterations in the p53 gene are commonly observed in human cancers, resulting in suppression of the regulatory functions of p53 which contributes to transformation of cells.	('suppression', 'NegReg', (94, 105))	('Inactivating alterations', 'Var', (0, 24))	('transformation', 'CPA', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('p53', 'Gene', (32, 35))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('p53', 'Gene', (137, 140))	('regulatory functions', 'MPA', (113, 133))
17289	22354696	Mutations in p53 are observed in breast cancer, however with a lower frequency (~ 20%) compared to other solid tumors.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('solid tumors', 'Disease', 'MESH:D009369', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('Mutations', 'Var', (0, 9))	('observed', 'Reg', (21, 29))	('p53', 'Gene', (13, 16))	('solid tumors', 'Disease', (105, 117))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('breast cancer', 'Disease', (33, 46))
17290	22354696	Although it has been well established that p53 mutations correlate with high grade and triple negativity, the p53 mutation spectrum across the various different histological types of breast cancer has not been well defined.	('correlate', 'Reg', (57, 66))	('triple negativity', 'Disease', (87, 104))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('p53', 'Gene', (43, 46))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', (183, 196))	('high grade', 'Disease', (72, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
17294	22354696	The pleomorphic variant of ILC (PILC) accounts for less than 1% of all breast carcinomas and not more than 10% of all ILC.	('breast carcinomas', 'Disease', (71, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('breast carcinomas', 'Phenotype', 'HP:0003002', (71, 88))	('pleomorphic', 'Var', (4, 15))	('ILC', 'Gene', (27, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('breast carcinomas', 'Disease', 'MESH:D001943', (71, 88))
17302	22354696	Then, proteinase K was added and the samples were incubated for 1 h at 56 C. After that, samples were incubated at 95 C for 10 min to inactivate proteinase K. For the detection of mutations, genomic DNA was amplified with primers flanking exons 4, 5, 6, 7, 8 and 9 of the TP53 gene (Table 1).	('mutations', 'Var', (180, 189))	('TP53', 'Gene', '7157', (272, 276))	('TP53', 'Gene', (272, 276))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('proteinase', 'molecular_function', 'GO:0004175', ('145', '155'))	('proteinase', 'molecular_function', 'GO:0004175', ('6', '16'))
17307	22354696	Throughout the immunohistochemical analysis, negative controls were obtained by omitting the primary antibody and staining of a colon cancer tissue with a verified p53 mutation was used as a positive control.	('colon cancer', 'Disease', (128, 140))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('mutation', 'Var', (168, 176))	('p53', 'Gene', (164, 167))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
17311	22354696	Using the freely available IARC TP53 database, we have scrutinized the following; the functions of the domains in which the mutated residues are located, the known functions of the wild-type residues, the effect of the mutations, the predicted effect on splicing, functional predictions based on the structure change and previously reported tumor sites (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('TP53', 'Gene', '7157', (32, 36))	('tumor', 'Disease', (341, 346))	('splicing', 'biological_process', 'GO:0045292', ('254', '262'))	('TP53', 'Gene', (32, 36))	('mutations', 'Var', (219, 228))	('tumor', 'Disease', 'MESH:D009369', (341, 346))
17312	22354696	Because a large body of literature has shown that p53 accumulation can be caused by mutations in TP53, we set out to investigate the correlation between p53 accumulation and mutation.	('TP53', 'Gene', '7157', (97, 101))	('mutations', 'Var', (84, 93))	('TP53', 'Gene', (97, 101))	('p53', 'Gene', (50, 53))	('caused', 'Reg', (74, 80))	('accumulation', 'PosReg', (54, 66))
17316	22354696	Many research groups have investigated the distribution of p53 mutations and its correlation with immunohistochemistry in invasive carcinomas but data focusing on different variants of ILC are limited.	('mutations', 'Var', (63, 72))	('p53', 'Gene', (59, 62))	('invasive carcinomas', 'Disease', (122, 141))	('invasive carcinomas', 'Disease', 'MESH:D009361', (122, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))
17317	22354696	Eleven mutations were detected in 41 cases studied (26%) which is in line with the literature which states that the overall frequency of p53 mutations in breast cancer is approximately 20%.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutations', 'Var', (141, 150))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('p53', 'Gene', (137, 140))
17318	22354696	Even though some of these potentially pathogenic mutations (4 out of 11 mutations) do not result in an amino acid change, they have been reported before in different solid tumors including breast cancer.	('solid tumors', 'Disease', 'MESH:D009369', (166, 178))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutations', 'Var', (49, 58))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('solid tumors', 'Disease', (166, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('breast cancer', 'Disease', (189, 202))	('pathogenic', 'Reg', (38, 48))
17319	22354696	Moreover, silent mutations in p53 may also lead to a functional response by interfering with binding to MDM2.	('interfering', 'NegReg', (76, 87))	('binding', 'molecular_function', 'GO:0005488', ('93', '100'))	('lead to', 'Reg', (43, 50))	('binding', 'Interaction', (93, 100))	('p53', 'Gene', (30, 33))	('MDM2', 'Gene', '4193', (104, 108))	('MDM2', 'Gene', (104, 108))	('silent mutations', 'Var', (10, 26))	('functional response', 'MPA', (53, 72))
17320	22354696	In this scenario, single silent point mutations in p53 mRNA can disrupt its binding to MDM2 resulting in aberrant p53 synthesis and degradation.	('synthesis', 'biological_process', 'GO:0009058', ('118', '127'))	('p53', 'Gene', (51, 54))	('p53 synthesis', 'MPA', (114, 127))	('degradation', 'MPA', (132, 143))	('single silent point mutations', 'Var', (18, 47))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('MDM2', 'Gene', '4193', (87, 91))	('degradation', 'biological_process', 'GO:0009056', ('132', '143'))	('binding', 'Interaction', (76, 83))	('MDM2', 'Gene', (87, 91))	('disrupt', 'NegReg', (64, 71))
17321	22354696	Of note is the fact that these polymorphisms were shown to be related with cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('related', 'Reg', (62, 69))	('polymorphisms', 'Var', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
17322	22354696	Especially the amino acid change 72P > R (Table 3) has been shown to be associated with breast cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('associated', 'Reg', (72, 82))	('72P > R', 'Var', (33, 40))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
17323	22354696	The observation of this significantly increased frequency of pathogenic mutations in PILC -more than half of which do probably give rise to a non-functional protein based on predictions of computer models and for some based on literature (Table 2)- is also in line with mouse studies in which stochastic somatic inactivation of p53 and E-cadherin in the mammary gland induced the development of mouse PILC.	('mutations', 'Var', (72, 81))	('mouse', 'Species', '10090', (395, 400))	('cadherin', 'molecular_function', 'GO:0008014', ('338', '346'))	('PILC', 'Gene', (85, 89))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('induced', 'PosReg', (368, 375))	('p53', 'Protein', (328, 331))	('development of mouse PILC', 'CPA', (380, 405))	('E-cadherin', 'Protein', (336, 346))	('mouse', 'Species', '10090', (270, 275))
17324	22354696	However, it would not be unexpected if there were activating mutations among them since mutant p53 protein can also have a distinct function in cancer such as promoting invasion and metastases.	('metastases', 'Disease', 'MESH:D009362', (182, 192))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('promoting', 'PosReg', (159, 168))	('cancer', 'Disease', (144, 150))	('mutant', 'Var', (88, 94))	('p53', 'Gene', (95, 98))	('metastases', 'Disease', (182, 192))	('protein', 'Protein', (99, 106))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
17325	22354696	In conclusion, the clinically more aggressive pleomorphic variant of ILC bears a significantly higher frequency of p53 mutations compared to the classic variant, Moreover, since inactivation of p53 and E-cadherin in mice leads to the development of PILC, we envisage that p53 mutations may play a role in carcinogenesis of PILC.	('inactivation', 'Var', (178, 190))	('E-cadherin', 'Protein', (202, 212))	('carcinogenesis', 'Disease', 'MESH:D063646', (305, 319))	('mice', 'Species', '10090', (216, 220))	('mutations', 'Var', (276, 285))	('carcinogenesis', 'Disease', (305, 319))	('PILC', 'Disease', (249, 253))	('p53', 'Gene', (194, 197))	('cadherin', 'molecular_function', 'GO:0008014', ('204', '212'))	('mutations', 'Var', (119, 128))
17327	31444332	Intriguingly, somatic inactivation of E-cadherin alone in mouse mammary epithelial cells (MMECs) is insufficient to induce tumor formation.	('inactivation', 'Var', (22, 34))	('mouse', 'Species', '10090', (58, 63))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('insufficient', 'Disease', (100, 112))	('insufficient', 'Disease', 'MESH:D000309', (100, 112))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('induce', 'Reg', (116, 122))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))	('E-cadherin', 'Protein', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
17336	31444332	Mammary gland-specific inactivation of E-cadherin in combination with loss of p53 or PTEN markedly enhanced mammary tumor development thus confirming the tumor suppressive role of E-cadherin.	('p53', 'Gene', '22060', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('enhanced', 'PosReg', (99, 107))	('E-cadherin', 'Protein', (39, 49))	('loss', 'Var', (70, 74))	('cadherin', 'molecular_function', 'GO:0008014', ('182', '190'))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('p53', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PTEN', 'Gene', '19211', (85, 89))	('PTEN', 'Gene', (85, 89))	('tumor', 'Disease', (116, 121))	('inactivation', 'Var', (23, 35))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))	('tumor', 'Disease', (154, 159))
17337	31444332	Intriguingly, somatic inactivation of E-cadherin by itself is not sufficient to induce mammary tumor formation, but rather seems to hamper survival of mouse mammary epithelial cells (MMECs).	('inactivation', 'Var', (22, 34))	('mouse', 'Species', '10090', (151, 156))	('hamper', 'NegReg', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))	('E-cadherin', 'Protein', (38, 48))	('survival', 'CPA', (139, 147))	('tumor', 'Disease', (95, 100))
17338	31444332	In addition, genetic inactivation of E-cadherin in MMEC lines or mouse mammary epithelial organoids does not induce single cell dissociation nor epithelial-mesenchymal transition (EMT).	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('145', '178'))	('mouse', 'Species', '10090', (65, 70))	('cadherin', 'molecular_function', 'GO:0008014', ('39', '47'))	('genetic inactivation', 'Var', (13, 33))	('E-cadherin', 'Protein', (37, 47))	('epithelial-mesenchymal transition', 'CPA', (145, 178))	('EMT', 'biological_process', 'GO:0001837', ('180', '183'))
17339	31444332	We found that E-cadherin-deficient MMECs extrude into the fibrous stroma where they form dynamic but non-tumorigenic cell clusters that only progress to ILC upon partial relaxation of actomyosin.	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('ILC', 'Disease', (153, 156))	('fibrous stroma', 'Disease', 'MESH:D010411', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('fibrous stroma', 'Disease', (58, 72))	('actomyosin', 'Protein', (184, 194))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('E-cadherin-deficient', 'Protein', (14, 34))	('actomyosin', 'cellular_component', 'GO:0042641', ('184', '194'))	('partial', 'Var', (162, 169))	('tumor', 'Disease', (105, 110))
17346	31444332	Moreover, the extruded MMECs represented the majority of GFP-marked E-cadherin-deficient MMECs in Wcre;Cdh1F/F;mTmG mice, whereas no extrusion of GFP-positive control MMECs was observed in Wcre;mTmG mice (Fig.	('mice', 'Species', '10090', (116, 120))	('mTmG', 'Var', (111, 115))	('Cdh1', 'Gene', '12550', (103, 107))	('mice', 'Species', '10090', (199, 203))	('Cdh1', 'Gene', (103, 107))	('GFP-marked', 'Var', (57, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))
17347	31444332	The clusters of extruded cells did not increase in size over time, which is in line with our previous observation that loss of E-cadherin by itself does not induce mammary tumor formation in mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('loss', 'Var', (119, 123))	('tumor', 'Disease', (172, 177))	('cadherin', 'molecular_function', 'GO:0008014', ('129', '137'))	('mice', 'Species', '10090', (191, 195))	('E-cadherin', 'Protein', (127, 137))	('formation', 'biological_process', 'GO:0009058', ('178', '187'))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
17359	31444332	Next, we derived E-cadherin-proficient and -deficient subclones by picking GFP-positive MMECS in the presence of Y-27632 from Wcre;mTmG and Wcre;Cdh1F/F;mTmG MMECs (Fig.	('Cdh1', 'Gene', '12550', (145, 149))	('Cdh1', 'Gene', (145, 149))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('Y-27632', 'Var', (113, 120))	('Y-27632', 'Chemical', 'MESH:C108830', (113, 120))
17366	31444332	Remarkably, once cell adhesion was restored, Wcre;Cdh1F/F;mTmG MMECs grew significantly faster than Wcre;mTmG MMECs, likely due to loss of cell contact inhibition as previously reported to be controlled by E-cadherin signaling (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('208', '216'))	('cell contact', 'CPA', (139, 151))	('signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('contact inhibition', 'biological_process', 'GO:0060242', ('144', '162'))	('loss', 'NegReg', (131, 135))	('cell adhesion', 'biological_process', 'GO:0007155', ('17', '30'))	('Cdh1', 'Gene', '12550', (50, 54))	('faster', 'PosReg', (88, 94))	('Cdh1', 'Gene', (50, 54))	('mTmG', 'Var', (58, 62))	('grew', 'CPA', (69, 73))
17375	31444332	H1152 inhibits ROCK with increased specificity and potency compared to Y-27632.	('ROCK', 'MPA', (15, 19))	('H1152', 'Var', (0, 5))	('inhibits', 'NegReg', (6, 14))	('potency', 'MPA', (51, 58))	('specificity', 'MPA', (35, 46))	('H1152', 'Chemical', 'MESH:C459092', (0, 5))	('Y-27632', 'Chemical', 'MESH:C108830', (71, 78))
17379	31444332	The optimal concentration of H1152 only partially inhibited MLC phosphorylation indicating that too much relaxation is not tolerated.	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('MLC', 'Gene', '170790', (60, 63))	('MLC', 'Gene', (60, 63))	('H1152', 'Chemical', 'MESH:C459092', (29, 34))	('H1152', 'Var', (29, 34))	('inhibited', 'NegReg', (50, 59))
17380	31444332	We recently found that protein-truncating mutations in Ppp1r12a (encoding MYPT1) drive ILC formation in mice.	('drive', 'Reg', (81, 86))	('ILC', 'Disease', (87, 90))	('Ppp1r12a', 'Gene', '17931', (55, 63))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('mice', 'Species', '10090', (104, 108))	('formation', 'biological_process', 'GO:0009058', ('91', '100'))	('Ppp1r12a', 'Gene', (55, 63))	('protein-truncating mutations', 'Var', (23, 51))
17383	31444332	Therefore, we wondered if truncated MYPT1 could inhibit actomyosin contractility and thereby rescue adhesion of Wcre;Cdh1F/F;mTmG MMECs upon Y-27632 withdrawal.	('adhesion', 'MPA', (100, 108))	('actomyosin contractility', 'MPA', (56, 80))	('Y-27632', 'Chemical', 'MESH:C108830', (141, 148))	('rescue', 'PosReg', (93, 99))	('Cdh1', 'Gene', (117, 121))	('Cdh1', 'Gene', '12550', (117, 121))	('actomyosin', 'cellular_component', 'GO:0042641', ('56', '66'))	('truncated', 'Var', (26, 35))	('inhibit', 'NegReg', (48, 55))
17386	31444332	Loss of t-MYPT1 significantly increased MLC activity, reflected by increased pMLC IF staining along the actin stress fibers confirming that t-MYPT1 reduces actomyosin contractility (Fig.	('actomyosin', 'cellular_component', 'GO:0042641', ('156', '166'))	('MLC', 'Gene', '170790', (40, 43))	('MLC', 'Gene', (40, 43))	('actomyosin contractility', 'MPA', (156, 180))	('MLC', 'Gene', (78, 81))	('MLC', 'Gene', '170790', (78, 81))	('t-MYPT1', 'Gene', (8, 15))	('reduces', 'NegReg', (148, 155))	('increased', 'PosReg', (67, 76))	('increased', 'PosReg', (30, 39))	('Loss', 'Var', (0, 4))	('t-MYPT1', 'Var', (140, 147))
17388	31444332	Accordingly, the expression of t-MYPT1 also rescued cell adhesion and survival of Wcre;Cdh1F/F;mTmG MMECs in the absence of Y-27632 (Fig.	('rescued', 'PosReg', (44, 51))	('t-MYPT1', 'Gene', (31, 38))	('cell adhesion', 'CPA', (52, 65))	('Cdh1', 'Gene', '12550', (87, 91))	('cell adhesion', 'biological_process', 'GO:0007155', ('52', '65'))	('Cdh1', 'Gene', (87, 91))	('Y-27632', 'Chemical', 'MESH:C108830', (124, 131))	('expression', 'Var', (17, 27))	('survival', 'CPA', (70, 78))
17392	31444332	Since the PP1 recognition motif of MYPT1 has been shown to drive PP1 activity upon binding of PP1, we generated a t-MYPT1 variant lacking the PP1 recognition motif (t-MYPT1DeltaPP1) (Fig.	('PP1', 'Gene', (10, 13))	('PP1', 'Gene', '19047', (65, 68))	('activity', 'MPA', (69, 77))	('PP1', 'Gene', '19047', (142, 145))	('PP1', 'Gene', (65, 68))	('PP1', 'Gene', '19047', (94, 97))	('PP1', 'Gene', (94, 97))	('PP1', 'Gene', (142, 145))	('binding', 'Interaction', (83, 90))	('drive', 'PosReg', (59, 64))	('PP1', 'Gene', '19047', (177, 180))	('PP1', 'Gene', (177, 180))	('t-MYPT1', 'Gene', (114, 121))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('variant', 'Var', (122, 129))	('lacking', 'NegReg', (130, 137))	('PP1', 'Gene', '19047', (10, 13))
17393	31444332	Stable expression of t-MYPT1 and t-MYPT1DeltaPP1 showed that loss of the PP1 recognition domain impaired dephosphorylation of pMLC in Wcre;Cdh1F/F;mTmG MMECs (Fig.	('PP1', 'Gene', '19047', (45, 48))	('PP1', 'Gene', (45, 48))	('PP1', 'Gene', '19047', (73, 76))	('PP1', 'Gene', (73, 76))	('MLC', 'Gene', '170790', (127, 130))	('MLC', 'Gene', (127, 130))	('Cdh1', 'Gene', '12550', (139, 143))	('dephosphorylation', 'biological_process', 'GO:0016311', ('105', '122'))	('Cdh1', 'Gene', (139, 143))	('impaired', 'NegReg', (96, 104))	('loss', 'Var', (61, 65))
17404	31444332	In line with these findings, survival of E-cadherin-deficient MMECs on collagen I could be rescued by expression of t-MYPT1 but not by t-MYPT1DeltaPP1, which is unable to reduce actomyosin contractility (Fig.	('collagen', 'molecular_function', 'GO:0005202', ('71', '79'))	('actomyosin', 'cellular_component', 'GO:0042641', ('178', '188'))	('E-cadherin-deficient', 'Protein', (41, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('t-MYPT1', 'Var', (116, 123))	('reduce actomyosin contractility', 'Phenotype', 'HP:0002486', (171, 202))	('PP1', 'Gene', (147, 150))	('PP1', 'Gene', '19047', (147, 150))
17406	31444332	We performed intraductal injections with lentiviruses encoding MYPT1, t-MYPT1, t-MYPTDeltaPP1, and empty control in mammary glands of Wcre;Cdh1F/F mice and determined tumor burden 20 weeks post-injection (Fig.	('mice', 'Species', '10090', (147, 151))	('PP1', 'Gene', (90, 93))	('PP1', 'Gene', '19047', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('Cdh1', 'Gene', '12550', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Cdh1', 'Gene', (139, 143))	('tumor', 'Disease', (167, 172))	('t-MYPT1', 'Var', (70, 77))	('MYPT1', 'Gene', (63, 68))
17407	31444332	As seen before, expression of t-MYPT1 consistently induced formation of classic mouse ILCs characterized by the lack of E-cadherin expression and an Indian file growth pattern in tumor-associated stroma (Fig.	('E-cadherin', 'Protein', (120, 130))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('expression', 'Var', (16, 26))	('mouse', 'Species', '10090', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('growth pattern', 'biological_process', 'GO:0040007', ('161', '175'))	('growth pattern', 'biological_process', 'GO:0007150', ('161', '175'))	('t-MYPT1', 'Gene', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('induced', 'Reg', (51, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('122', '130'))	('lack', 'NegReg', (112, 116))	('tumor', 'Disease', (179, 184))
17408	31444332	Expression of full-length MYPT1 also induced ILC formation, although tumors formed less frequently and were on average smaller in size.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Expression', 'Var', (0, 10))	('induced', 'Reg', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('MYPT1', 'Gene', (26, 31))	('formation', 'biological_process', 'GO:0009058', ('49', '58'))	('ILC', 'Disease', (45, 48))
17412	31444332	However, because these cells do persist for a prolonged period of time they have the opportunity to gain additional mutations that allow tumor initiation.	('gain', 'PosReg', (100, 104))	('tumor', 'Disease', (137, 142))	('mutations', 'Var', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
17413	31444332	The accumulation and persistence of E-cadherin-deficient MMECs in the fibrous stroma might therefore explain the increased susceptibility of CDH1 mutation carriers to develop ILC.	('mutation', 'Var', (146, 154))	('develop', 'PosReg', (167, 174))	('CDH1', 'Gene', (141, 145))	('CDH1', 'Gene', '12550', (141, 145))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('ILC', 'Disease', (175, 178))	('fibrous stroma', 'Disease', 'MESH:D010411', (70, 84))	('fibrous stroma', 'Disease', (70, 84))	('E-cadherin-deficient', 'Protein', (36, 56))
17417	31444332	Survival of these cells is promoted by the basal lamina components, laminin-332 and collagen IV, but not by collagen I, which is the principle component of the fibrous stroma.	('laminin-332', 'Var', (68, 79))	('fibrous stroma', 'Disease', 'MESH:D010411', (160, 174))	('fibrous stroma', 'Disease', (160, 174))	('collagen', 'molecular_function', 'GO:0005202', ('108', '116'))	('Survival', 'CPA', (0, 8))	('basal lamina', 'cellular_component', 'GO:0005604', ('43', '55'))	('promoted', 'PosReg', (27, 35))	('collagen', 'molecular_function', 'GO:0005202', ('84', '92'))
17422	31444332	These mutations might involve alterations that reduce actomyosin contractility or alterations (such as p53 loss) that enable E-cadherin-deficient MECs to survive high levels of actomyosin contractility.	('reduce', 'NegReg', (47, 53))	('p53', 'Gene', (103, 106))	('loss', 'NegReg', (107, 111))	('actomyosin', 'cellular_component', 'GO:0042641', ('177', '187'))	('actomyosin', 'cellular_component', 'GO:0042641', ('54', '64'))	('actomyosin contractility', 'MPA', (54, 78))	('cadherin', 'molecular_function', 'GO:0008014', ('127', '135'))	('p53', 'Gene', '22060', (103, 106))	('reduce actomyosin contractility', 'Phenotype', 'HP:0002486', (47, 78))	('E-cadherin-deficient', 'Protein', (125, 145))	('mutations', 'Var', (6, 15))
17424	31444332	Accordingly, amplification of the MYPT1 homolog MYPT2 or hemizygous deletion of MYH9 are frequently observed in human ILC.	('MYH9', 'Gene', (80, 84))	('ILC', 'Disease', (118, 121))	('MYPT2', 'Gene', (48, 53))	('MYH9', 'Gene', '4627', (80, 84))	('amplification', 'Var', (13, 26))	('observed', 'Reg', (100, 108))	('MYPT2', 'Gene', '4660', (48, 53))	('human', 'Species', '9606', (112, 117))
17425	31444332	The lack of homozygous MYH9 deletions in ILC patients supports the notion E-cadherin-deficient cells do not tolerate complete inhibition of actomyosin contractility.	('actomyosin', 'cellular_component', 'GO:0042641', ('140', '150'))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('MYH9', 'Gene', '4627', (23, 27))	('MYH9', 'Gene', (23, 27))	('deletions', 'Var', (28, 37))	('patients', 'Species', '9606', (45, 53))	('ILC', 'Disease', (41, 44))
17426	31444332	Moreover, mutations in RHOA as well as RhoGEF and RhoGAP genes are common in CDH1-mutated diffuse-type gastric cancer.	('RhoGEF', 'Gene', '110596', (39, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('RhoGEF', 'molecular_function', 'GO:0005089', ('39', '45'))	('common', 'Reg', (67, 73))	('RhoGEF', 'Gene', (39, 45))	('RHOA', 'Gene', '11848', (23, 27))	('RhoGAP genes', 'Gene', (50, 62))	('CDH1', 'Gene', (77, 81))	('gastric cancer', 'Disease', (103, 117))	('RHOA', 'Gene', (23, 27))	('mutations', 'Var', (10, 19))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('CDH1', 'Gene', '12550', (77, 81))
17427	31444332	At least several of the RHOA mutations have been identified as dominant-negative and lead to RhoA pathway inhibition.	('RhoA', 'Gene', (93, 97))	('mutations', 'Var', (29, 38))	('RhoA', 'Gene', '11848', (93, 97))	('RHOA', 'Gene', '11848', (24, 28))	('inhibition', 'NegReg', (106, 116))	('RHOA', 'Gene', (24, 28))
17428	31444332	Also the observed CLDN18-ARHGAP fusions result in inactivation of ROCK signaling and reduction of actomyosin contractility.	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('fusions', 'Var', (32, 39))	('CLDN18', 'Gene', '56492', (18, 24))	('ROCK signaling', 'MPA', (66, 80))	('actomyosin', 'cellular_component', 'GO:0042641', ('98', '108'))	('CLDN18', 'Gene', (18, 24))	('reduction', 'NegReg', (85, 94))	('inactivation', 'NegReg', (50, 62))	('actomyosin contractility', 'MPA', (98, 122))
17429	31444332	Alternatively, PI3K pathway mutations, which are very common in ILC, may activate the RhoGTPase Rac1 via non-canonical PI3K signaling, resulting in RhoA inhibition and reduced actomyosin contractility.	('PI3K', 'molecular_function', 'GO:0016303', ('15', '19'))	('RhoA', 'Gene', (148, 152))	('GTP', 'Chemical', 'MESH:D006160', (89, 92))	('inhibition', 'NegReg', (153, 163))	('actomyosin contractility', 'MPA', (176, 200))	('PI3K signaling', 'biological_process', 'GO:0014065', ('119', '133'))	('PI3K', 'molecular_function', 'GO:0016303', ('119', '123'))	('PI3K pathway', 'Pathway', (15, 27))	('RhoA', 'Gene', '11848', (148, 152))	('Rac1', 'Gene', '19353', (96, 100))	('activate', 'PosReg', (73, 81))	('Rac1', 'Gene', (96, 100))	('actomyosin', 'cellular_component', 'GO:0042641', ('176', '186'))	('mutations', 'Var', (28, 37))	('reduced', 'NegReg', (168, 175))
17431	31444332	In conclusion, this study provides insights into ILC development by uncovering the direct consequences of E-cadherin inactivation in the mouse mammary gland and reveals actomyosin contractility as a critical barrier to ILC development.	('mouse', 'Species', '10090', (137, 142))	('inactivation', 'Var', (117, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('108', '116'))	('actomyosin', 'cellular_component', 'GO:0042641', ('169', '179'))	('E-cadherin', 'Protein', (106, 116))
17438	31444332	Imaging was performed on an inverted Leica SP8 multiphoton microscope with a chameleon Vision-S (Coherent Inc., Santa Clare, CA, www.coherent.com), equipped with four HyD detectors: HyD1 (<455 nm), HyD2 (455-490 nm), HyD3 (500-550 nm), and HyD4 (560-650 nm).	('<455 nm', 'Var', (188, 195))	('SP8', 'Gene', (43, 46))	('560-650 nm', 'Var', (246, 256))	('500-550 nm', 'Var', (223, 233))	('SP8', 'Gene', '320145', (43, 46))	('HyD1', 'CellLine', 'CVCL:1S58', (182, 186))
17447	31444332	MYPT1 was isolated with Age1-Sal1 or Age1-Age1 overhangs and a 3' FLAG tag from cDNA derived from the NMuMG cell line RNA using Phusion Flash High-Fidelity DNA Polymerase (Thermo Scientific).	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('Age1-Age1', 'Var', (37, 46))	('Sal1', 'Gene', (29, 33))	('RNA', 'cellular_component', 'GO:0005562', ('118', '121'))	('Sal1', 'Gene', '11354', (29, 33))	('NMuMG', 'CellLine', 'CVCL:0075', (102, 107))
17456	31444332	The SIN.LV.SF pINDUCER20 KRASG12D plasmid was digested with EcoRV to remove KRASG12D and inserted with the blunted tMYPT1 cDNA described above to generate SIN.LV.SF pINDUCER20 tMYPT1.	('SIN', 'biological_process', 'GO:0031028', ('4', '7'))	('SIN', 'biological_process', 'GO:0031028', ('155', '158'))	('SIN', 'Disease', (4, 7))	('SIN', 'Disease', 'None', (4, 7))	('SIN', 'Disease', (155, 158))	('KRASG12D', 'Var', (76, 84))	('SIN', 'Disease', 'None', (155, 158))
17465	31444332	Quantification was performed by dissolving the crystal violet in 10% acetic acid in demineralized water and measuring the absorbance at 590 nm.	('water', 'Chemical', 'MESH:D014867', (98, 103))	('crystal violet', 'Chemical', 'MESH:D005840', (47, 61))	('measuring', 'Reg', (108, 117))	('acetic acid', 'Chemical', 'MESH:D019342', (69, 80))	('dissolving', 'Var', (32, 42))	('absorbance at 590 nm', 'MPA', (122, 142))
17466	31444332	Formalin-fixed and paraffin-embedded sections were processed as described and incubated overnight at 4  C with GFP (1:200;Abcam #13970), Cytokeratin-8 (1:200; DSHB Troma-1), Cytokeratin-14 (1:200; Covance PRB-155P), pMLC (1:100; Cell Signaling #3671), E-cadherin (1:200; E-Bioscience #610181), laminin (1:100; Abcam #11575), primary antibodies.	('MLC', 'Gene', (217, 220))	('Cytokeratin-14', 'Gene', '16664', (174, 188))	('Cytokeratin-8', 'Gene', '16691', (137, 150))	('Signaling', 'biological_process', 'GO:0023052', ('234', '243'))	('Cytokeratin-8', 'Gene', (137, 150))	('Cytokeratin-14', 'Gene', (174, 188))	('1:200', 'Var', (264, 269))	('cadherin', 'molecular_function', 'GO:0008014', ('254', '262'))	('paraffin', 'Chemical', 'MESH:D010232', (19, 27))	('MLC', 'Gene', '170790', (217, 220))	('1:200', 'Var', (152, 157))
17474	31444332	Membranes were washed three times with TBS-T and incubated with one of the following secondary antibodies: anti-Rabbit HRP (1:2000; DAKO, P0260), Anti-Mouse HRP (1:2000; DAKO, P0448), anti-Rat HRP(1:2000; Invitrogen, 62-9520), or anti-mouse IRDye 680 nm (1:5000; Li-COR 926-32222) in 5% nonfat dry milk or 5% BSA in TBS-T for 1 h at room temperature.	('Anti-Mouse', 'Var', (146, 156))	('anti-mouse', 'Var', (230, 240))	('Rabbit', 'Species', '9986', (112, 118))	('Rat', 'Species', '10116', (189, 192))	('anti-Rat', 'Var', (184, 192))	('dry milk', 'Disease', (294, 302))	('mouse', 'Species', '10090', (235, 240))	('dry milk', 'Disease', 'MESH:D016269', (294, 302))	('Mouse', 'Species', '10090', (151, 156))
17614	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))
17625	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))
17664	33495416	Cellular functions are dysregulated during tumorigenesis, including alternative splicing and translational and RNA processing.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('RNA processing', 'biological_process', 'GO:0006396', ('111', '125'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('alternative splicing', 'Var', (68, 88))	('RNA processing', 'MPA', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('splicing', 'biological_process', 'GO:0045292', ('80', '88'))	('tumor', 'Disease', (43, 48))	('translational', 'MPA', (93, 106))
17712	33495416	Notably, HNRNPU, HNRNPL, and HNRNPA2B1 were the three most frequently altered genes (14%, 2.9%, and 2.5%, respectively), and amplification, mutation, and deep deletion were the three most common types of mutations.	('amplification', 'Var', (125, 138))	('HNRNPU', 'Gene', (9, 15))	('mutation', 'Var', (140, 148))	('HNRNPA2B1', 'Gene', '3181', (29, 38))	('HNRNPL', 'Gene', '3191', (17, 23))	('HNRNPA2B1', 'Gene', (29, 38))	('HNRNPU', 'Gene', '3192', (9, 15))	('deep deletion', 'Var', (154, 167))	('HNRNPL', 'Gene', (17, 23))
17722	33495416	Next, we studied the potential biological processes of the top 50 genes that positively and negatively correlated with HNRNPU mutation in BRCA using Linkomics (Supplementary Figure 2C-2E).	('HNRNPU', 'Gene', '3192', (119, 125))	('BRCA', 'Phenotype', 'HP:0003002', (138, 142))	('BRCA', 'Gene', '672', (138, 142))	('mutation', 'Var', (126, 134))	('BRCA', 'Gene', (138, 142))	('negatively', 'NegReg', (92, 102))	('HNRNPU', 'Gene', (119, 125))
17738	33495416	MTT assay revealed that HNRNPU knockdown substantially reduced the proliferation ability of ZR-75-1 and MDA-MB-330 cells (Figure 8A, 8B).	('reduced', 'NegReg', (55, 62))	('HNRNPU', 'Gene', '3192', (24, 30))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (104, 114))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('HNRNPU', 'Gene', (24, 30))	('proliferation ability', 'CPA', (67, 88))	('knockdown', 'Var', (31, 40))
17739	33495416	Moreover, the wound-healing and Matrigel invasion assays revealed that HNRNPU knockdown significantly inhibited the migration and invasion abilities of ZR-75-1 and MDA-MB-330 cells (P < 0.05, Figure 8C-8H).	('MDA-MB-330', 'CellLine', 'CVCL:0619', (164, 174))	('HNRNPU', 'Gene', (71, 77))	('inhibited', 'NegReg', (102, 111))	('knockdown', 'Var', (78, 87))	('wound-healing', 'biological_process', 'GO:0042060', ('14', '27'))	('HNRNPU', 'Gene', '3192', (71, 77))
17740	33495416	Further analysis of HNRNPU knockdown in ZR-75-1 and MDA-MB-330 cells revealed that HNRNPU depletion can increase the expression level of the epithelial marker E-cadherin and decrease the expression levels of the mesenchymal markers vimentin, N-cadherin, and matrix metallopeptidase 9, suggesting that HNRNPM is important for the EMT phenotype (Figure 8I-8L).	('MDA-MB-330', 'CellLine', 'CVCL:0619', (52, 62))	('N-cadherin', 'Gene', (242, 252))	('N-cadherin', 'Gene', '1000', (242, 252))	('matrix metallopeptidase 9', 'Gene', '4318', (258, 283))	('vimentin', 'cellular_component', 'GO:0045098', ('232', '240'))	('vimentin', 'Gene', '7431', (232, 240))	('HNRNPU', 'Gene', (20, 26))	('HNRNPM', 'Gene', '4670', (301, 307))	('vimentin', 'Gene', (232, 240))	('depletion', 'Var', (90, 99))	('HNRNPM', 'Gene', (301, 307))	('expression level', 'MPA', (117, 133))	('HNRNPU', 'Gene', '3192', (20, 26))	('expression levels', 'MPA', (187, 204))	('HNRNPU', 'Gene', (83, 89))	('E-cadherin', 'Gene', (159, 169))	('increase', 'PosReg', (104, 112))	('E-cadherin', 'Gene', '999', (159, 169))	('vimentin', 'cellular_component', 'GO:0045099', ('232', '240'))	('cadherin', 'molecular_function', 'GO:0008014', ('161', '169'))	('decrease', 'NegReg', (174, 182))	('cadherin', 'molecular_function', 'GO:0008014', ('244', '252'))	('EMT', 'biological_process', 'GO:0001837', ('329', '332'))	('HNRNPU', 'Gene', '3192', (83, 89))	('matrix metallopeptidase 9', 'Gene', (258, 283))
17741	33495416	Taken together, our results suggest that HNRNPU knockdown significantly inhibits the proliferation, migration, and invasion of BRCA cells in vitro.	('migration', 'CPA', (100, 109))	('BRCA', 'Gene', '672', (127, 131))	('HNRNPU', 'Gene', '3192', (41, 47))	('inhibits', 'NegReg', (72, 80))	('BRCA', 'Phenotype', 'HP:0003002', (127, 131))	('HNRNPU', 'Gene', (41, 47))	('BRCA', 'Gene', (127, 131))	('knockdown', 'Var', (48, 57))
17750	33495416	revealed that HNRNPA2B1 knockdown inhibits cell proliferation, induces apoptosis, and prolonges the S phase of the cell cycle in MCF-7 and MDA-MB-231 cells via the STAT3 and ERK1/2 signaling pathways.	('apoptosis', 'CPA', (71, 80))	('induces', 'Reg', (63, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (139, 149))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('S phase of the cell cycle', 'CPA', (100, 125))	('HNRNPA2B1', 'Gene', (14, 23))	('ERK1/2', 'Gene', (174, 180))	('ERK1/2', 'Gene', '5595;5594', (174, 180))	('STAT3', 'Gene', (164, 169))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('cell proliferation', 'CPA', (43, 61))	('STAT3', 'Gene', '6774', (164, 169))	('MCF-7', 'CellLine', 'CVCL:0031', (129, 134))	('knockdown', 'Var', (24, 33))	('HNRNPA2B1', 'Gene', '3181', (14, 23))	('inhibits', 'NegReg', (34, 42))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('ERK1', 'molecular_function', 'GO:0004707', ('174', '178'))	('cell cycle', 'biological_process', 'GO:0007049', ('115', '125'))	('prolonges', 'NegReg', (86, 95))	('S phase', 'biological_process', 'GO:0051320', ('100', '107'))
17751	33495416	showed that HNRNPC repression inhibits cell proliferation and tumor growth in BRCA cells.	('HNRNPC', 'Gene', '3183', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('HNRNPC', 'Gene', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('BRCA', 'Phenotype', 'HP:0003002', (78, 82))	('BRCA', 'Gene', (78, 82))	('repression', 'Var', (19, 29))	('BRCA', 'Gene', '672', (78, 82))	('cell proliferation', 'CPA', (39, 57))	('inhibits', 'NegReg', (30, 38))
17760	33495416	Furthermore, subgroup analysis revealed that high expression of HNRNPU significantly indicated poor OS in patients with BRCA with LNM.	('BRCA', 'Gene', (120, 124))	('HNRNPU', 'Gene', '3192', (64, 70))	('HNRNPU', 'Gene', (64, 70))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (106, 114))	('BRCA', 'Phenotype', 'HP:0003002', (120, 124))	('BRCA', 'Gene', '672', (120, 124))
17800	32435886	Prognostic relevance of the loss of stromal CD34 positive fibroblasts in invasive lobular carcinoma of the breast CD34+ fibroblasts are constitutive stromal components of virtually all organs, including the mammary stroma, being involved in matrix synthesis, antigen presentation, and tumor-associated stromal remodeling.	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (90, 113))	('CD34+', 'Var', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (82, 99))	('antigen presentation', 'biological_process', 'GO:0019882', ('259', '279'))	('invasive lobular carcinoma of the breast', 'Disease', 'MESH:D001943', (73, 113))	('tumor', 'Disease', (285, 290))	('invasive lobular carcinoma of the breast', 'Disease', (73, 113))	('synthesis', 'biological_process', 'GO:0009058', ('248', '257'))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
17806	32435886	Stromal loss of CD34+ fibroblasts was significantly associated with lower overall and disease-free survival rates (p = 0.012 and 0.013, respectively).	('Stromal loss', 'Disease', (0, 12))	('lower', 'NegReg', (68, 73))	('overall', 'CPA', (74, 81))	('CD34+', 'Var', (16, 21))	('disease-free survival rates', 'CPA', (86, 113))	('Stromal loss', 'Disease', 'MESH:D003317', (0, 12))
17816	32435886	In fact, CD34+ fibroblasts are generally absent in the stroma of most carcinomas as has been demonstrated for a variety of carcinoma entities.	('carcinomas', 'Disease', 'MESH:D009369', (70, 80))	('absent', 'NegReg', (41, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('CD34+', 'Var', (9, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('carcinoma entities', 'Disease', (123, 141))	('carcinomas', 'Disease', (70, 80))	('carcinoma entities', 'Disease', 'MESH:D009369', (123, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
17831	32435886	Consistent with our previously published data, semiquantitative assessment of the proportion of CD34+ fibroblasts in the tumor stroma of ILC revealed their partial preservation, with pronounced intertumoral heterogeneity (Table 2).	('CD34+', 'Var', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumoral', 'Disease', (199, 206))	('tumoral', 'Disease', 'MESH:D009369', (199, 206))	('tumor stroma', 'Disease', 'MESH:D009369', (121, 133))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor stroma', 'Disease', (121, 133))
17835	32435886	Stromal loss of CD34+ fibroblasts was significantly associated with lower overall overall survival (OS) rates (5-year overall survival CD34-, 73%; CD34+, 90%; p = 0.012), (Fig.	('Stromal loss', 'Disease', (0, 12))	('lower', 'NegReg', (68, 73))	('CD34+', 'Var', (16, 21))	('overall overall survival', 'MPA', (74, 98))	('Stromal loss', 'Disease', 'MESH:D003317', (0, 12))	('CD34-', 'Var', (135, 140))
17836	32435886	3a) and lower disease-free survival (DFS) rates (5-year disease-free survival CD34-, 75%; CD34+, 91%; p = 0.013) (Fig.	('CD34+', 'Var', (90, 95))	('DFS', 'Disease', (37, 40))	('DFS', 'Disease', 'None', (37, 40))	('lower disease-free', 'Disease', 'MESH:D008569', (8, 26))	('lower disease-free', 'Disease', (8, 26))
17840	32435886	This subset of ILC with loss of CD34+ fibroblasts resembles the stromal characteristics of IBC-NST, whereas 26% of the studied cases demonstrate a predominantly or uniformly positive tumor stroma for CD34+ fibroblasts, pointing to the existence of distinct stromal subtypes for ILC.	('CD34+', 'Var', (200, 205))	('positive', 'PosReg', (174, 182))	('ILC', 'Disease', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor stroma', 'Disease', 'MESH:D009369', (183, 195))	('tumor stroma', 'Disease', (183, 195))
17842	32435886	While there was no statistically significant difference for tumor size, pT stage, grading, or distant metastasis until December 2018 with respect to the proportion of CD34+ fibroblasts in the tumor stroma of ILC, the absence of CD34+ stromal fibroblasts strongly correlated with positive lymph node status and the respective pN stage, being in line with earlier findings of our group.	('tumor stroma', 'Disease', 'MESH:D009369', (192, 204))	('tumor', 'Disease', (192, 197))	('tumor stroma', 'Disease', (192, 204))	('CD34+', 'Var', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('correlated', 'Reg', (263, 273))	('absence', 'Var', (217, 224))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('positive lymph node status', 'Disease', (279, 305))
17863	32435886	Since ILC responds less well to chemotherapy than IBC-NST, targeted immunotherapy by antibodies against PD-L1 might constitute a promising treatment option for at least a subset of ILC.	('antibodies', 'Var', (85, 95))	('PD-L1', 'Gene', '29126', (104, 109))	('ILC', 'Disease', (6, 9))	('ILC', 'Disease', (181, 184))	('PD-L1', 'Gene', (104, 109))
17868	32435886	Stromal loss of CD34+ fibroblasts correlated with the presence of lymph node metastases and, in addition, with worse overall and disease-free survival.	('Stromal loss', 'Disease', (0, 12))	('CD34+', 'Var', (16, 21))	('metastases', 'Disease', (77, 87))	('Stromal loss', 'Disease', 'MESH:D003317', (0, 12))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('overall', 'CPA', (117, 124))
17909	28553141	Identified risk factors include 1) genetic events such as Klinefelter's syndrome or BRCA1/2 mutations, 2) endocrine risk factors with hyperestrogenism related to obesity, exogenous estrogens, and testicular dystrophic lesions, 3) environmental exposures to radiation, high temperatures or electromagnetic fields, and 4) sociodemographic factors such as increasing age, race, African or Ashkenazi Jewish ancestry, and excessive alcohol use.	('obesity', 'Disease', (162, 169))	('alcohol', 'Chemical', 'MESH:D000438', (427, 434))	('testicular dystrophic lesions', 'Disease', 'MESH:D013733', (196, 225))	('BRCA1/2', 'Gene', (84, 91))	('mutations', 'Var', (92, 101))	('testicular dystrophic lesions', 'Disease', (196, 225))	("Klinefelter's syndrome", 'Disease', 'MESH:D007713', (58, 80))	('obesity', 'Phenotype', 'HP:0001513', (162, 169))	('alcohol use', 'Phenotype', 'HP:0030955', (427, 438))	('BRCA1/2', 'Gene', '672;675', (84, 91))	("Klinefelter's syndrome", 'Disease', (58, 80))	('obesity', 'Disease', 'MESH:D009765', (162, 169))	('men', 'Species', '9606', (237, 240))
17910	28553141	Whereas invasive ductal carcinoma (IDC) is commonly associated with mutations of BRCA1 and PT53, BRCA2 mutations are common in both IDC and LBC, and CDH1 are more common in LBC.	('PT53', 'Gene', (91, 95))	('common', 'Reg', (117, 123))	('mutations', 'Var', (103, 112))	('BRCA1', 'Gene', (81, 86))	('BRCA2', 'Gene', (97, 102))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (8, 33))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (17, 33))	('IDC', 'Disease', (132, 135))	('associated', 'Reg', (52, 62))	('BRCA2', 'Gene', '675', (97, 102))	('CDH1', 'Gene', (149, 153))	('invasive ductal carcinoma', 'Disease', (8, 33))	('LBC', 'Disease', (140, 143))	('mutations', 'Var', (68, 77))	('CDH1', 'Gene', '999', (149, 153))	('BRCA1', 'Gene', '672', (81, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))
17916	28553141	The loss of e-cadherin staining may be due to hypermethylation of the CDH1 gene promoter, deletion, or mutation.	('deletion', 'Var', (90, 98))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('CDH1', 'Gene', (70, 74))	('CDH1', 'Gene', '999', (70, 74))	('hypermethylation', 'Var', (46, 62))	('e-cadherin', 'Gene', '999', (12, 22))	('e-cadherin', 'Gene', (12, 22))	('mutation', 'Var', (103, 111))	('loss', 'NegReg', (4, 8))
17918	28553141	Epigenetic silencing of the CDH1 promoter rather than downregulation has been proposed; however, insufficient evidence is available and further investigation is required to prove or disprove this hypothesis.	('CDH1', 'Gene', (28, 32))	('CDH1', 'Gene', '999', (28, 32))	('Epigenetic silencing', 'Var', (0, 20))	('insufficient', 'Disease', (97, 109))	('insufficient', 'Disease', 'MESH:D000309', (97, 109))
17919	28553141	Before its identification in LBC, loss of CDH1 was first implicated in the tumorigenesis of diffuse gastric cancer; these two cancers share histopathological characteristics including individual or small clusters of signet-ring cells in an infiltrative growth pattern.	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('loss', 'Var', (34, 38))	('CDH1', 'Gene', (42, 46))	('implicated', 'Reg', (57, 67))	('CDH1', 'Gene', '999', (42, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('growth pattern', 'biological_process', 'GO:0007150', ('253', '267'))	('growth pattern', 'biological_process', 'GO:0040007', ('253', '267'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('gastric cancer', 'Disease', (100, 114))	('tumor', 'Disease', (75, 80))
17920	28553141	It has also been recognized that patients with genetic CDH1 mutations are at an increased risk for both types of malignancies, and women who harbor this mutation have a similar risk of developing breast cancer as women with a BRCA1/2 mutation.	('CDH1', 'Gene', (55, 59))	('women', 'Species', '9606', (131, 136))	('patients', 'Species', '9606', (33, 41))	('BRCA1/2', 'Gene', '672;675', (226, 233))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('malignancies', 'Disease', (113, 125))	('breast cancer', 'Disease', (196, 209))	('CDH1', 'Gene', '999', (55, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('women', 'Species', '9606', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('mutations', 'Var', (60, 69))	('BRCA1/2', 'Gene', (226, 233))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))
17922	28553141	FOXA1, a transcriptional modulator of the endoplasmic reticulum, is elevated secondary to somatic mutations in 3%-4% of LBCs, whereas in IDC, mutations are not specific to this chromosomal region.	('FOXA1', 'Gene', (0, 5))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('42', '63'))	('FOXA1', 'Gene', '3169', (0, 5))	('mutations', 'Var', (98, 107))	('elevated', 'PosReg', (68, 76))	('chromosomal region', 'cellular_component', 'GO:0098687', ('177', '195'))
17923	28553141	By contrast, IDC more often shows mutation of GATA3, a mutually exclusive event to FOXA1 mutations.	('GATA3', 'Gene', (46, 51))	('FOXA1', 'Gene', (83, 88))	('mutation', 'Var', (34, 42))	('GATA3', 'Gene', '2625', (46, 51))	('mutations', 'Var', (89, 98))	('FOXA1', 'Gene', '3169', (83, 88))
17925	28553141	Shortened telomeres in breast cancers are most common in HER-2-positive carcinomas and triple-negative breast cancers and are independently predictive of poor clinical outcomes.	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('carcinomas', 'Disease', 'MESH:D002277', (72, 82))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('breast cancers', 'Disease', 'MESH:D001943', (103, 117))	('breast cancers', 'Disease', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Shortened telomeres', 'Phenotype', 'HP:0031413', (0, 19))	('breast cancers', 'Disease', 'MESH:D001943', (23, 37))	('breast cancers', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('breast cancers', 'Phenotype', 'HP:0003002', (103, 117))	('HER-2', 'Gene', '2064', (57, 62))	('carcinomas', 'Disease', (72, 82))	('HER-2', 'Gene', (57, 62))	('Shortened telomeres', 'Var', (0, 19))	('common', 'Reg', (47, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('breast cancers', 'Phenotype', 'HP:0003002', (23, 37))
17952	28553141	The growth pattern of these tumors, likely due to the poor cell-cell contacts associated with loss of e-cadherin, creates a diffuse tumor mass that precludes clinical and imaging detection.	('cadherin', 'molecular_function', 'GO:0008014', ('104', '112'))	('growth pattern', 'biological_process', 'GO:0040007', ('4', '18'))	('e-cadherin', 'Gene', '999', (102, 112))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('growth pattern', 'biological_process', 'GO:0007150', ('4', '18'))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('loss', 'Var', (94, 98))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('e-cadherin', 'Gene', (102, 112))
18003	32547631	It is reported that women with microscopic metastatic SLNs (pN0 [i+] and pN1 mi or metastatic foci <=2 mm) do not benefit from completion ALND in overall and disease-free survival and axillary recurrence rate.	('pN1 mi', 'Var', (73, 79))	('axillary recurrence', 'CPA', (184, 203))	('SLN', 'Gene', '6588', (54, 57))	('women', 'Species', '9606', (20, 25))	('SLN', 'Gene', (54, 57))	('pN0 [i+]', 'Var', (60, 68))
18031	32547631	For breast cancer patients with microscopic metastatic spread (i.e., pN0 [i+] and pN1 mi) in SLN(s), completion ALND is usually not performed.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('pN0 [i+]', 'Var', (69, 77))	('breast cancer', 'Disease', (4, 17))	('SLN', 'Gene', (93, 96))	('patients', 'Species', '9606', (18, 26))	('pN1 mi', 'Var', (82, 88))	('SLN', 'Gene', '6588', (93, 96))
18041	32547631	We demonstrated a 100% sensitivity for macrometastasis in intraoperative SLN cytological examination with TIC, and utilizing this cytological method, proposed a practically useful intraoperative two-step strategy to examine the SLNs in breast cancer patients.	('TIC', 'Phenotype', 'HP:0100033', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('breast cancer', 'Disease', (236, 249))	('macrometastasis', 'Var', (39, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('patients', 'Species', '9606', (250, 258))	('SLN', 'Gene', (73, 76))	('SLN', 'Gene', '6588', (73, 76))	('SLN', 'Gene', (228, 231))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('SLN', 'Gene', '6588', (228, 231))
18110	28864931	However, in a 2013 meta-analysis, FDG PET/CT had higher sensitivity and accuracy than BS for detection of bone metastases in patients with breast cancer.	('FDG', 'Chemical', 'MESH:D019788', (34, 37))	('bone metastases', 'Disease', (106, 121))	('FDG PET/CT', 'Var', (34, 44))	('bone metastases', 'Disease', 'MESH:D009362', (106, 121))	('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))	('higher', 'PosReg', (49, 55))	('patients', 'Species', '9606', (125, 133))
18156	23949920	In IDC, (epigenetic) inactivation of the AJ occurs at later stages, which is thought to induce an epithelial to mesenchymal transition (EMT) and subsequent tumor progression.	('EMT', 'biological_process', 'GO:0001837', ('136', '139'))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('epithelial to mesenchymal transition', 'CPA', (98, 134))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('98', '134'))	('epigenetic) inactivation', 'Var', (9, 33))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('induce', 'Reg', (88, 94))	('IDC', 'Disease', (3, 6))
18167	23949920	Upon disruption of the AJ complex, YAP can be activated by PP2A and subsequently translocate into the nucleus where it drives transcriptional activation.	('YAP', 'MPA', (35, 38))	('activated', 'PosReg', (46, 55))	('PP2A', 'Gene', '5524', (59, 63))	('disruption', 'Var', (5, 15))	('nucleus', 'cellular_component', 'GO:0005634', ('102', '109'))	('transcriptional activation', 'MPA', (126, 152))	('PP2A', 'Gene', (59, 63))
18203	23949920	Cells were grown to confluence, washed with PBS containing Mg2+ and Ca2+ (PBS+), scraped from the plate and suspended in buffer A (10 mM HEPES pH 7.9, 1.5 mM MgCL2, 10 mM KCl and freshly added 1 mM DTT, 0.5 mM PMSF, 5ug/ml leupeptin, 5ug/ml aprotinin).	('PBS', 'Chemical', 'MESH:D007854', (74, 77))	('MgCL2', 'Chemical', 'MESH:D015636', (158, 163))	('PBS', 'Chemical', 'MESH:D007854', (44, 47))	('HEPES', 'Chemical', 'MESH:D006531', (137, 142))	('DTT', 'Chemical', 'MESH:D004229', (198, 201))	('PBS+', 'Chemical', 'MESH:D007854', (74, 78))	('Mg2+', 'Var', (59, 63))	('leupeptin', 'Chemical', 'MESH:C032854', (223, 232))	('Ca2+', 'Var', (68, 72))	('Mg2+', 'Chemical', '-', (59, 63))	('KCl', 'Chemical', 'MESH:D011189', (171, 174))	('Ca2+', 'Chemical', 'MESH:D000069285', (68, 72))	('PMSF', 'Chemical', 'MESH:D010664', (210, 214))
18220	23949920	Secondary antibodies were incubated in 4 % BSA/PBS for 1 h (goat anti-rabbit Alexa-555, cat A21428, goat anti-mouse highly cross-adsorbed Alexa-488 and Alexa-568, cat A11029 and A11031, and goat anti-rabbit highly cross-adsorbed Alexa-488 and Alexa-568, cat A11036 and A11034, all from Invitrogen).	('rabbit', 'Species', '9986', (70, 76))	('A11031', 'Var', (178, 184))	('goat', 'Species', '9925', (190, 194))	('goat', 'Species', '9925', (60, 64))	('rabbit', 'Species', '9986', (200, 206))	('Alexa-568', 'Chemical', 'MESH:C000607448', (152, 161))	('cat A21428', 'Var', (88, 98))	('cat', 'molecular_function', 'GO:0004096', ('88', '91'))	('Alexa-555', 'Chemical', '-', (77, 86))	('PBS', 'Chemical', 'MESH:D007854', (47, 50))	('mouse', 'Species', '10090', (110, 115))	('Alexa-488', 'Chemical', '-', (138, 147))	('A11034', 'Var', (269, 275))	('Alexa-568', 'Chemical', 'MESH:C000607448', (243, 252))	('goat', 'Species', '9925', (100, 104))	('cat', 'molecular_function', 'GO:0004096', ('163', '166'))	('Alexa-488', 'Chemical', '-', (229, 238))	('cat', 'molecular_function', 'GO:0004096', ('254', '257'))
18234	23949920	We substantiated the correlation between E-cadherin loss and nuclear YAP localization in ILC by analyzing YAP expression in a set of E-cadherin expressing and E-cadherin mutant (lobular) breast cancer cell lines.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('cadherin', 'molecular_function', 'GO:0008014', ('161', '169'))	('localization', 'biological_process', 'GO:0051179', ('73', '85'))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cadherin', 'molecular_function', 'GO:0008014', ('135', '143'))	('mutant', 'Var', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Disease', (187, 200))
18237	23949920	In these mice, inactivation of E-cadherin is causal to the formation of invasive and metastatic tumors that mimic human ILC.	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('E-cadherin', 'Protein', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('causal', 'Reg', (45, 51))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('human', 'Species', '9606', (114, 119))	('mice', 'Species', '10090', (9, 13))	('cadherin', 'molecular_function', 'GO:0008014', ('33', '41'))	('inactivation', 'Var', (15, 27))
18240	23949920	In order to corroborate our finding that nuclear YAP expression is a hallmark of E-cadherin mutant breast cancer, we performed nuclear fractionation of human and mouse cell lines, which were compared using western blot analyses.	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('mouse', 'Species', '10090', (162, 167))	('rat', 'Species', '10116', (19, 22))	('human', 'Species', '9606', (152, 157))	('mutant', 'Var', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
18256	23949920	We have previously demonstrated that loss of junctional integrity through mutational inactivation of E-cadherin leads to a p120-catenin and MRIP-dependent activation of the Rho-Rock pathway in metastatic ILC.	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('p120-catenin', 'Gene', (123, 135))	('Rho-Rock pathway', 'Pathway', (173, 189))	('MRIP', 'Gene', (140, 144))	('E-cadherin', 'Protein', (101, 111))	('mutational inactivation', 'Var', (74, 97))	('rat', 'Species', '10116', (26, 29))	('metastatic ILC', 'Disease', (193, 207))	('MRIP', 'Gene', '23164', (140, 144))	('p120-catenin', 'Gene', '1500', (123, 135))	('activation', 'PosReg', (155, 165))
18262	23949920	These findings were validated in human and mouse E-cadherin mutant cell lines, which showed an increase in nuclear YAP localization compared to E-cadherin expressing cell lines.	('increase', 'PosReg', (95, 103))	('nuclear YAP localization', 'MPA', (107, 131))	('cadherin', 'molecular_function', 'GO:0008014', ('146', '154'))	('human', 'Species', '9606', (33, 38))	('localization', 'biological_process', 'GO:0051179', ('119', '131'))	('cadherin', 'molecular_function', 'GO:0008014', ('51', '59'))	('mutant', 'Var', (60, 66))	('mouse', 'Species', '10090', (43, 48))
18263	23949920	We hypothesize that upon loss of E-cadherin and subsequent inactivation of the AJ complex, YAP translocates to the nucleus where it may induce a transcriptional program favoring ILC tumor development and progression.	('transcriptional', 'MPA', (145, 160))	('tumor', 'Disease', (182, 187))	('inactivation', 'Var', (59, 71))	('E-cadherin', 'Protein', (33, 43))	('nucleus', 'cellular_component', 'GO:0005634', ('115', '122'))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('favoring', 'PosReg', (169, 177))	('ILC', 'Disease', (178, 181))	('cadherin', 'molecular_function', 'GO:0008014', ('35', '43'))	('loss', 'NegReg', (25, 29))	('AJ complex', 'Gene', (79, 89))	('progression', 'CPA', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('induce', 'Reg', (136, 142))
18264	23949920	In conclusion, our data suggest that YAP translocation to the nucleus is a consequence of early mutational inactivation of E-cadherin and subsequent p120-mediated activation of Rock-dependent actin polymerization.	('Rock-dependent actin polymerization', 'MPA', (177, 212))	('p120', 'Gene', (149, 153))	('mutational', 'Var', (96, 106))	('activation', 'PosReg', (163, 173))	('YAP', 'Disease', (37, 40))	('nucleus', 'cellular_component', 'GO:0005634', ('62', '69'))	('inactivation', 'NegReg', (107, 119))	('actin polymerization', 'biological_process', 'GO:0030041', ('192', '212'))	('cadherin', 'molecular_function', 'GO:0008014', ('125', '133'))	('E-cadherin', 'Protein', (123, 133))	('p120', 'Gene', '1500', (149, 153))
18268	24996432	NKX3.1 is also shown to inhibit estrogen receptor (ER) signalling in breast carcinoma models.	('breast carcinoma', 'Phenotype', 'HP:0003002', (69, 85))	('signalling', 'biological_process', 'GO:0023052', ('55', '65'))	('NKX3.1', 'Var', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('ER', 'Gene', '2099', (51, 53))	('breast carcinoma', 'Disease', (69, 85))	('breast carcinoma', 'Disease', 'MESH:D001943', (69, 85))	('estrogen receptor', 'Gene', (32, 49))	('estrogen receptor', 'Gene', '2099', (32, 49))	('inhibit', 'NegReg', (24, 31))
18281	24996432	Interestingly, NKX3.1 was shown to inhibit ER signalling in murine models of breast cancer.	('breast cancer', 'Disease', (77, 90))	('ER', 'Gene', '2099', (43, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('murine', 'Species', '10090', (60, 66))	('signalling', 'biological_process', 'GO:0023052', ('46', '56'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('NKX3.1', 'Var', (15, 21))	('inhibit', 'NegReg', (35, 42))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
18283	24996432	AR expression in breast carcinomas is associated with better clinical outcomes independent of ER status; decreased AR expression is seen in end-stage breast carcinoma metastases; and loss of AR labelling predicts earlier recurrences in triple negative breast carcinomas.	('breast carcinomas', 'Phenotype', 'HP:0003002', (252, 269))	('breast carcinoma metastases', 'Disease', (150, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))	('decreased', 'NegReg', (105, 114))	('breast carcinoma metastases', 'Disease', 'MESH:D009362', (150, 177))	('breast carcinomas', 'Disease', 'MESH:D001943', (17, 34))	('AR', 'Gene', '367', (115, 117))	('breast carcinomas', 'Disease', (17, 34))	('ER', 'Gene', '2099', (94, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('breast carcinoma', 'Phenotype', 'HP:0003002', (17, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('AR', 'Gene', '367', (191, 193))	('breast carcinoma', 'Phenotype', 'HP:0003002', (150, 166))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('breast carcinomas', 'Phenotype', 'HP:0003002', (17, 34))	('AR', 'Gene', '367', (0, 2))	('breast carcinomas', 'Disease', 'MESH:D001943', (252, 269))	('breast carcinomas', 'Disease', (252, 269))	('loss', 'Var', (183, 187))	('breast carcinoma', 'Phenotype', 'HP:0003002', (252, 268))
18314	24996432	AR-positive carcinomas also have a better overall clinical outcome, and loss of AR expression is associated with breast cancer metastases and the development of early recurrence.	('AR', 'Gene', '367', (80, 82))	('breast cancer metastases', 'Disease', 'MESH:D009362', (113, 137))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('AR', 'Gene', '367', (0, 2))	('loss', 'Var', (72, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (12, 22))	('carcinomas', 'Disease', 'MESH:D002277', (12, 22))	('expression', 'MPA', (83, 93))	('carcinomas', 'Disease', (12, 22))	('associated', 'Reg', (97, 107))	('breast cancer metastases', 'Disease', (113, 137))
18321	24996432	Interestingly, NKX3.1 is shown to inhibit ER signalling in murine breast carcinoma.	('ER', 'Gene', '2099', (42, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('breast carcinoma', 'Disease', 'MESH:D001943', (66, 82))	('breast carcinoma', 'Disease', (66, 82))	('NKX3.1', 'Var', (15, 21))	('inhibit', 'NegReg', (34, 41))	('murine', 'Species', '10090', (59, 65))	('signalling', 'biological_process', 'GO:0023052', ('45', '55'))	('breast carcinoma', 'Phenotype', 'HP:0003002', (66, 82))
18326	24996432	All but one case of NKX3.1 positivity were seen in luminal A carcinomas, which are an ER/PR-positive and Her2 negative subset of carcinomas with lower risk of local recurrence and overall better prognosis.	('A carcinomas', 'Disease', 'MESH:D002277', (59, 71))	('positivity', 'Var', (27, 37))	('Her2', 'Gene', (105, 109))	('ER', 'Gene', '2099', (86, 88))	('Her2', 'Gene', '2064', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('A carcinomas', 'Disease', (59, 71))	('PR', 'Gene', '5241', (89, 91))	('carcinomas', 'Disease', 'MESH:D002277', (61, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('carcinomas', 'Disease', (61, 71))	('NKX3.1', 'Gene', (20, 26))	('carcinomas', 'Disease', (129, 139))	('carcinomas', 'Disease', 'MESH:D002277', (129, 139))
18330	24996432	Finally, in the work-up of a metastatic carcinoma of unknown primary, the presence of NKX3.1 labelling in prostate and breast carcinomas is unlikely to cause diagnostic confusion with exception of a rare circumstance of a male patient with lobular breast carcinoma and prostate carcinoma.	('prostate carcinoma', 'Phenotype', 'HP:0012125', (269, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinoma', 'Disease', (255, 264))	('carcinoma', 'Disease', (278, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('carcinoma', 'Disease', (40, 49))	('confusion', 'Phenotype', 'HP:0001289', (169, 178))	('carcinoma', 'Disease', (126, 135))	('breast carcinoma', 'Phenotype', 'HP:0003002', (248, 264))	('breast carcinomas', 'Disease', 'MESH:D001943', (119, 136))	('breast carcinomas', 'Disease', (119, 136))	('breast carcinoma', 'Phenotype', 'HP:0003002', (119, 135))	('carcinoma', 'Disease', 'MESH:D002277', (278, 287))	('lobular breast carcinoma and prostate carcinoma', 'Disease', 'MESH:D018275', (240, 287))	('carcinoma', 'Disease', 'MESH:D002277', (255, 264))	('NKX3.1', 'Gene', (86, 92))	('carcinoma', 'Disease', 'MESH:D002277', (40, 49))	('presence', 'Var', (74, 82))	('breast carcinomas', 'Phenotype', 'HP:0003002', (119, 136))	('patient', 'Species', '9606', (227, 234))	('carcinoma', 'Disease', 'MESH:D002277', (126, 135))
18344	21509772	Nulliparity was associated with increased risk for all breast cancer subtypes, compared to women with AFB <20 years, but the association was stronger for lobular (OR 1.72, 95% CI 1.34-2.20) than for ductal (OR 1.19, 95% CI 1.08-1.31) subtypes (P=0.004).	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('AFB', 'Chemical', '-', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('women', 'Species', '9606', (91, 96))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('Nulliparity', 'Var', (0, 11))
18379	21509772	Adult BMI was categorized in three groups as average weight (<25 kg/m2), overweight (25-29.9 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (104, 109))	('25-29.9 kg/m2', 'Var', (85, 98))	('obese', 'Disease', (104, 109))	('overweight', 'Phenotype', 'HP:0025502', (73, 83))
18393	21509772	Nulliparity was associated with increased risks for ductal and lobular breast cancer when compared to women with a first birth < 20 years of age, and the association was stronger for lobular (OR, 1.72; 95% CI, 1.34-2.20) than for ductal (OR, 1.19; 95% CI, 1.08-1.31) histology (Table 2).	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('ductal', 'Disease', (52, 58))	('women', 'Species', '9606', (102, 107))	('lobular breast cancer', 'Disease', (63, 84))	('lobular breast cancer', 'Disease', 'MESH:D013274', (63, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Nulliparity', 'Var', (0, 11))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (63, 84))
18402	21509772	Similarly, in nulliparous women, high BMI (>=25 kg/m2) was associated with a statistically significantly elevated lobular breast cancer risk, but not for ductal or mixed ductal-lobular breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('ductal-lobular breast cancer', 'Disease', 'MESH:D013274', (170, 198))	('elevated lobular breast cancer', 'Disease', (105, 135))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (114, 135))	('women', 'Species', '9606', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (177, 198))	('high BMI', 'Var', (33, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('-lobular breast cancer', 'Phenotype', 'HP:0006625', (176, 198))	('elevated lobular breast cancer', 'Disease', 'MESH:D013274', (105, 135))	('ductal-lobular breast cancer', 'Disease', (170, 198))
18436	21509772	Regardless of histological subtype, a higher incidence of breast cancer with later age at first birth or nulliparity is a consistent finding in epidemiologic studies, though the mechanism is unclear.	('nulliparity', 'Var', (105, 116))	('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))
18516	30619463	Conclusion: Our results demonstrate that there is a significant difference in distribution of 21-gene RS in T1-T2N0 estrogen receptor-positive breast cancer with different histologic subtypes.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('estrogen receptor', 'Gene', '2099', (116, 133))	('T1-T2N0', 'Var', (108, 115))	('RS', 'Chemical', '-', (102, 104))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('estrogen receptor', 'Gene', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
18523	30619463	A RS is then used to assign patients into one of three prognostic groups including low-risk (RS < 18), intermediate-risk (RS 18-30) or high-risk (RS > 30).	('RS', 'Chemical', '-', (122, 124))	('RS', 'Chemical', '-', (93, 95))	('RS', 'Var', (146, 148))	('patients', 'Species', '9606', (28, 36))	('RS', 'Chemical', '-', (2, 4))	('RS 18-30', 'Var', (122, 130))	('RS', 'Chemical', '-', (146, 148))	('RS <', 'Var', (93, 97))
18531	30619463	We extracted the following variables from the SEER dataset: age, race/ethnicity, tumor grade, histologic subtypes, tumor stage, progesterone receptor (PR) status, surgical procedure, radiotherapy, chemotherapy and 21-gene RS.	('RS', 'Chemical', '-', (222, 224))	('ER', 'Gene', '2099', (48, 50))	('progesterone receptor', 'Gene', (128, 149))	('progesterone receptor', 'Gene', '5241', (128, 149))	('21-gene RS', 'Var', (214, 224))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('PR', 'Gene', '5241', (151, 153))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
18548	30619463	However, patients with tubular carcinoma and intermediate RS had a significantly lower percentage of chemotherapy receipt than other histologic subtypes (21.6% vs. 26.2-33.4%; P < 0.001) (Figure 2).	('patients', 'Species', '9606', (9, 17))	('lower', 'NegReg', (81, 86))	('chemotherapy', 'CPA', (101, 113))	('intermediate RS', 'Var', (45, 60))	('RS', 'Chemical', '-', (58, 60))	('tubular carcinoma', 'Disease', 'MESH:D000230', (23, 40))	('tubular carcinoma', 'Disease', (23, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
18558	30619463	Most previous studies involving the 21-gene RS were from invasive breast carcinoma NOS or other subtypes dominated by invasive ductal carcinoma.	('RS', 'Chemical', '-', (44, 46))	('21-gene RS', 'Var', (36, 46))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (118, 143))	('invasive breast carcinoma NOS', 'Disease', 'MESH:D018270', (57, 86))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (127, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('invasive ductal carcinoma', 'Disease', (118, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('invasive breast carcinoma NOS', 'Disease', (57, 86))	('breast carcinoma', 'Phenotype', 'HP:0003002', (66, 82))
18562	30619463	Two recent studies with large cohorts have assessed the distribution of 21-gene RS in invasive breast carcinoma.	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (86, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('RS', 'Chemical', '-', (80, 82))	('invasive breast carcinoma', 'Disease', (86, 111))	('21-gene RS', 'Var', (72, 82))
18578	30619463	We also found the 21-gene RS may impact the decision-making of chemotherapy in patients with special histologic subtypes.	('RS', 'Chemical', '-', (26, 28))	('decision-making of chemotherapy', 'CPA', (44, 75))	('patients', 'Species', '9606', (79, 87))	('21-gene RS', 'Var', (18, 28))	('impact', 'Reg', (33, 39))
18651	19000869	21 patients with nonpalpable, pathology-confirmed BI-RADS 4 or 5 breast lesions (10 benign, 11 malignant) detected by mammography were studied.	('breast lesions', 'Disease', (65, 79))	('patients', 'Species', '9606', (3, 11))	('BI-RADS', 'Var', (50, 57))
18668	19000869	showed that strain and strain-rate images were most effective when diagnosing BI-RADS (Breast Imaging-Reporting and Data System) 3 lesions with lipomatous involution and somewhat less effective with BI-RADS 4 or 5 lesions.	('BI-RADS', 'Var', (78, 85))	('lipomatous involution', 'Disease', (144, 165))	('lipomatous involution', 'Disease', 'MESH:D008080', (144, 165))
18735	19000869	The greatest advantage of this novel imaging method is that the viscoelastic parameters obtained can be used to clearly differentiate between malignant and benign lesions for patients with nonpalpable, early stage, BI-RADS 4 and 5 breast tumors.	('breast tumors', 'Disease', (231, 244))	('breast tumors', 'Disease', 'MESH:D001943', (231, 244))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('patients', 'Species', '9606', (175, 183))	('BI-RADS', 'Var', (215, 222))	('breast tumors', 'Phenotype', 'HP:0100013', (231, 244))
18896	32709042	For ILC, the progression incidence was 8.2 times higher during episodes with CTCs >=5 compared with episodes with CTCs <5 (95% CI 2.5-26, p < 0.001).	('CTCs >=5', 'Var', (77, 85))	('a', 'Gene', '351', (90, 91))	('progression', 'MPA', (13, 24))	('ILC', 'Disease', (4, 7))	('a', 'Gene', '351', (36, 37))	('higher', 'PosReg', (49, 55))
18902	32709042	With higher cut-offs (>=100, >=200, and >=400 U/mL), stronger evidence for negative prognostic effects was observed for OS but not for PFS in both ILC and NST cases, with the most pronounced effect evident in NST cases (Supplementary Figure S7).	('S7', 'Gene', '6264', (241, 243))	('>=100', 'Var', (22, 27))	('NST', 'Disease', (209, 212))	('a', 'Gene', '351', (151, 152))	('>=200', 'Var', (29, 34))	('a', 'Gene', '351', (230, 231))	('a', 'Gene', '351', (104, 105))	('a', 'Gene', '351', (214, 215))	('>=400 U/mL', 'Var', (40, 50))	('a', 'Gene', '351', (36, 37))	('a', 'Gene', '351', (78, 79))	('a', 'Gene', '351', (160, 161))
18929	32709042	A mutation or dysfunction in the CDH1 gene is common (55%-100%), resulting in either a decreased expression or total loss of important cell-cell adhesion proteins included in the cadherin-catenin complex (E-cadherin and alpha-, beta-, and gamma-catenins).	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('135', '153'))	('loss', 'NegReg', (117, 121))	('E-cadherin', 'Gene', (205, 215))	('E-cadherin', 'Gene', '999', (205, 215))	('dysfunction', 'Var', (14, 25))	('a', 'Gene', '351', (224, 225))	('a', 'Gene', '351', (216, 217))	('a', 'Gene', '351', (246, 247))	('cadherin', 'molecular_function', 'GO:0008014', ('179', '187'))	('a', 'Gene', '351', (189, 190))	('a', 'Gene', '351', (180, 181))	('cadherin', 'Gene', (179, 187))	('cadherin', 'Gene', '999', (179, 187))	('a', 'Gene', '351', (92, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('207', '215'))	('a', 'Gene', '351', (85, 86))	('expression', 'MPA', (97, 107))	('A', 'Gene', '351', (0, 1))	('a', 'Gene', '351', (220, 221))	('a', 'Gene', '351', (131, 132))	('catenin complex', 'cellular_component', 'GO:0016342', ('188', '203'))	('a', 'Gene', '351', (5, 6))	('a', 'Gene', '351', (243, 244))	('a', 'Gene', '351', (235, 236))	('CDH1', 'Gene', '999', (33, 37))	('cadherin', 'Gene', '999', (207, 215))	('a', 'Gene', '351', (240, 241))	('cadherin', 'Gene', (207, 215))	('alpha-, beta-', 'Gene', '351', (220, 233))	('a', 'Gene', '351', (145, 146))	('CDH1', 'Gene', (33, 37))	('a', 'Gene', '351', (208, 209))	('a', 'Gene', '351', (114, 115))	('a', 'Gene', '351', (231, 232))
18995	32709042	; writing:original draft preparation, U.N.; writing:review and editing, U.N., P.-O.B., K.A., C.F., C.L.T.J., and M.F.	('a', 'Gene', '351', (59, 60))	('A', 'Gene', '351', (89, 90))	('P.-O.B.', 'Var', (78, 85))	('C.F.', 'Var', (93, 97))	('a', 'Gene', '351', (21, 22))	('a', 'Gene', '351', (31, 32))	('a', 'Gene', '351', (29, 30))	('C.L.T.J.', 'Var', (99, 107))	('a', 'Gene', '351', (16, 17))	('a', 'Gene', '351', (109, 110))
19007	30607169	Histologic findings indicated lobular breast carcinoma (positive GATA3, loss of E-cadherin expression) metastatic to the thyroid with a luminal profile.	('E-cadherin', 'Gene', (80, 90))	('metastatic', 'CPA', (103, 113))	('GATA3', 'Gene', '2625', (65, 70))	('E-cadherin', 'Gene', '999', (80, 90))	('loss', 'NegReg', (72, 76))	('breast carcinoma', 'Phenotype', 'HP:0003002', (38, 54))	('lobular breast carcinoma', 'Disease', (30, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('82', '90'))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (30, 54))	('positive', 'Var', (56, 64))	('GATA3', 'Gene', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
19019	30607169	Her family history included breast cancer in her sister and a daughter with the p53 mutation.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('p53', 'Gene', (80, 83))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('p53', 'Gene', '7157', (80, 83))	('mutation', 'Var', (84, 92))
19064	28871133	Kaplan-Meier plots showed that the breast cancer-specific survival (BCSS) of IDC-L patients was significantly better than IDC patients (P < 0.001) and tended to be better than ILC patients (P = 0.166).	('IDC-L', 'Var', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('better', 'PosReg', (110, 116))	('breast cancer', 'Disease', (35, 48))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (180, 188))
19079	28871133	Compared with IDC, IDC-L patients had strikingly lower grade tumors (Grade 3 & UD: 23.4% vs 41.5%, P < 0.001, R = 0.110) and higher proportion of cases with a positive ER and PR status (93.0% vs 73.9%, P < 0.001, R = 0.133; 80.9% vs 64.0%, P < 0.001, R = 0.106, respectively).	('PR', 'Gene', '5241', (175, 177))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ER', 'Gene', '2099', (168, 170))	('and', 'Protein', (171, 174))	('patients', 'Species', '9606', (25, 33))	('positive', 'Var', (159, 167))	('lower', 'NegReg', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
19084	28871133	IDC-L was also found to be a risk factor for a low BCSS rate compared with IDC in both the ER-positive (HR = 1.06, 95% CI: 1.01-1.11, P = 0.02) and ER-negative (HR = 1.32, 95% CI: 1.19-1.47, P < 0.001) subgroups.	('IDC-L', 'Var', (0, 5))	('BCSS rate', 'CPA', (51, 60))	('low', 'NegReg', (47, 50))	('ER', 'Gene', '2099', (148, 150))	('ER', 'Gene', '2099', (91, 93))
19095	28871133	Furthermore, we found that when stratified according to their ER status, patients with IDC-L had a worse BCSS than those with IDC, which was observed for patients in both the ER-positive and ER-negative subgroups.	('ER', 'Gene', '2099', (175, 177))	('ER', 'Gene', '2099', (62, 64))	('patients', 'Species', '9606', (154, 162))	('BCSS', 'Disease', (105, 109))	('IDC-L', 'Var', (87, 92))	('ER', 'Gene', '2099', (191, 193))	('patients', 'Species', '9606', (73, 81))
19185	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))
19186	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))
19189	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))
19196	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))
19207	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))
19212	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))
19214	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))
19221	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))	('false', 'biological_process', 'GO:0071878', ('123', '128'))	('false', 'biological_process', 'GO:0071878', ('75', '80'))	('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))	('false', 'biological_process', 'GO:0071877', ('123', '128'))	('IDC', 'Gene', '4000', (191, 194))	('false', 'biological_process', 'GO:0071877', ('75', '80'))	('IDC', 'Gene', (191, 194))
19274	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 suppressor', 'biological_process', 'GO:0051726', ('67', '83'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('alterations', 'Reg', (154, 165))	('tumor', 'Disease', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
19303	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))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('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))	('DNA methylation', 'biological_process', 'GO:0006306', ('28', '43'))	('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))
19321	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))
19332	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))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('12', '32'))
19333	31300453	This raises a concern for cancer detection tests since the presence of hypermethylation in normal tissue can be a source of false positives.	('false', 'biological_process', 'GO:0071878', ('124', '129'))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('false', 'biological_process', 'GO:0071877', ('124', '129'))	('hypermethylation', 'Var', (71, 87))
19356	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))	('APC', 'cellular_component', 'GO:0005680', ('33', '36'))	('CCND2', 'Gene', (38, 43))	('APC', 'cellular_component', 'GO:0005680', ('110', '113'))	('CCND2', 'Gene', '894', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('HER2', 'Gene', '2064', (163, 167))	('AKR1B1', 'Gene', (115, 121))	('RASGRF2', 'Gene', '5924', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('ZNF671', 'Gene', (197, 203))
19357	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))	('DNA methylation', 'biological_process', 'GO:0006306', ('67', '82'))	('breast cancers', 'Disease', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('DNA methylation', 'biological_process', 'GO:0006306', ('22', '37'))	('aberrant', 'Var', (58, 66))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))
19358	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 suppressor', 'biological_process', 'GO:0051726', ('90', '106'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('90', '106'))	('methylation', 'biological_process', 'GO:0032259', ('66', '77'))	('methylation', 'Var', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
19359	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', 'biological_process', 'GO:0032259', ('10', '21'))	('methylation alterations', 'Var', (10, 33))
19381	30423024	Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture-based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in up to 395 cancer-related genes.	('short variant', 'Var', (250, 263))	('ILC', 'Gene', (50, 53))	('ILC', 'Gene', (139, 142))	('ILC', 'Gene', '20301', (50, 53))	('ILC', 'Gene', '20301', (139, 142))	('ER', 'Gene', '2099', (151, 153))	('copy number variants', 'Var', (272, 292))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('estrogen receptor', 'Gene', (62, 79))	('indel', 'Var', (265, 270))	('estrogen receptor', 'Gene', '2099', (62, 79))	('cancer', 'Disease', (326, 332))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('ER', 'Gene', '2099', (81, 83))	('rearrangements', 'Var', (298, 312))
19382	30423024	Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared with breast specimens, NF1 alterations are enriched only in ILC metastases (mILC).	('IDC', 'Disease', (72, 75))	('NF1', 'Gene', '4763', (108, 111))	('mILC', 'Gene', '20301', (161, 165))	('ILC', 'Gene', (64, 67))	('ILC', 'Gene', '20301', (145, 148))	('ILC', 'Gene', '20301', (162, 165))	('NF1', 'Gene', (108, 111))	('mILC', 'Gene', (161, 165))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('alterations', 'Var', (112, 123))	('ILC', 'Gene', '20301', (64, 67))	('metastases', 'Disease', (149, 159))	('ESR1', 'Gene', '2099', (8, 12))	('metastases', 'Disease', 'MESH:D009362', (45, 55))	('ESR1', 'Gene', (8, 12))	('ILC', 'Gene', (145, 148))	('alterations', 'Var', (13, 24))	('metastases', 'Disease', (45, 55))	('ILC', 'Gene', (162, 165))
19383	30423024	NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations [odds ratio = 0.24, P < 0.027] and are frequently polyclonal in ctDNA assays.	('alterations', 'Var', (4, 15))	('mutations', 'Var', (110, 119))	('ESR1', 'Gene', '2099', (105, 109))	('NF1', 'Gene', '4763', (0, 3))	('NF1', 'Gene', (0, 3))	('ESR1', 'Gene', (105, 109))
19384	30423024	Assessment of paired specimens shows that NF1 alterations arise in the setting of acquired resistance.	('alterations', 'Var', (46, 57))	('arise', 'Reg', (58, 63))	('acquired resistance', 'MPA', (82, 101))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', (42, 45))
19385	30423024	An in vitro model of CDH1 mutated ER-positive breast cancer demonstrates that NF1 knockdown confers a growth advantage in the presence of 4-hydroxy tamoxifen.	('CDH1', 'Gene', '999', (21, 25))	('knockdown', 'Var', (82, 91))	('4-hydroxy tamoxifen', 'Chemical', '-', (138, 157))	('growth', 'MPA', (102, 108))	('NF1', 'Gene', (78, 81))	('CDH1', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutated', 'Var', (26, 33))	('NF1', 'Gene', '4763', (78, 81))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('breast cancer', 'Disease', (46, 59))	('ER', 'Gene', '2099', (34, 36))
19388	30423024	This study identifies alteration of NF1 as enriched specifically in mILC.	('alteration', 'Var', (22, 32))	('NF1', 'Gene', (36, 39))	('mILC', 'Gene', '20301', (68, 72))	('NF1', 'Gene', '4763', (36, 39))	('mILC', 'Gene', (68, 72))
19389	30423024	Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance.	('NF1', 'Gene', '4763', (118, 121))	('ESR1', 'Gene', (24, 28))	('relapsed ctDNA', 'Disease', (59, 73))	('alterations', 'Var', (29, 40))	('loss', 'NegReg', (122, 126))	('ESR1', 'Gene', '2099', (24, 28))	('NF1', 'Gene', (118, 121))
19392	30423024	This study identifies an enrichment of NF1 loss of function alterations and high tumor mutational burden in metastatic, therapy-refractory ILC.	('ILC', 'Gene', (139, 142))	('loss of function', 'NegReg', (43, 59))	('ILC', 'Gene', '20301', (139, 142))	('NF1', 'Gene', (39, 42))	('NF1', 'Gene', '4763', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('alterations', 'Var', (60, 71))	('metastatic', 'Disease', (108, 118))	('tumor', 'Disease', (81, 86))
19398	30423024	Recent evidence suggests that the management of acquired resistance to endocrine therapy can be informed by specific genomic changes, as exemplified by the mutations of the ligand binding domains of ESR1 and mutations of the PI3K/mTOR pathway leading to bypass resistance.	('bypass resistance', 'Disease', (254, 271))	('ESR1', 'Gene', (199, 203))	('binding', 'molecular_function', 'GO:0005488', ('180', '187'))	('mutations', 'Var', (156, 165))	('mutations', 'Var', (208, 217))	('PI3K', 'molecular_function', 'GO:0016303', ('225', '229'))	('leading to', 'Reg', (243, 253))	('ligand', 'molecular_function', 'GO:0005488', ('173', '179'))	('ESR1', 'Gene', '2099', (199, 203))	('mTOR', 'Gene', (230, 234))	('mTOR', 'Gene', '2475', (230, 234))
19403	30423024	We assessed all classes of genomic alterations (GA) including short variant, copy number, and rearrangement alterations, as described previously.	('copy number', 'Var', (77, 88))	('GA', 'Chemical', '-', (48, 50))	('short variant', 'Var', (62, 75))	('rearrangement alterations', 'Var', (94, 119))
19411	30423024	Alterations in CDH1 were predominantly frameshift and nonsense point mutations (87%), but also included point mutations at splice sites (9%), missense mutations (2%), and homozygous deletions (1%).	('frameshift', 'Var', (39, 49))	('Alterations', 'Var', (0, 11))	('nonsense point mutations', 'Var', (54, 78))	('CDH1', 'Gene', (15, 19))	('CDH1', 'Gene', '999', (15, 19))	('missense mutations', 'Var', (142, 160))	('point mutations', 'Var', (104, 119))
19417	30423024	While the overall frequency of ERBB2 alterations was slightly higher in mIDCs versus mILCs (13.3% versus 8.3%), ERBB2 short variants were more common in mILCs [7.8% versus 2.6%, odds ratio (OR) = 3, P = 0.032].	('short variants', 'Var', (118, 132))	('ERBB2', 'Gene', '2064', (112, 117))	('ERBB2', 'Gene', (112, 117))	('mILC', 'Gene', '20301', (85, 89))	('mILC', 'Gene', (153, 157))	('alterations', 'Var', (37, 48))	('ERBB2', 'Gene', '2064', (31, 36))	('mIDCs', 'Disease', (72, 77))	('mILC', 'Gene', '20301', (153, 157))	('ERBB2', 'Gene', (31, 36))	('common', 'Reg', (143, 149))	('mILC', 'Gene', (85, 89))
19423	30423024	In examining the frequency of GA in breast disease and in distant metastases in each disease (ER-positive IDC and ILC) (Figure 3A; supplementary Tables S2 and S3, available at Annals of Oncology online), alterations of ESR1 were enriched in both mILC and mIDC, (Figure 3A).	('metastases', 'Disease', (66, 76))	('mILC', 'Gene', '20301', (246, 250))	('Oncology', 'Phenotype', 'HP:0002664', (186, 194))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('ESR1', 'Gene', (219, 223))	('alterations', 'Var', (204, 215))	('mIDC', 'Disease', (255, 259))	('breast disease', 'Disease', (36, 50))	('ILC', 'Gene', (247, 250))	('ILC', 'Gene', '20301', (247, 250))	('ER', 'Gene', '2099', (94, 96))	('breast disease', 'Disease', 'MESH:D001941', (36, 50))	('GA', 'Chemical', '-', (30, 32))	('ILC', 'Gene', (114, 117))	('mILC', 'Gene', (246, 250))	('ILC', 'Gene', '20301', (114, 117))	('ESR1', 'Gene', '2099', (219, 223))
19424	30423024	Additional alterations were amplifications (8.4%) and the E380Q alteration (10.8%).	('amplifications', 'Var', (28, 42))	('E380Q', 'Var', (58, 63))	('E380Q', 'Mutation', 'rs1057519827', (58, 63))
19426	30423024	For the NF1 mutated mILC specimens where zygosity was assessable, 11/14 (79%) of NF1 alterations were homozygous.	('mILC', 'Gene', (20, 24))	('NF1', 'Gene', (8, 11))	('NF1', 'Gene', '4763', (8, 11))	('NF1', 'Gene', (81, 84))	('mutated', 'Var', (12, 19))	('mILC', 'Gene', '20301', (20, 24))	('NF1', 'Gene', '4763', (81, 84))	('alterations', 'Var', (85, 96))
19429	30423024	Using CDH1 alterations as a proxy to identify ILC cases, alterations of NF1 were specifically enriched in CDH1-mutant, recurrent disease (Figure 3B;P = 0.009 CDH1-mut recurrent versus CDH1-mut primary).	('NF1', 'Gene', (72, 75))	('CDH1', 'Gene', '999', (106, 110))	('NF1', 'Gene', '4763', (72, 75))	('recurrent disease', 'Disease', (119, 136))	('CDH1', 'Gene', '999', (158, 162))	('CDH1', 'Gene', '999', (6, 10))	('CDH1', 'Gene', (184, 188))	('alterations', 'Var', (57, 68))	('CDH1', 'Gene', (6, 10))	('CDH1', 'Gene', '999', (184, 188))	('CDH1', 'Gene', (106, 110))	('ILC', 'Gene', '20301', (46, 49))	('CDH1', 'Gene', (158, 162))	('ILC', 'Gene', (46, 49))
19430	30423024	Thirty-three of 569 ILCs and IDCs assayed with a liquid ctDNA assay (FoundationACT; FACT) harbored NF1 alterations; of these, 5/33 (15%) had strong polyclonality as designated by three or more NF1 alterations.	('NF1', 'Gene', '4763', (193, 196))	('NF1', 'Gene', (193, 196))	('alterations', 'Var', (103, 114))	('polyclonality', 'MPA', (148, 161))	('NF1', 'Gene', (99, 102))	('ILC', 'Gene', (20, 23))	('ILC', 'Gene', '20301', (20, 23))	('NF1', 'Gene', '4763', (99, 102))
19432	30423024	In contrast, of 34 samples with a CDH1 alteration, all 34 harbored only one CDH1 variant.	('alteration', 'Var', (39, 49))	('CDH1', 'Gene', '999', (34, 38))	('CDH1', 'Gene', (76, 80))	('harbored', 'Reg', (58, 66))	('CDH1', 'Gene', '999', (76, 80))	('CDH1', 'Gene', (34, 38))
19433	30423024	Limiting this analysis only to lobular carcinomas, 3/4 (75%) of NF1 altered cases exhibited polyclonality.	('lobular carcinomas', 'Disease', (31, 49))	('polyclonality', 'Var', (92, 105))	('lobular carcinomas', 'Disease', 'MESH:D018275', (31, 49))	('NF1', 'Gene', (64, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('exhibited', 'Reg', (82, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('NF1', 'Gene', '4763', (64, 67))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (31, 48))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (31, 49))	('altered', 'Reg', (68, 75))
19435	30423024	Two of these patients had multiple genomic profiling assays carried out demonstrating emergence of NF1 alteration after hormonal therapy treatment and resistance (Figure 3C).	('NF1', 'Gene', '4763', (99, 102))	('patients', 'Species', '9606', (13, 21))	('alteration', 'Var', (103, 113))	('NF1', 'Gene', (99, 102))
19437	30423024	In all ER-positive breast cancer, NF1 GA's significantly co-occur with CDH1 inactivation (OR = 2.2, P = 0.049).	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('NF1', 'Gene', (34, 37))	('CDH1', 'Gene', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('inactivation', 'Var', (76, 88))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('GA', 'Chemical', '-', (38, 40))	('NF1', 'Gene', '4763', (34, 37))	('breast cancer', 'Disease', (19, 32))	('ER', 'Gene', '2099', (7, 9))	('CDH1', 'Gene', '999', (71, 75))
19443	30423024	To assess whether NF1 alterations may potentiate endocrine therapy resistance when a CDH1 and AKT pathway alteration are already present, we reviewed six paired samples with a NF1 GA. Half (3/6, 50%) of cases had an acquired NF1 alteration appear in the second specimen, with the first older specimen being NF1 wildtype.	('AKT', 'Gene', '207', (94, 97))	('NF1', 'Gene', '4763', (176, 179))	('NF1', 'Gene', '4763', (307, 310))	('NF1', 'Gene', (176, 179))	('GA', 'Chemical', '-', (180, 182))	('CDH1', 'Gene', '999', (85, 89))	('NF1', 'Gene', (225, 228))	('potentiate', 'PosReg', (38, 48))	('alteration', 'Var', (229, 239))	('NF1', 'Gene', '4763', (18, 21))	('AKT', 'Gene', (94, 97))	('NF1', 'Gene', '4763', (225, 228))	('endocrine therapy resistance', 'MPA', (49, 77))	('alterations', 'Var', (22, 33))	('NF1', 'Gene', (18, 21))	('CDH1', 'Gene', (85, 89))	('NF1', 'Gene', (307, 310))
19445	30423024	Moreover, two of the three samples had an ESR1 alteration in the first sample - one with a subclonal ESR1 missense alteration (Y537C) and another with an ESR1 amplification.	('ESR1', 'Gene', '2099', (101, 105))	('ESR1', 'Gene', (154, 158))	('ESR1', 'Gene', (42, 46))	('Y537C', 'Var', (127, 132))	('Y537C', 'Mutation', 'p.Y537C', (127, 132))	('ESR1', 'Gene', (101, 105))	('ESR1', 'Gene', '2099', (154, 158))	('ESR1', 'Gene', '2099', (42, 46))
19446	30423024	In both cases, the recurrent sample lost the ESR1 alteration while gaining an NF1 loss of function alteration (supplementary Table S6, available at Annals of Oncology online).	('loss of function', 'NegReg', (82, 98))	('ESR1', 'Gene', (45, 49))	('alteration', 'Var', (99, 109))	('NF1', 'Gene', (78, 81))	('Oncology', 'Phenotype', 'HP:0002664', (158, 166))	('NF1', 'Gene', '4763', (78, 81))	('ESR1', 'Gene', '2099', (45, 49))	('lost', 'NegReg', (36, 40))
19448	30423024	In co-mixing experiments, NF1 knockdown enhanced the resistance of cancer cells to 4-hydroxytamoxifen (4-OHT) treatment only when E-Cadherin was reduced (Figure 3E;P < 0.00001).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('E-Cadherin', 'Gene', (130, 140))	('cancer', 'Disease', (67, 73))	('4-hydroxytamoxifen', 'Chemical', '-', (83, 101))	('resistance', 'MPA', (53, 63))	('Cadherin', 'molecular_function', 'GO:0008014', ('132', '140'))	('NF1', 'Gene', (26, 29))	('E-Cadherin', 'Gene', '999', (130, 140))	('NF1', 'Gene', '4763', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('knockdown', 'Var', (30, 39))	('4-OHT', 'Chemical', 'MESH:C032278', (103, 108))	('enhanced', 'PosReg', (40, 48))
19458	30423024	Mutational burden was significantly higher in recurrent versus primary tumors (P < 0.0001) and in CDH1-mut versus CDH1-wt tumors (P = 0.0002).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('higher', 'PosReg', (36, 42))	('CDH1', 'Gene', '999', (98, 102))	('Mutational', 'Var', (0, 10))	('CDH1', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('CDH1', 'Gene', '999', (114, 118))	('recurrent', 'Disease', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (71, 77))	('CDH1', 'Gene', (98, 102))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
19460	30423024	Examining the genomic context of point mutations in all mILC cases, we observed a significant enrichment of C>T and C>G alterations (P = 7e-08 and P = 5e-14, respectively) particularly in the canonical APOBEC TCA and TCT contexts (Figure 4D; P < 1e-100).	('TCA', 'Chemical', 'MESH:D014238', (209, 212))	('mILC', 'Gene', (56, 60))	('APOBEC', 'cellular_component', 'GO:0030895', ('202', '208'))	('C>T', 'Var', (108, 111))	('mILC', 'Gene', '20301', (56, 60))	('C>G alterations', 'Var', (116, 131))
19463	30423024	This study identified NF1 alteration as a mechanism of acquired endocrine therapy resistance that is unique to ILC.	('NF1', 'Gene', (22, 25))	('acquired endocrine therapy resistance', 'MPA', (55, 92))	('NF1', 'Gene', '4763', (22, 25))	('alteration', 'Var', (26, 36))	('ILC', 'Gene', (111, 114))	('ILC', 'Gene', '20301', (111, 114))
19465	30423024	The mutual exclusivity with ESR1 mutation and chronologic emergence concurrent with relapse on endocrine therapy converge to support the notion of NF1 loss as such a mechanism of acquired resistance.	('mutation', 'Var', (33, 41))	('ESR1', 'Gene', (28, 32))	('NF1', 'Gene', '4763', (147, 150))	('NF1', 'Gene', (147, 150))	('loss', 'NegReg', (151, 155))	('ESR1', 'Gene', '2099', (28, 32))
19466	30423024	The specificity of NF1 alterations in mILC relative to mIDC may result from cross talk or cooperation with other pathways.	('NF1', 'Gene', (19, 22))	('mILC', 'Gene', '20301', (38, 42))	('NF1', 'Gene', '4763', (19, 22))	('alterations', 'Var', (23, 34))	('mILC', 'Gene', (38, 42))
19468	30423024	An analysis of six paired samples showed that NF1 alterations appeared in the context of pre-existing CDH1 and AKT pathway alterations.	('CDH1', 'Gene', '999', (102, 106))	('AKT', 'Gene', '207', (111, 114))	('NF1', 'Gene', (46, 49))	('NF1', 'Gene', '4763', (46, 49))	('alterations', 'Var', (50, 61))	('AKT', 'Gene', (111, 114))	('pre', 'molecular_function', 'GO:0003904', ('89', '92'))	('CDH1', 'Gene', (102, 106))
19475	30423024	Preclinical models of ILC have identified FGFR1 amplifications as regulators of cell growth and mediators of endocrine therapy resistance.	('amplifications', 'Var', (48, 62))	('FGFR1', 'Gene', (42, 47))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('FGFR1', 'Gene', '2260', (42, 47))	('ILC', 'Gene', (22, 25))	('ILC', 'Gene', '20301', (22, 25))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
19477	30423024	These findings suggest that activation of RAS pathway signaling, be it through FGFR1 amplification or NF1 loss, may confer endocrine therapy resistance in lobular carcinomas.	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('lobular carcinomas', 'Disease', (155, 173))	('endocrine therapy resistance', 'MPA', (123, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('RAS pathway signaling', 'Pathway', (42, 63))	('NF1', 'Gene', (102, 105))	('FGFR1', 'Gene', (79, 84))	('NF1', 'Gene', '4763', (102, 105))	('amplification', 'Var', (85, 98))	('activation', 'PosReg', (28, 38))	('lobular carcinomas', 'Disease', 'MESH:D018275', (155, 173))	('FGFR1', 'Gene', '2260', (79, 84))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (155, 172))	('loss', 'NegReg', (106, 110))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (155, 173))
19479	30423024	However, we cannot exclude other possibilities for the higher frequency of NF1 alterations in metastases.	('metastases', 'Disease', (94, 104))	('alterations', 'Var', (79, 90))	('NF1', 'Gene', (75, 78))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('NF1', 'Gene', '4763', (75, 78))
19480	30423024	For instance, if NF1 alteration increased metastatic dissemination, a higher frequency of alterations may be observed in the metastases.	('metastases', 'Disease', (125, 135))	('metastatic dissemination', 'CPA', (42, 66))	('metastases', 'Disease', 'MESH:D009362', (125, 135))	('NF1', 'Gene', (17, 20))	('alteration', 'Var', (21, 31))	('NF1', 'Gene', '4763', (17, 20))	('increased', 'PosReg', (32, 41))
19494	29610289	Using perturbation screens in breast tumour cells with CRISPR-Cas9 engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1.	('breast tumour', 'Disease', (30, 43))	('mutations', 'Var', (83, 92))	('inhibition', 'NegReg', (162, 172))	('ROS1', 'Gene', (196, 200))	('PR', 'Gene', '5241', (59, 61))	('breast tumour', 'Phenotype', 'HP:0100013', (30, 43))	('Cas', 'cellular_component', 'GO:0005650', ('62', '65'))	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('ROS1', 'Gene', '6098', (196, 200))	('tyrosine', 'Chemical', 'MESH:D014443', (180, 188))	('deficiency', 'Disease', 'MESH:D007153', (147, 157))	('breast tumour', 'Disease', 'MESH:D001943', (30, 43))	('E-cadherin', 'Protein', (136, 146))	('CDH1', 'Gene', (78, 82))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('CDH1', 'Gene', '999', (78, 82))	('deficiency', 'Disease', (147, 157))
19496	29610289	ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120-catenin phosphorylation and localisation.	('induced', 'Reg', (16, 23))	('defect', 'NegReg', (126, 132))	('ROS1', 'Gene', (0, 4))	('localisation', 'biological_process', 'GO:0051179', ('194', '206'))	('mitotic abnormalities', 'Disease', (24, 45))	('inhibitors', 'Var', (5, 15))	('p120-catenin', 'Gene', (161, 173))	('ROS1', 'Gene', '6098', (0, 4))	('cadherin', 'molecular_function', 'GO:0008014', ('71', '79'))	('cytokinesis', 'CPA', (136, 147))	('mitotic abnormalities', 'Disease', 'MESH:C536987', (24, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('174', '189'))	('localisation', 'MPA', (194, 206))	('cytokinesis', 'biological_process', 'GO:0000910', ('136', '147'))	('multinucleation', 'CPA', (50, 65))	('p120-catenin', 'Gene', '1500', (161, 173))
19497	29610289	In vivo, ROS1 inhibitors produced profound anti-tumour effects in multiple models of E-cadherin defective breast cancer.	('ROS1', 'Gene', '6098', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('defective breast cancer', 'Disease', (96, 119))	('defective breast cancer', 'Disease', 'MESH:D001943', (96, 119))	('cadherin', 'molecular_function', 'GO:0008014', ('87', '95'))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('E-cadherin', 'Protein', (85, 95))	('tumour', 'Disease', (48, 54))	('inhibitors', 'Var', (14, 24))	('ROS1', 'Gene', (9, 13))
19499	29610289	E-cadherin defects are frequently found in breast cancer (>13 %) and gastric cancer (>14%) and are particularly prevalent in lobular breast cancers, which account for 15% of all mammary carcinomas.	('defects', 'Var', (11, 18))	('lobular breast cancers', 'Disease', 'MESH:D013274', (125, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('prevalent', 'Reg', (112, 121))	('found', 'Reg', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('breast cancers', 'Phenotype', 'HP:0003002', (133, 147))	('lobular breast cancers', 'Disease', (125, 147))	('carcinomas', 'Disease', (186, 196))	('E-cadherin', 'Protein', (0, 10))	('gastric cancer', 'Disease', (69, 83))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (125, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('breast cancer', 'Disease', (43, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('carcinomas', 'Disease', 'MESH:D002277', (186, 196))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))
19502	29610289	In lobular breast cancer, loss of E-cadherin expression occurs early on in the tumourigenic process and is seen in up to 90% of cases often co-occurring with mutations in the PI3-kinase coding gene, PIK3CA.	('PIK3CA', 'Gene', (199, 205))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('lobular breast cancer', 'Disease', 'MESH:D013274', (3, 24))	('PIK3CA', 'Gene', '5290', (199, 205))	('lobular breast cancer', 'Disease', (3, 24))	('expression', 'MPA', (45, 55))	('loss', 'NegReg', (26, 30))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (3, 24))	('E-cadherin', 'Protein', (34, 44))	('cadherin', 'molecular_function', 'GO:0008014', ('36', '44'))	('mutations', 'Var', (158, 167))	('tumour', 'Disease', (79, 85))
19509	29610289	To identify candidate therapeutic targets for breast cancers with loss of E-cadherin, we used CRISPR-Cas9 mutagenesis in MCF7 breast tumour cells (ERalpha-positive, luminal A, PIK3CA mutant; described hereafter as MCF7Parental cells) to generate daughter clones, MCF7A02, MCF7B04 and MCF7B05, with frameshift mutations in CDH1 and loss of E-cadherin expression (Fig.	('breast cancers', 'Disease', 'MESH:D001943', (46, 60))	('breast cancers', 'Disease', (46, 60))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('loss', 'NegReg', (331, 335))	('MCF7B05', 'CellLine', 'CVCL:6860', (284, 291))	('mutagenesis', 'biological_process', 'GO:0006280', ('106', '117'))	('MCF7B04', 'CellLine', 'CVCL:6860', (272, 279))	('breast cancers', 'Phenotype', 'HP:0003002', (46, 60))	('CDH1', 'Gene', '999', (322, 326))	('Cas', 'cellular_component', 'GO:0005650', ('101', '104'))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('cadherin', 'molecular_function', 'GO:0008014', ('341', '349'))	('PIK3CA', 'Gene', (176, 182))	('CDH1', 'Gene', (322, 326))	('frameshift mutations', 'Var', (298, 318))	('MCF7', 'CellLine', 'CVCL:0031', (272, 276))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('MCF7', 'CellLine', 'CVCL:0031', (121, 125))	('MCF7 breast tumour', 'Disease', (121, 139))	('MCF7', 'CellLine', 'CVCL:0031', (263, 267))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('E-cadherin', 'Protein', (339, 349))	('breast tumour', 'Phenotype', 'HP:0100013', (126, 139))	('ER', 'Gene', '2099', (147, 149))	('MCF7', 'CellLine', 'CVCL:0031', (214, 218))	('MCF7 breast tumour', 'Disease', 'MESH:D001943', (121, 139))	('MCF7A02', 'CellLine', 'CVCL:0031', (263, 270))	('MCF7', 'CellLine', 'CVCL:0031', (284, 288))	('PR', 'Gene', '5241', (98, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('PIK3CA', 'Gene', '5290', (176, 182))
19510	29610289	Compared to MCF7Parental cells, E-cadherin defective cells displayed a rounded morphology also seen in breast tumour cells harbouring naturally occurring E-cadherin mutations (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('34', '42'))	('cadherin', 'molecular_function', 'GO:0008014', ('156', '164'))	('breast tumour', 'Disease', (103, 116))	('breast tumour', 'Phenotype', 'HP:0100013', (103, 116))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('MCF7', 'CellLine', 'CVCL:0031', (12, 16))	('E-cadherin', 'Gene', (154, 164))	('breast tumour', 'Disease', 'MESH:D001943', (103, 116))	('mutations', 'Var', (165, 174))
19512	29610289	The drug sensitivity screens identified a series of candidate E-cadherin synthetic lethal drugs, including PF-03758309 (a PAK inhibitor), PF-03814735 (an Aurora kinase inhibitor), PI3K/mTOR inhibitors (BEZ-235, PF-04691502 and Everolimus), the ROS1/MET/ALK inhibitors crizotinib (PF02341066, Pfizer) and foretinib (GSK1363089, GSK) (Fig.	('PF02341066', 'Var', (280, 290))	('PF-03758309', 'Var', (107, 118))	('ALK', 'Gene', (253, 256))	('foretinib', 'Chemical', 'MESH:C544831', (304, 313))	('PAK', 'Gene', (122, 125))	('PAK', 'Gene', '10298', (122, 125))	('mTOR', 'Gene', (185, 189))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('161', '177'))	('ROS1', 'Gene', (244, 248))	('cadherin', 'molecular_function', 'GO:0008014', ('64', '72'))	('GSK1363089', 'Var', (315, 325))	('mTOR', 'Gene', '2475', (185, 189))	('drug sensitivity', 'Phenotype', 'HP:0020174', (4, 20))	('GSK', 'molecular_function', 'GO:0050321', ('327', '330'))	('PI3K', 'molecular_function', 'GO:0016303', ('180', '184'))	('ROS1', 'Gene', '6098', (244, 248))	('ALK', 'Gene', '238', (253, 256))	('GSK', 'molecular_function', 'GO:0050321', ('315', '318'))	('PF-03814735', 'Var', (138, 149))	('crizotinib', 'Chemical', 'MESH:D000077547', (268, 278))
19522	29610289	Two further E-cadherin defective clones derived by MCF7 CRISPR-Cas9 targeting, MCF7B04 and MCF7B05, were also significantly more sensitive to either foretinib or crizotinib than the parental cells (Fig.	('sensitive', 'MPA', (129, 138))	('MCF7', 'CellLine', 'CVCL:0031', (79, 83))	('MCF7B05', 'CellLine', 'CVCL:6860', (91, 98))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('defective', 'NegReg', (23, 32))	('foretinib', 'Chemical', 'MESH:C544831', (149, 158))	('Cas', 'cellular_component', 'GO:0005650', ('63', '66'))	('MCF7B04', 'Var', (79, 86))	('E-cadherin', 'Protein', (12, 22))	('crizotinib', 'MPA', (162, 172))	('MCF7', 'Gene', (51, 55))	('MCF7B04', 'CellLine', 'CVCL:6860', (79, 86))	('more', 'PosReg', (124, 128))	('PR', 'Gene', '5241', (60, 62))	('MCF7', 'CellLine', 'CVCL:0031', (91, 95))	('MCF7', 'CellLine', 'CVCL:0031', (51, 55))	('crizotinib', 'Chemical', 'MESH:D000077547', (162, 172))	('MCF7B05', 'Var', (91, 98))
19528	29610289	We also found E-cadherin defective cells to be sensitive to a recently described ROS1 kinase inhibitor, PF-06463922 (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('86', '102'))	('ROS1', 'Gene', (81, 85))	('ROS1', 'Gene', '6098', (81, 85))	('PF-06463922', 'Var', (104, 115))	('PF-06463922', 'Chemical', 'MESH:C000590786', (104, 115))	('sensitive', 'Reg', (47, 56))
19530	29610289	Conversely, expression of a crizotinib-refractory p.G2032R mutant ROS1 fusion cDNA caused crizotinib resistance in E-cadherin defective cells (Fig.	('p.G2032R', 'Mutation', 'rs1057519788', (50, 58))	('caused', 'Reg', (83, 89))	('p.G2032R', 'Var', (50, 58))	('crizotinib resistance', 'MPA', (90, 111))	('ROS1', 'Gene', (66, 70))	('crizotinib', 'Chemical', 'MESH:D000077547', (28, 38))	('ROS1', 'Gene', '6098', (66, 70))	('cadherin', 'molecular_function', 'GO:0008014', ('117', '125'))	('crizotinib', 'Chemical', 'MESH:D000077547', (90, 100))
19535	29610289	We found that the "E-cadherin defective" or "E-cadherin wild-type" status defined by western blotting was consistent with E-cadherin protein expression data determined by mass spectrometry (MS), as well as E-cadherin mRNA expression and CDH1 mutation data (Fig.	('CDH1', 'Gene', '999', (237, 241))	('cadherin', 'molecular_function', 'GO:0008014', ('20', '28'))	('CDH1', 'Gene', (237, 241))	('mutation', 'Var', (242, 250))
19536	29610289	For example, each of the tumour cell line models with CDH1 truncating mutations or homozygous deletions lacked E-cadherin protein expression; similarly breast tumour cell lines with CDH1 promoter hypermethylation, also lacked full length E-cadherin protein (Fig.	('expression', 'MPA', (130, 140))	('CDH1', 'Gene', '999', (182, 186))	('CDH1', 'Gene', (54, 58))	('breast tumour', 'Disease', 'MESH:D001943', (152, 165))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('cadherin', 'molecular_function', 'GO:0008014', ('240', '248'))	('CDH1', 'Gene', (182, 186))	('breast tumour', 'Disease', (152, 165))	('E-cadherin protein', 'Protein', (111, 129))	('breast tumour', 'Phenotype', 'HP:0100013', (152, 165))	('lacked', 'NegReg', (104, 110))	('E-cadherin protein', 'Protein', (238, 256))	('promoter hypermethylation', 'Var', (187, 212))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('cadherin', 'molecular_function', 'GO:0008014', ('113', '121'))	('tumour', 'Disease', (25, 31))	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('tumour', 'Disease', (159, 165))	('lacked', 'NegReg', (219, 225))	('deletions', 'Var', (94, 103))	('full length', 'MPA', (226, 237))	('CDH1', 'Gene', '999', (54, 58))
19545	29610289	the presence or absence of mutations or other defects in key cancer driver genes or proteins) and target inhibition data (in this case sensitivity to ROS1 siRNA) from tumour cell line profiling experiments to identify multiple, often complimentary, molecular features that correlate with target inhibition, quantifying these effects as non-linear information correlation coefficients (ICs), between 1 (perfect correlation/features associated with resistance to target inhibition) and -1 (perfect negative correlation/features associated with sensitivity to target inhibition); REVEALER ICs <-0.1 or >0.1 are regarded as profound correlations.	('mutations', 'Var', (27, 36))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('ROS1', 'Gene', (150, 154))	('tumour', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('ROS1', 'Gene', '6098', (150, 154))	('cancer', 'Disease', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ER', 'Gene', '2099', (583, 585))
19557	29610289	In addition, ROS1 copy number or ROS1 variants, although rare in our tumour cell line panel, did not appear to correlate with crizotinib/foretinib sensitivity (Supplementary Table S9).	('tumour', 'Disease', (69, 75))	('ROS1', 'Gene', (13, 17))	('variants', 'Var', (38, 46))	('ROS1', 'Gene', '6098', (13, 17))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('crizotinib', 'Chemical', 'MESH:D000077547', (126, 136))	('foretinib', 'Chemical', 'MESH:C544831', (137, 146))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('crizotinib/foretinib', 'MPA', (126, 146))	('correlate', 'Reg', (111, 120))	('ROS1', 'Gene', (33, 37))	('ROS1', 'Gene', '6098', (33, 37))
19561	29610289	When querying this data for drug sensitivity effects associated with CDH1 gene copy number loss, we found sensitivity to crizotinib (PF-02341066) to be the most significant effect (Fig.	('copy number loss', 'Var', (79, 95))	('CDH1', 'Gene', (69, 73))	('CDH1', 'Gene', '999', (69, 73))	('drug sensitivity', 'Phenotype', 'HP:0020174', (28, 44))	('crizotinib', 'Chemical', 'MESH:D000077547', (121, 131))
19562	29610289	The mean area under the curve (AUC) for crizotinib was 0.0713 in explants with CDH1 copy number loss (n = 5) and 0.138 in explants without CDH1 copy number loss (n = 12; False Discovery Rate (FDR) 0.214).	('CDH1', 'Gene', (79, 83))	('CDH1', 'Gene', '999', (79, 83))	('copy number loss', 'Var', (84, 100))	('crizotinib', 'Chemical', 'MESH:D000077547', (40, 50))	('CDH1', 'Gene', (139, 143))	('CDH1', 'Gene', '999', (139, 143))
19569	29610289	S11B-D), suggesting that ROS1 inhibition could also target E-cadherin defective breast tumour cells in this particular setting.	('cadherin', 'molecular_function', 'GO:0008014', ('61', '69'))	('S11B', 'Var', (0, 4))	('ROS1', 'Gene', (25, 29))	('S11B', 'SUBSTITUTION', 'None', (0, 4))	('breast tumour', 'Disease', (80, 93))	('ROS1', 'Gene', '6098', (25, 29))	('breast tumour', 'Phenotype', 'HP:0100013', (80, 93))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('breast tumour', 'Disease', 'MESH:D001943', (80, 93))	('E-cadherin', 'Protein', (59, 69))
19584	29610289	In E-cadherin wild type cells, exposure to a ROS1 inhibitor still resulted in the formation of two mononuclear daughter cells (Fig.	('ROS1', 'Gene', (45, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('5', '13'))	('ROS1', 'Gene', '6098', (45, 49))	('resulted in', 'Reg', (66, 77))	('inhibitor', 'Var', (50, 59))	('formation', 'biological_process', 'GO:0009058', ('82', '91'))
19589	29610289	p120 catenin also normally interacts with E-cadherin at the cell membrane where it is tyrosine phosphorylated, raising the possibility that loss of E-cadherin could impair p120 function.	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('cell membrane', 'cellular_component', 'GO:0005886', ('60', '73'))	('tyrosine', 'Chemical', 'MESH:D014443', (86, 94))	('E-cadherin', 'Protein', (148, 158))	('p120', 'Gene', '1500', (0, 4))	('impair', 'NegReg', (165, 171))	('p120', 'Gene', '1500', (172, 176))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('p120', 'Gene', (0, 4))	('p120', 'Gene', (172, 176))	('loss', 'Var', (140, 144))
19597	29610289	Our data suggest that ROS1 inhibitors exacerbate an existing p120 defect in E-cadherin defective cells and impair cytokinesis to such an extent that abnormal mitoses form; this elicits a DNA damage response (e.g.	('ROS1', 'Gene', (22, 26))	('exacerbate', 'PosReg', (38, 48))	('DNA damage response', 'MPA', (187, 206))	('ROS1', 'Gene', '6098', (22, 26))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('cytokinesis', 'CPA', (114, 125))	('p120', 'Gene', '1500', (61, 65))	('cadherin', 'molecular_function', 'GO:0008014', ('78', '86'))	('impair', 'NegReg', (107, 113))	('elicits', 'Reg', (177, 184))	('p120', 'Gene', (61, 65))	('inhibitors', 'Var', (27, 37))	('DNA damage response', 'biological_process', 'GO:0006974', ('187', '206'))	('cytokinesis', 'biological_process', 'GO:0000910', ('114', '125'))
19600	29610289	Consistent with the concept that E-cadherin defects might cause a dependency upon processes controlled by actomyosin networks, such as cleavage furrow maturation, we also noted that the Rho GTPase effector kinase CDC42BPA (CDC42-binding kinase, MRCKalpha) which controls actomyosin function was also identified as a robust synthetic lethal effect in our earlier siRNA screens (Supplementary Fig.	('CDC42', 'Gene', '998', (213, 218))	('CDC42', 'Gene', '998', (223, 228))	('CDC42', 'Gene', (213, 218))	('binding', 'molecular_function', 'GO:0005488', ('229', '236'))	('defects', 'Var', (44, 51))	('actomyosin', 'cellular_component', 'GO:0042641', ('106', '116'))	('CDC42', 'Gene', (223, 228))	('cleavage furrow', 'cellular_component', 'GO:0032154', ('135', '150'))	('MRCKalpha', 'Gene', '8476', (245, 254))	('cadherin', 'molecular_function', 'GO:0008014', ('35', '43'))	('MRCKalpha', 'Gene', (245, 254))	('CDC42BPA', 'Gene', (213, 221))	('actomyosin', 'cellular_component', 'GO:0042641', ('271', '281'))	('CDC42BPA', 'Gene', '8476', (213, 221))
19604	29610289	E-cadherin defective mammary tumours from K14cre;Cdh1F/F;Trp53F/F (KEP) female mice were orthotopically transplanted into recipient mice and once established, animals were treated with foretinib, crizotinib or drug vehicle.	('Cdh1F/F', 'Gene', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumours', 'Disease', (29, 36))	('mice', 'Species', '10090', (79, 83))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('mice', 'Species', '10090', (132, 136))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('K14cre', 'Var', (42, 48))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))	('defective', 'NegReg', (11, 20))	('foretinib', 'Chemical', 'MESH:C544831', (185, 194))	('E-cadherin', 'Protein', (0, 10))	('crizotinib', 'Chemical', 'MESH:D000077547', (196, 206))
19614	29610289	E-cadherin defects are a common characteristic of human tumours.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('defects', 'Var', (11, 18))	('tumours', 'Disease', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('human', 'Species', '9606', (50, 55))	('E-cadherin', 'Protein', (0, 10))
19623	29610289	For example, we also found that other proteins associated with actomyosin control such as MRCKalpha are also synthetic lethal with E-cadherin defects; these could conceivably play a part in the ROS1/E-cadherin synthetic lethal effect.	('E-cadherin', 'Protein', (131, 141))	('ROS1', 'Gene', '6098', (194, 198))	('defects', 'Var', (142, 149))	('cadherin', 'molecular_function', 'GO:0008014', ('201', '209'))	('actomyosin', 'cellular_component', 'GO:0042641', ('63', '73'))	('MRCKalpha', 'Gene', '8476', (90, 99))	('cadherin', 'molecular_function', 'GO:0008014', ('133', '141'))	('play', 'Reg', (175, 179))	('MRCKalpha', 'Gene', (90, 99))	('ROS1', 'Gene', (194, 198))
19625	29610289	Similarly, although we were able to elicit E-cadherin synthetic lethal effects with multiple different ROS1 siRNA reagents and to partially reverse crizotinib sensitivity with a p.G2032R mutant ROS1 fusion cDNA (Fig.	('elicit', 'Reg', (36, 42))	('crizotinib', 'Chemical', 'MESH:D000077547', (148, 158))	('ROS1', 'Gene', '6098', (194, 198))	('p.G2032R', 'Mutation', 'rs1057519788', (178, 186))	('E-cadherin', 'Protein', (43, 53))	('ROS1', 'Gene', (103, 107))	('p.G2032R', 'Var', (178, 186))	('cadherin', 'molecular_function', 'GO:0008014', ('45', '53'))	('ROS1', 'Gene', '6098', (103, 107))	('synthetic lethal effects', 'MPA', (54, 78))	('reverse', 'NegReg', (140, 147))	('crizotinib sensitivity', 'MPA', (148, 170))	('ROS1', 'Gene', (194, 198))
19633	29610289	Colonies were recovered and profiled using PCR and Sanger sequencing to determine the presence of CDH1 mutations.	('CDH1', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('CDH1', 'Gene', '999', (98, 102))
19641	29610289	In vivo efficacy studies were conducted using K14cre;Cdh1F/F;Trp53F/F (KEP) or BCM2665 PDX tumour bearing mice as previously described.	('Cdh1F/F', 'Var', (53, 60))	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('mice', 'Species', '10090', (106, 110))	('tumour', 'Disease', (91, 97))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('K14cre;Cdh1F/F', 'Var', (46, 60))
19642	29610289	Experiments on K14cre;Cdh1F/F;Trp53F/F (KEP) tumour bearing mice were carried out at the Netherlands Cancer Institute according to local and international regulations and ethical guidelines, and were approved by the local animal experimental committee at the Netherlands Cancer Institute (DEC-NKI AvD:30100 2015 407 appendix 1, WP 5791 and WP 5900).	('K14cre;Cdh1F/F;Trp53F/F', 'Var', (15, 38))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('Cdh1F/F;Trp53F/F', 'Var', (22, 38))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (271, 277))	('AvD', 'cellular_component', 'GO:0044754', ('297', '300'))	('mice', 'Species', '10090', (60, 64))	('tumour', 'Disease', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))
19643	29610289	Balb/c nudes were implanted with K14cre;Cdh1F/F;Trp53F/F (KEP) tumour sections in their 4th mammary gland on the right side as described previously.	('K14cre', 'Var', (33, 39))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('Cdh1F/F', 'Gene', (40, 47))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Disease', (63, 69))
19644	29610289	Once tumours reached 200 mm3 in volume, mice were randomized into cohorts who received either crizotinib/foretinib 25mg/kg or 50mg/kg a day via oral gavage for 28 days or the drug vehicle.	('crizotinib', 'Chemical', 'MESH:D000077547', (94, 104))	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('crizotinib/foretinib', 'Var', (94, 114))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumours', 'Disease', (5, 12))	('foretinib', 'Chemical', 'MESH:C544831', (105, 114))	('mice', 'Species', '10090', (40, 44))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
19654	29610289	E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('defects', 'Var', (11, 18))	('E-cadherin', 'Protein', (0, 10))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('common', 'Reg', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
19755	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))
19786	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))
19793	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))
19795	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.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('human', 'Species', '9606', (82, 87))	('cancers', 'Disease', (88, 95))	('variants', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Ep-CAM', 'Gene', (133, 139))	('Ep-CAM', 'Gene', '4072', (133, 139))	('patients', 'Species', '9606', (111, 119))
19800	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))
19826	24748570	All women diagnosed with an invasive breast cancer with a lobular component based on ICD-O codes 8520, 8522, and 8524 assigned by CSS were potentially eligible as lobular cases.	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('invasive breast cancer', 'Disease', (28, 50))	('8520', 'Var', (97, 101))	('8522', 'Var', (103, 107))	('women', 'Species', '9606', (4, 9))	('invasive breast cancer', 'Disease', 'MESH:D001943', (28, 50))	('CSS', 'Chemical', '-', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
19838	24748570	In addition, we assessed whether or not risk estimates differed among women with invasive lobular (ICD-O codes 8520 and 8524) versus invasive ductal-lobular (ICD-O code 8522) carcinomas.	('invasive lobular', 'Disease', (81, 97))	('8524', 'Var', (120, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('carcinomas', 'Disease', (175, 185))	('carcinomas', 'Disease', 'MESH:D002277', (175, 185))	('women', 'Species', '9606', (70, 75))
19926	22629394	For lung cancer, ACs (code 814) and SCCs (code 807) were selected as the most prevalent among those affecting the lung and having distinct clinical, pathological, and molecular characteristics.	('code 814', 'Var', (22, 30))	('ACs', 'molecular_function', 'GO:0043884', ('17', '20'))	('prevalent', 'Reg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('SCC', 'Gene', (36, 39))	('lung cancer', 'Disease', (4, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('ACs', 'molecular_function', 'GO:0003987', ('17', '20'))	('SCC', 'Gene', '6317', (36, 39))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('code 807', 'Var', (42, 50))	('ACs', 'Disease', (17, 20))
20053	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', 'biological_process', 'GO:0019835', ('223', '231'))	('necrosis', 'biological_process', 'GO:0001906', ('223', '231'))	('necrosis', 'Disease', (223, 231))	('necrosis', 'biological_process', 'GO:0008220', ('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))	('necrosis', 'biological_process', 'GO:0070265', ('223', '231'))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('necrosis', 'biological_process', 'GO:0008219', ('223', '231'))	('nuclear', 'Var', (201, 208))
20070	32120324	Conversely, DCIS with necrosis/degeneration or suboptimal fixation may appear dyscohesive.	('necrosis', 'biological_process', 'GO:0070265', ('22', '30'))	('necrosis', 'biological_process', 'GO:0008219', ('22', '30'))	('necrosis/degeneration', 'Disease', (22, 43))	('necrosis', 'biological_process', 'GO:0019835', ('22', '30'))	('dyscohesive', 'Disease', (78, 89))	('suboptimal', 'Var', (47, 57))	('necrosis', 'biological_process', 'GO:0001906', ('22', '30'))	('necrosis', 'biological_process', 'GO:0008220', ('22', '30'))	('necrosis/degeneration', 'Disease', 'MESH:D009336', (22, 43))	('DCIS', 'Disease', (12, 16))
20076	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))
20088	32120324	Functional inactivation or downregulation of E-cadherin can occur through genetic or epigenetic mechanisms.	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('epigenetic', 'Var', (85, 95))	('downregulation', 'NegReg', (27, 41))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))
20089	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))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('E-cadherin', 'Gene', '999', (12, 22))	('loss', 'NegReg', (4, 8))	('promoter hypermethylation', 'Var', (178, 203))	('expression', 'MPA', (23, 33))
20090	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))	('result', 'Reg', (137, 143))	('protein', 'Protein', (161, 168))	('missense mutations', 'Var', (85, 103))	('CDH1', 'Gene', '999', (21, 25))	('mutations', 'Var', (8, 17))	('truncating', 'MPA', (41, 51))	('CDH1', 'Gene', (21, 25))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
20091	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))
20102	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))
20107	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', 'Var', (48, 55))	('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))	('increase', 'PosReg', (96, 104))	('breast cancer', 'Disease', (108, 121))
20111	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))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cadherin', 'molecular_function', 'GO:0008014', ('206', '214'))	('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))
20123	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))
20136	19280264	The mean tumor size in the neoadjuvant group (4.9 cm) was significantly larger than in patients who underwent surgery first (2.5 cm, p < 0.0001).	('larger', 'PosReg', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('neoadjuvant', 'Var', (27, 38))	('patients', 'Species', '9606', (87, 95))
20168	19280264	The proportion of patients presenting with a palpable tumor was significantly higher in the neoadjuvant group (92%) compared with the surgery-first group (53%, p < 0.0001).	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('neoadjuvant', 'Var', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Disease', (54, 59))
20169	19280264	Similarly the rate of palpable axillary nodes at presentation was higher (45% versus 11%, p < 0.0001) and the rate of documented axillary lymph node metastases by fine-needle aspiration was also higher (48% versus 7%, p < 0.0001) in the neoadjuvant group.	('metastases', 'Disease', (149, 159))	('higher', 'PosReg', (195, 201))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('aspiration', 'Phenotype', 'HP:0002835', (175, 185))	('higher', 'PosReg', (66, 72))	('neoadjuvant', 'Var', (237, 248))
20182	19280264	Specifically, the final rate of BCS across the neoadjuvant and surgery-first cohorts were 33%, 21%, 20%, and 4%, and 56%, 33%, 11%, and 13%, respectively, for tumors< 2 cm, 2.1-4 cm, 4.1-6 cm, and over 6 cm (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('4.1-6 cm', 'Var', (183, 191))
20219	19280264	It is known that large tumors, low grade, and ER positivity are associated with minor response to neoadjuvant chemotherapy.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('low grade', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('ER', 'Gene', '2099', (46, 48))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
20336	27047651	It has been demonstrated that loss of expression of the cell-cell adhesion molecule E-cadherin in ILC may decrease adhesiveness of cells and facilitate this type of infiltration.	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('facilitate', 'PosReg', (141, 151))	('expression', 'MPA', (38, 48))	('cell-cell adhesion molecule', 'molecular_function', 'GO:0098632', ('56', '83'))	('loss of', 'Var', (30, 37))	('decrease', 'NegReg', (106, 114))	('adhesiveness of cells', 'CPA', (115, 136))	('decrease adhesiveness of cells', 'Phenotype', 'HP:0008352', (106, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('86', '94'))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('56', '74'))
20339	27047651	In the present case, positive (CK7 and CD 138) and negative CK20 helped the pathologist in confirming the diagnosis of metastatic breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('negative', 'NegReg', (51, 59))	('CD 138', 'Gene', (39, 45))	('CK20', 'Gene', (60, 64))	('CK20', 'Gene', '54474', (60, 64))	('CD 138', 'Gene', '6382', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('CK7', 'Var', (31, 34))
20390	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))
20391	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))
20411	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))	('TisN0M0', 'Var', (93, 100))	('T1bN0M0', 'Var', (111, 118))	('TNM', 'Gene', (51, 54))
20466	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))
20473	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))	('FGFR', 'molecular_function', 'GO:0005007', ('363', '367'))	('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))	('breast cancers', 'Disease', 'MESH:D001943', (39, 53))	('breast cancers', 'Disease', (39, 53))	('ERBB2', 'Gene', (337, 342))	('ZNF703', 'Gene', '80139', (356, 362))	('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))
20475	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))
20477	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))
20478	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.	('tumours', 'Disease', (203, 210))	('TP53', 'Gene', (325, 329))	('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))	('growth pattern', 'biological_process', 'GO:0007150', ('376', '390'))	('BRCA2', 'Gene', (267, 272))	('TP53', 'Gene', '7157', (235, 239))	('familial breast cancer', 'Disease', 'MESH:D001943', (24, 46))	('related', 'Reg', (128, 135))	('familial breast cancer', 'Disease', (24, 46))	('tumours', 'Disease', (299, 306))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cadherin', 'molecular_function', 'GO:0008014', ('346', '354'))	('ATM', 'Gene', (274, 277))	('mutation', 'Var', (102, 110))	('growth pattern', 'biological_process', 'GO:0040007', ('376', '390'))	('HER2', 'Gene', (308, 312))	('tumours', 'Phenotype', 'HP:0002664', (299, 306))	('BRCA2', 'Gene', '675', (267, 272))	('tumours', 'Disease', 'MESH:D009369', (299, 306))
20479	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))
20483	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.	('binding', 'molecular_function', 'GO:0005488', ('123', '130'))	('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))	('cell adhesion', 'biological_process', 'GO:0007155', ('72', '85'))	('dysfunction', 'Var', (42, 53))	('cell adhesion complex', 'cellular_component', 'GO:0098636', ('72', '93'))	('cadherin', 'molecular_function', 'GO:0008014', ('106', '114'))	('E-cadherin', 'Gene', (104, 114))	('beta-catenin', 'Gene', (140, 152))
20484	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))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('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))
20486	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))
20487	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))
20489	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))
20500	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))
20507	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))	('CCL', 'molecular_function', 'GO:0044101', ('103', '106'))	('PIK3CA', 'Gene', (202, 208))	('CCL', 'Chemical', '-', (103, 106))	('PIK3CA', 'Gene', '5290', (202, 208))	('mutations', 'Var', (209, 218))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))
20511	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))
20514	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))
20516	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', 'MESH:D017695', (185, 198))	('caused', 'Reg', (109, 115))	('tissue injury', 'Disease', (185, 198))
20518	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))
20519	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))	('DNA damage response', 'biological_process', 'GO:0006974', ('92', '111'))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('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))
20524	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))
20525	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.	('CCND1', 'Gene', (187, 192))	('HER2', 'Gene', '2064', (200, 204))	('PIK3CA', 'Gene', '5290', (144, 150))	('metastatic deposits', 'CPA', (234, 253))	('GATA3', 'Gene', '2625', (158, 163))	('TP53', 'Gene', (138, 142))	('GATA3', 'Gene', (158, 163))	('prevalent', 'Reg', (213, 222))	('MYC', 'Gene', (182, 185))	('mutations', 'Var', (125, 134))	('HER2', 'Gene', (200, 204))	('PIK3CA', 'Gene', (144, 150))	('CDH1', 'Gene', '999', (152, 156))	('behaviour', 'biological_process', 'GO:0007610', ('94', '103'))	('TP53', 'Gene', '7157', (138, 142))	('CDH1', 'Gene', (152, 156))	('amplification', 'Var', (165, 178))	('MYC', 'Gene', '4609', (182, 185))	('CCND1', 'Gene', '595', (187, 192))
20530	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))
20531	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.	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('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))	('AKT1', 'Gene', (47, 51))	('EGFR', 'Gene', (106, 110))	('TP53', 'Gene', (27, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (260, 273))	('ERBB2', 'Gene', (64, 69))	('primary tumour', 'Disease', 'MESH:D009369', (307, 321))	('NF1', 'Gene', '4763', (53, 56))	('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))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('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))
20532	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))	('tumours', 'Disease', 'MESH:D009369', (344, 351))	('APOBEC', 'cellular_component', 'GO:0030895', ('235', '241'))	('metastases', 'Disease', 'MESH:D009362', (317, 327))	('homologous recombination deficiency', 'Var', (265, 300))	('primary tumour', 'Disease', (336, 350))	('homologous recombination', 'biological_process', 'GO:0035825', ('265', '289'))	('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))	('metastases', 'Disease', 'MESH:D009362', (68, 78))	('higher', 'PosReg', (307, 313))
20534	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))
20535	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))
20537	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))	('metastases', 'Disease', (189, 199))	('mutations', 'Var', (111, 120))	('tumour', 'Disease', 'MESH:D009369', (304, 310))	('metastases', 'Disease', (166, 176))	('metastases', 'Disease', 'MESH:D009362', (275, 285))	('metastases', 'Disease', (33, 43))	('metastases', 'Disease', 'MESH:D009362', (189, 199))	('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))
20553	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))
20557	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))
20559	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))
20560	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))
20561	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))
20562	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))
20566	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))
20569	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))	('CDK', 'molecular_function', 'GO:0004693', ('156', '159'))	('HER2', 'Gene', (239, 243))	('PI3K', 'molecular_function', 'GO:0016303', ('325', '329'))	('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))
20570	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))
20577	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))
20588	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))	('AZD5363', 'Var', (23, 30))	('mutations', 'Var', (81, 90))	('PIK3CA', 'Gene', (74, 80))
20596	26008969	The Small cell fraction also showed copy number increases in six target genes (FGFR1, Myc, CCND1, HER2, TOP2A and ZNF217) associated with breast cancer.	('CCND1', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Myc', 'Gene', (86, 89))	('FGFR1', 'Gene', (79, 84))	('HER2', 'Gene', (98, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('TOP2A', 'Gene', (104, 109))	('cell fraction', 'cellular_component', 'GO:0000267', ('10', '23'))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('TOP2A', 'Gene', '7153', (104, 109))	('increases', 'PosReg', (48, 57))	('ZNF217', 'Gene', (114, 120))	('Myc', 'Gene', '4609', (86, 89))	('ZNF217', 'Gene', '7764', (114, 120))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Disease', (138, 151))	('FGFR1', 'Gene', '2260', (79, 84))	('copy number', 'Var', (36, 47))	('HER2', 'Gene', '2064', (98, 102))	('CCND1', 'Gene', '595', (91, 96))
20615	26008969	In further assessment of the small cell fraction, we show that these cells express either or both epithelial and mesenchymal markers as well as copy number increases in six genes previously identified to be altered in breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('cell fraction', 'cellular_component', 'GO:0000267', ('35', '48'))	('copy number', 'Var', (144, 155))	('epithelial', 'CPA', (98, 108))	('increases', 'PosReg', (156, 165))	('breast cancers', 'Phenotype', 'HP:0003002', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('breast cancers', 'Disease', 'MESH:D001943', (218, 232))	('breast cancers', 'Disease', (218, 232))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
20657	26008969	Six genes have been reported to contribute to about 44% of driver mutations in breast cancer (copy number increase or amplicons): MYC, FGFR1 (Chromosome 8); CCND1 (Chromosome 11); HER2, TOP2A (Chromosome 17); and ZNF217 (Chromosome 20).	('mutations', 'Var', (66, 75))	('Chromosome', 'cellular_component', 'GO:0005694', ('164', '174'))	('HER2', 'Gene', (180, 184))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('TOP2A', 'Gene', '7153', (186, 191))	('breast cancer', 'Disease', (79, 92))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('FGFR1', 'Gene', (135, 140))	('Chromosome', 'cellular_component', 'GO:0005694', ('221', '231'))	('MYC', 'Gene', (130, 133))	('C', 'Chemical', 'MESH:D002244', (193, 194))	('CCND1', 'Gene', '595', (157, 162))	('C', 'Chemical', 'MESH:D002244', (142, 143))	('C', 'Chemical', 'MESH:D002244', (221, 222))	('HER2', 'Gene', '2064', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('MYC', 'Gene', '4609', (130, 133))	('CCND1', 'Gene', (157, 162))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('Chromosome', 'cellular_component', 'GO:0005694', ('142', '152'))	('Chromosome', 'cellular_component', 'GO:0005694', ('193', '203'))	('C', 'Chemical', 'MESH:D002244', (158, 159))	('FGFR1', 'Gene', '2260', (135, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('TOP2A', 'Gene', (186, 191))	('ZNF217', 'Gene', (213, 219))	('ZNF217', 'Gene', '7764', (213, 219))	('C', 'Chemical', 'MESH:D002244', (164, 165))
20659	26008969	Next, we compared the total proportion of cells with a copy number increase in any of these probes with a concomitant increase in CEN17 copy number (an indicator of cell polyploidy and cancer progression).	('copy', 'MPA', (136, 140))	('CEN17', 'Gene', (130, 135))	('polyploidy', 'Disease', 'MESH:D011123', (170, 180))	('N', 'Chemical', 'MESH:D009584', (132, 133))	('increase', 'PosReg', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('increase', 'PosReg', (67, 75))	('polyploidy', 'Disease', (170, 180))	('copy number', 'Var', (55, 66))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
20662	26008969	We found that cultured cells with single or multiple CEN17 signals had a copy number increase in one or more target probes, with 21/27 (77.8%) samples showing a proportion of cells with target gene copy number increase (range, 7.1%-80%; mean, 35.9%) and 25/27 (92.6%) samples showing a proportion of cells with a copy number increase in CEN17 (range, 10.3%-85.7%; mean, 46.2%; Figure 4D).	('N', 'Chemical', 'MESH:D009584', (55, 56))	('copy number', 'Var', (313, 324))	('copy number', 'Var', (198, 209))	('signals', 'Var', (59, 66))	('C', 'Chemical', 'MESH:D002244', (337, 338))	('CEN17', 'Gene', (337, 342))	('N', 'Chemical', 'MESH:D009584', (339, 340))	('C', 'Chemical', 'MESH:D002244', (53, 54))	('CEN17', 'Gene', (53, 58))	('copy number', 'MPA', (73, 84))	('increase', 'PosReg', (210, 218))	('increase', 'PosReg', (85, 93))
20663	26008969	There was no distinct correlation between CEN17 polysomy and target gene amplification in cultured CTCs, which is similar to that reported in other studies.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('polysomy', 'Var', (48, 56))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('CEN17', 'Gene', (42, 47))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('C', 'Chemical', 'MESH:D002244', (99, 100))
20664	26008969	Overall, the detection of copy number increases in cancer-associated genes within the Small cultured cell population confirms the presence of cancer cells, and we surmise that these Small cells were likely derived from CTCs.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('increases', 'PosReg', (38, 47))	('copy number', 'Var', (26, 37))	('C', 'Chemical', 'MESH:D002244', (221, 222))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('C', 'Chemical', 'MESH:D002244', (219, 220))	('cancer', 'Disease', (142, 148))
20689	26008969	Among these ten samples cluster formation occurred in 2/4 (50%) patients with pT1N0M0 disease at later time points, as compared to 5/6 (83%) patients with a higher pathological stage of the disease (p = 0.260).	('occurred', 'Reg', (42, 50))	('patients', 'Species', '9606', (64, 72))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('formation', 'biological_process', 'GO:0009058', ('32', '41'))	('pT1N0M0 disease', 'Var', (78, 93))	('cluster formation', 'CPA', (24, 41))	('patients', 'Species', '9606', (141, 149))
20701	26008969	We further used pooled samples to carry out DNA FISH for six genes previously reported to contribute to driver mutations in breast cancer: MYC, FGFR1, CCND1, HER2, TOP2A, and ZNF217 (Figure 4).	('FGFR1', 'Gene', (144, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('MYC', 'Gene', (139, 142))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('mutations', 'Var', (111, 120))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Disease', (124, 137))	('HER2', 'Gene', '2064', (158, 162))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('N', 'Chemical', 'MESH:D009584', (176, 177))	('N', 'Chemical', 'MESH:D009584', (153, 154))	('CCND1', 'Gene', '595', (151, 156))	('MYC', 'Gene', '4609', (139, 142))	('FGFR1', 'Gene', '2260', (144, 149))	('ZNF217', 'Gene', (175, 181))	('ZNF217', 'Gene', '7764', (175, 181))	('CCND1', 'Gene', (151, 156))	('TOP2A', 'Gene', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('HER2', 'Gene', (158, 162))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('TOP2A', 'Gene', '7153', (164, 169))
20710	26008969	This is more advantageous than using cell lines, since prolonged culture and multiple passages often lead to phenotypes that are no longer representative of the original tumor in terms of the cell's epigenetics and gene expression.	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('epigenetics', 'Var', (199, 210))	('original tumor', 'Disease', (161, 175))	('gene expression', 'biological_process', 'GO:0010467', ('215', '230'))	('original tumor', 'Disease', 'MESH:D009369', (161, 175))	('lead to', 'Reg', (101, 108))
20721	26008969	to expand breast epithelial CTCs into spheroids also observed a similar increase in spheroid formation from patients with more aggressive tumors, despite variations in the enrichment technique (which selects for epithelial cells under normoxia).	('C', 'Chemical', 'MESH:D002244', (28, 29))	('aggressive tumors', 'Disease', (127, 144))	('increase', 'PosReg', (72, 80))	('variations', 'Var', (154, 164))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('spheroid formation', 'CPA', (84, 102))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('C', 'Chemical', 'MESH:D002244', (30, 31))	('aggressive tumors', 'Disease', 'MESH:D001523', (127, 144))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
20774	26008969	12760-013) at recommended concentrations in wells of 16-well glass chamber slides (Lab-Tek Products, Miles Laboratories, Naperville, IL).	('12760-013', 'Var', (0, 9))	('Tek', 'Gene', (87, 90))	('Tek', 'Gene', '7010', (87, 90))	('N', 'Chemical', 'MESH:D009584', (121, 122))
20877	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))
20880	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))
20886	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))	('breast cancer', 'Disease', (89, 102))	('MRI', 'Var', (172, 175))	('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))
20901	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))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
20919	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))
20922	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))
20930	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))
20933	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))
20939	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))
20944	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))
20948	28648876	We report a case of triple negative breast carcinoma that spread to the jejunum.	('breast carcinoma', 'Disease', 'MESH:D001943', (36, 52))	('breast carcinoma', 'Phenotype', 'HP:0003002', (36, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('triple negative', 'Var', (20, 35))	('breast carcinoma', 'Disease', (36, 52))
21090	31519988	Furthermore, the combination of pathway aberrations in a tumour defines its disease mechanism, and distinct disease mechanisms underlie the inter-tumour heterogeneity in terms of disease progression and responses to therapies.	('tumour', 'Disease', (146, 152))	('tumour', 'Disease', 'MESH:D009369', (57, 63))	('tumour', 'Disease', (57, 63))	('aberrations', 'Var', (40, 51))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
21104	31519988	For example, the phosphoinositide 3-kinase (PI3K) pathway can be aberrantly activated by mutation/amplification of PIK3CA, mutation/deletion of PTEN, or mutation of AKT1, and so on.	('activated', 'PosReg', (76, 85))	('AKT1', 'Gene', (165, 169))	('PTEN', 'Gene', (144, 148))	('mutation/amplification', 'Var', (89, 111))	('mutation/deletion', 'Var', (123, 140))	('PIK3CA', 'Gene', (115, 121))	('PTEN', 'Gene', '5728', (144, 148))	('PIK3CA', 'Gene', '5290', (115, 121))	('AKT1', 'Gene', '207', (165, 169))	('mutation', 'Var', (153, 161))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
21134	31519988	On the other hand, while some studies suggest that alterations on RYR2 are likely passenger events, TCI consistently discovered that SGAs in RYR2 have impact on certain DEGs.	('RYR', 'cellular_component', 'GO:1990425', ('66', '69'))	('alterations', 'Var', (51, 62))	('RYR2', 'Gene', (141, 145))	('SGAs', 'Var', (133, 137))	('RYR2', 'Gene', '6262', (66, 70))	('RYR2', 'Gene', '6262', (141, 145))	('impact', 'Reg', (151, 157))	('RYR', 'cellular_component', 'GO:1990425', ('141', '144'))	('RYR2', 'Gene', (66, 70))	('DEGs', 'Disease', (169, 173))
21138	31519988	Specifically, AGAP2-AS1 and GSX2 are known to be associated with neuron system development and, therefore, alterations on these genes could be exclusive drivers of GBM.	('AGAP2', 'Gene', (14, 19))	('system development', 'biological_process', 'GO:0048731', ('72', '90'))	('alterations', 'Var', (107, 118))	('associated', 'Reg', (49, 59))	('AGAP2', 'Gene', '116986', (14, 19))	('GSX2', 'Gene', (28, 32))	('neuron system development', 'CPA', (65, 90))	('AS1', 'Gene', '5729', (20, 23))	('AS1', 'Gene', (20, 23))	('GSX2', 'Gene', '170825', (28, 32))
21143	31519988	50.1% of TCGA BRCA samples (891 samples from the input data of TCI) have mutations in CDH1, GATA3, or PIK3CA, which suggests module 1 as the most associated function module with the disease mechanism of BRCA.	('BRCA', 'Gene', '672', (203, 207))	('BRCA', 'Gene', (14, 18))	('PIK3CA', 'Gene', (102, 108))	('BRCA', 'Gene', '672', (14, 18))	('CDH1', 'Gene', (86, 90))	('BRCA', 'Gene', (203, 207))	('BRCA', 'Phenotype', 'HP:0003002', (14, 18))	('GATA3', 'Gene', (92, 97))	('PIK3CA', 'Gene', '5290', (102, 108))	('GATA3', 'Gene', '2625', (92, 97))	('CDH1', 'Gene', '999', (86, 90))	('BRCA', 'Phenotype', 'HP:0003002', (203, 207))	('mutations', 'Var', (73, 82))
21147	31519988	This may represent a novel functional module that would support the development of BRCA for some subgroups of patients (dominant SGAs mutations found in 18.2% samples).	('BRCA', 'Phenotype', 'HP:0003002', (83, 87))	('BRCA', 'Gene', '672', (83, 87))	('BRCA', 'Gene', (83, 87))	('mutations', 'Var', (134, 143))	('SGAs', 'Gene', (129, 133))	('patients', 'Species', '9606', (110, 118))
21156	31519988	Modules 4, 9, 13, and 14, which have the most novel drivers, are potentially newly discovered functional modules that guide tumour development for some subgroups of GBM patients (dominant SGA mutations found in 19.7%, 28.9%, 24.6% and 39.4% samples, respectively).	('patients', 'Species', '9606', (169, 177))	('SGA', 'Gene', (188, 191))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('mutations', 'Var', (192, 201))	('tumour', 'Disease', (124, 130))
21224	31519988	The most common significant DEG module across patient groups and DEG patient groups is module 11, with its dominant SGA EGFR.	('patient', 'Species', '9606', (46, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('module', 'Var', (87, 93))	('EGFR', 'Gene', '1956', (120, 124))	('patient', 'Species', '9606', (69, 76))	('EGFR', 'Gene', (120, 124))
21260	31519988	The standard deviation sigma of the Gaussian kernel is selected based on the distribution of pseudo-distances to convert short distances to high affinities and suppress long distances (0.05 for BRCA and 0.1 for GBM).	('short', 'Var', (121, 126))	('long distances', 'MPA', (169, 183))	('suppress', 'NegReg', (160, 168))	('high affinities', 'MPA', (140, 155))	('BRCA', 'Phenotype', 'HP:0003002', (194, 198))	('BRCA', 'Gene', '672', (194, 198))	('BRCA', 'Gene', (194, 198))
21263	31519988	From the METABRIC clinical data, we extracted eight features and added these to our BRCA dataset-the age at diagnosis, size of tumour, grade of disease, lymph node assessment, tumour histology type, ER status, PR status, and Her2 status.	('Her2', 'Gene', (225, 229))	('PR status', 'Var', (210, 219))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('Her2', 'Gene', '2064', (225, 229))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('BRCA', 'Phenotype', 'HP:0003002', (84, 88))	('BRCA', 'Gene', '672', (84, 88))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('tumour', 'Disease', (127, 133))	('BRCA', 'Gene', (84, 88))	('tumour', 'Disease', (176, 182))
21298	21126378	For the prognosis comparison, low expression was defined as Ki-67 < 20% and p53 <= 25% (median values for all evaluated tumors).	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('expression', 'MPA', (34, 44))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Ki-67', 'Var', (60, 65))
21321	21126378	In the univariate analysis of OS, age, tumor size, nodal status, distant metastasis at diagnosis, individual ER, PgR, and HER2 statuses, p53, Ki-67, the type of operation, adjuvant hormone therapy and intrinsic subtype were prognostic factors.	('distant metastasis', 'CPA', (65, 83))	('nodal', 'Gene', (51, 56))	('nodal', 'Gene', '4838', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('p53', 'Gene', '7157', (137, 140))	('Ki-67', 'Var', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('PgR', 'Gene', (113, 116))	('HER2', 'Gene', (122, 126))	('PgR', 'Gene', '5241', (113, 116))	('tumor', 'Disease', (39, 44))	('HER2', 'Gene', '2064', (122, 126))	('ER', 'Gene', '2099', (123, 125))	('p53', 'Gene', (137, 140))	('ER', 'Gene', '2099', (109, 111))
21371	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))	('deletion', 'Var', (131, 139))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))	('cadherin', 'molecular_function', 'GO:0008014', ('88', '96'))	('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))	('loss', 'NegReg', (42, 46))
21376	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))	('necrosis', 'biological_process', 'GO:0070265', ('177', '185'))	('necrosis', 'biological_process', 'GO:0008219', ('177', '185'))	('necrosis', 'biological_process', 'GO:0019835', ('177', '185'))	('necrosis', 'biological_process', 'GO:0008220', ('177', '185'))	('nuclear pleomorphism', 'Var', (115, 135))	('necrosis', 'Disease', (177, 185))	('comedo', 'Phenotype', 'HP:0025249', (165, 171))	('necrosis', 'biological_process', 'GO:0001906', ('177', '185'))
21403	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))
21451	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))
21453	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))	('cyclin', 'molecular_function', 'GO:0016538', ('255', '261'))	('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))
21454	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))	('cyclin', 'molecular_function', 'GO:0016538', ('205', '211'))	('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))
21457	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.	('FGL', 'CPA', (54, 57))	('whole chromosomes changes', 'CPA', (73, 98))	('apocrine', 'Var', (14, 22))	('chromosomes with', 'CPA', (147, 163))	('higher', 'PosReg', (47, 53))	('amplifications', 'MPA', (114, 128))	('CLCIS', 'Chemical', '-', (193, 198))
21468	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))	('cadherin', 'molecular_function', 'GO:0008014', ('107', '115'))	('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))
21482	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))
21486	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))	('histone deacetylation', 'biological_process', 'GO:0016575', ('74', '95'))	('promoter methylation', 'MPA', (46, 66))	('alteration', 'Reg', (166, 176))	('CGH', 'Gene', (249, 252))	('CGH', 'Gene', '3342', (249, 252))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
21488	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))	('cyclin D1', 'Gene', (323, 332))	('11q', 'Gene', (371, 374))	('17q11.2-17q12', 'Var', (227, 240))	('13q', 'Gene', (376, 379))	('HER2', 'Gene', (263, 267))	('CLCIS', 'Chemical', '-', (108, 113))	('cyclin', 'molecular_function', 'GO:0016538', ('323', '329'))	('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))
21490	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))
21492	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))
21544	18036272	In general, these studies provide additional evidence that altering the balance of proliferative and apoptotic signals can lead to the accumulation of cells within the luminal space of the acini, which is a characteristic of neoplastic breast lesions.	('altering', 'Var', (59, 67))	('lead to', 'Reg', (123, 130))	('neoplastic breast lesions', 'Disease', (225, 250))	('neoplastic breast lesions', 'Disease', 'MESH:D001943', (225, 250))	('neoplastic breast lesions', 'Phenotype', 'HP:0100013', (225, 250))	('accumulation', 'PosReg', (135, 147))
21554	18036272	The distinction between ALH and MALH is important because MALH represents a significantly lower risk for subsequent development of invasive carcinoma than does classic ALH.	('invasive carcinoma', 'Disease', 'MESH:D009361', (131, 149))	('invasive carcinoma', 'Disease', (131, 149))	('lower', 'NegReg', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('MALH', 'Var', (58, 62))
21572	18036272	Lu and colleagues examined ALH (and LCIS) lesions, as well as the associated invasive breast cancers, using chromosomal-CGH and identified alterations at chromosomes 6, 16, 17, and 22.	('invasive breast cancer', 'Disease', 'MESH:D001943', (77, 99))	('alterations', 'Var', (139, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancers', 'Disease', 'MESH:D001943', (86, 100))	('breast cancers', 'Disease', (86, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('LCIS', 'Phenotype', 'HP:0030076', (36, 40))	('invasive breast cancer', 'Disease', (77, 99))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
21573	18036272	Novel regions of copy number gain and loss, including gain at 2p11.2 and loss at 7p11-p11.1 and 22q11.1, were determined to be common to ALH.	('loss', 'NegReg', (73, 77))	('p11', 'Gene', (82, 85))	('copy number', 'Var', (17, 28))	('p11', 'Gene', (86, 89))	('p11', 'Gene', '6281', (82, 85))	('p11', 'Gene', (63, 66))	('gain', 'PosReg', (29, 33))	('gain', 'PosReg', (54, 58))	('p11', 'Gene', '6281', (86, 89))	('loss', 'NegReg', (38, 42))	('p11', 'Gene', '6281', (63, 66))
21578	18036272	Loss of 16q is one of the most frequent events found in breast cancer and appears to be the most consistent alteration found in ILC by both chromosomal-CGH and array-CGH.	('ILC', 'Disease', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('chromosomal-CGH', 'Var', (140, 155))	('Loss of 16q', 'Var', (0, 11))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))
21582	18036272	A comprehensive list of the alterations identified to date in lobular carcinomas is presented in Table 1.	('lobular carcinomas', 'Disease', (62, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('alterations', 'Var', (28, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('lobular carcinomas', 'Disease', 'MESH:D018275', (62, 80))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (62, 80))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (62, 79))
21590	18036272	Molecular studies investigating these lesions for LOH, protein expression of the E-cadherin adhesion complex, and mutations in CDH1 and LOH at 16q suggest a relationship between adjacent lesions.	('CDH1', 'Gene', '999', (127, 131))	('mutations', 'Var', (114, 123))	('LOH at', 'Gene', (136, 142))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('CDH1', 'Gene', (127, 131))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))
21595	18036272	Thus, in premalignant lobular lesions the detection of loss of 16q (the locus that harbors the E-cadherin gene) might point to possible progression toward an invasive phenotype, given the frequency of this alteration in invasive breast cancer and the functional effect of loss of CDH1.	('loss', 'NegReg', (272, 276))	('loss', 'Var', (55, 59))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('invasive breast cancer', 'Disease', (220, 242))	('point to', 'Reg', (118, 126))	('CDH1', 'Gene', (280, 284))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('CDH1', 'Gene', '999', (280, 284))	('invasive breast cancer', 'Disease', 'MESH:D001943', (220, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))
21596	18036272	Additional chromosomal alterations, including loss at 1p, 11q and 17p/q, and gain at 1q, identified in synchronous lobular lesions may also contribute to progression.	('synchronous lobular lesions', 'Disease', (103, 130))	('loss at 1p', 'Var', (46, 56))	('synchronous lobular lesions', 'Disease', 'MESH:D009378', (103, 130))	('contribute', 'Reg', (140, 150))	('gain', 'PosReg', (77, 81))
21597	18036272	In general, alterations identified in adjacent in situ and invasive lobular lesions could provide a selective advantage during tumor initiation, thereby encouraging tumor development and progression.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('invasive lobular lesions', 'Disease', 'MESH:D018275', (59, 83))	('alterations', 'Var', (12, 23))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('encouraging', 'PosReg', (153, 164))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('invasive lobular lesions', 'Disease', (59, 83))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('progression', 'CPA', (187, 198))	('tumor', 'Disease', (165, 170))
21605	29941485	Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R/InsR inhibitors Insulin-like growth factor 1 (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes.	('InsR', 'Gene', (102, 106))	('enhances', 'PosReg', (19, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('IGF1R', 'Gene', '3480', (33, 38))	('regulates', 'Reg', (164, 173))	('IGF1', 'Gene', (96, 100))	('Insulin-like growth factor 1', 'Gene', (118, 146))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('IGF1', 'Gene', (33, 37))	('cancer', 'Disease', (80, 86))	('IGF1R', 'Gene', (33, 38))	('IGF1R', 'Gene', '3480', (96, 101))	('IGF1', 'Gene', '3479', (148, 152))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (230, 236))	('IGF1R', 'Gene', (96, 101))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('IGF1', 'Gene', '3479', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('activation', 'PosReg', (47, 57))	('Insulin-like growth factor 1', 'Gene', '3479', (118, 146))	('breast cancer initiation', 'Disease', (174, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('IGF1', 'Gene', (148, 152))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Loss', 'Var', (0, 4))	('breast cancer initiation', 'Disease', 'MESH:D001943', (174, 198))	('Insulin-like growth factor', 'molecular_function', 'GO:0005159', ('118', '144'))	('InsR', 'Gene', '3643', (102, 106))	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('IGF1', 'Gene', '3479', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('IGF1', 'Gene', (28, 32))	('IGF1', 'Gene', '3479', (33, 37))	('sensitizes breast cancers', 'Disease', (62, 87))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('sensitizes breast cancers', 'Disease', 'MESH:D001943', (62, 87))
21606	29941485	We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R/insulin receptor (InsR) therapies in breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('InsR', 'Gene', '3643', (195, 199))	('IGF1R/insulin receptor', 'Gene', '3643', (171, 193))	('affects', 'Reg', (126, 133))	('response', 'MPA', (154, 162))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('IGF1', 'Gene', '3479', (134, 138))	('E-cadherin', 'Gene', (115, 125))	('breast cancer', 'Disease', (214, 227))	('CDH1', 'Gene', '999', (37, 41))	('E-cadherin', 'Gene', '999', (115, 125))	('InsR', 'Gene', (195, 199))	('CDH1', 'Gene', (37, 41))	('IGF1R', 'Gene', '3480', (134, 139))	('IGF1', 'Gene', '3479', (61, 65))	('IGF1', 'Gene', '3479', (171, 175))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('IGF1R', 'Gene', (134, 139))	('IGF1', 'Gene', (134, 138))	('loss', 'Var', (107, 111))	('E-cadherin', 'Gene', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('IGF1R', 'Gene', '3480', (171, 176))	('E-cadherin', 'Gene', '999', (25, 35))	('signaling', 'biological_process', 'GO:0023052', ('140', '149'))	('IGF1R/insulin receptor', 'Gene', (171, 193))	('insulin', 'molecular_function', 'GO:0016088', ('177', '184'))	('IGF1', 'Gene', (61, 65))	('IGF1R', 'Gene', (171, 176))	('IGF1', 'Gene', (171, 175))	('cadherin', 'molecular_function', 'GO:0008014', ('117', '125'))	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))
21614	29941485	IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R/InsR inhibition reduced proliferation in ILC tumor explant culture.	('inhibiting', 'NegReg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('IGF1R', 'Gene', '3480', (135, 140))	('growth', 'MPA', (54, 60))	('inhibition reduced', 'NegReg', (146, 164))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('IGF1R', 'Gene', (0, 5))	('tumor', 'Disease', (186, 191))	('InsR', 'Gene', '3643', (141, 145))	('IGF1R', 'Gene', '3480', (0, 5))	('InsR', 'Gene', (141, 145))	('inhibitors', 'Var', (14, 24))	('proliferation', 'CPA', (165, 178))	('IGF1R', 'Gene', (135, 140))
21615	29941485	We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R/InsR targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin deficient breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('IGF1R', 'Gene', (156, 161))	('IGF1R', 'Gene', (106, 111))	('cadherin', 'molecular_function', 'GO:0008014', ('35', '43'))	('deficient breast cancers', 'Disease', (212, 236))	('IGF1R', 'Gene', '3480', (63, 68))	('deficient breast cancers', 'Disease', 'MESH:D001943', (212, 236))	('IGF1R', 'Gene', (63, 68))	('cadherin', 'molecular_function', 'GO:0008014', ('203', '211'))	('InsR', 'Gene', '3643', (112, 116))	('increases', 'PosReg', (81, 90))	('deficient breast', 'Phenotype', 'HP:0003187', (212, 228))	('E-cadherin', 'Gene', (201, 211))	('E-cadherin', 'Gene', '999', (201, 211))	('E-cadherin', 'Gene', (33, 43))	('E-cadherin', 'Gene', '999', (33, 43))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('loss', 'Var', (25, 29))	('hyperactivates', 'PosReg', (44, 58))	('InsR', 'Gene', (112, 116))	('IGF1R', 'Gene', '3480', (156, 161))	('IGF1R', 'Gene', '3480', (106, 111))	('breast cancers', 'Phenotype', 'HP:0003002', (222, 236))	('sensitivity', 'MPA', (91, 102))
21624	29941485	This computational model identified E-cadherin as a putative regulator of IGF1 signaling, and data in the present study indicate that loss of E-cadherin expression can directly increase IGF1R pathway activation and associated phenotypes in breast cancer.	('IGF1', 'Gene', (74, 78))	('IGF1R', 'Gene', (186, 191))	('E-cadherin', 'Gene', (142, 152))	('E-cadherin', 'Gene', '999', (142, 152))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('loss', 'Var', (134, 138))	('activation', 'PosReg', (200, 210))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('IGF1', 'Gene', '3479', (186, 190))	('increase IGF1R', 'Phenotype', 'HP:0030269', (177, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('IGF1', 'Gene', '3479', (74, 78))	('IGF1R', 'Gene', '3480', (186, 191))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('breast cancer', 'Disease', (240, 253))	('increase', 'PosReg', (177, 185))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('cadherin', 'molecular_function', 'GO:0008014', ('144', '152'))	('IGF1', 'Gene', (186, 190))
21625	29941485	Insight into how E-cadherin regulates IGF1R is necessary to aid in our understanding of the oncogenic signaling network, specifically because the loss of E-cadherin i) is implicated in the ability of tumor cells to escape the primary tumor to potentially seed metastatic lesions and ii) is transcriptionally repressed and/or genetically lost in subsets of breast tumors.	('tumor', 'Disease', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('escape', 'CPA', (215, 221))	('tumors', 'Phenotype', 'HP:0002664', (363, 369))	('tumor', 'Disease', (200, 205))	('E-cadherin', 'Gene', (154, 164))	('E-cadherin', 'Gene', '999', (154, 164))	('breast tumors', 'Disease', (356, 369))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('IGF1R', 'Gene', '3480', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('breast tumors', 'Phenotype', 'HP:0100013', (356, 369))	('loss', 'Var', (146, 150))	('seed metastatic lesions', 'CPA', (255, 278))	('IGF1R', 'Gene', (38, 43))	('E-cadherin', 'Gene', (17, 27))	('E-cadherin', 'Gene', '999', (17, 27))	('tumor', 'Disease', (363, 368))	('cadherin', 'molecular_function', 'GO:0008014', ('156', '164'))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('implicated', 'Reg', (171, 181))	('breast tumors', 'Disease', 'MESH:D061325', (356, 369))
21627	29941485	ILC is defined by the loss of functional E-cadherin (CDH1), which occurs in 95% of ILC due to truncating mutations, loss of heterozygosity, and transcriptional repression.	('truncating', 'MPA', (94, 104))	('CDH1', 'Gene', (53, 57))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('loss', 'NegReg', (22, 26))	('ILC', 'Disease', (0, 3))	('transcriptional repression', 'Var', (144, 170))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))	('CDH1', 'Gene', '999', (53, 57))	('loss of heterozygosity', 'Var', (116, 138))
21630	29941485	In this study, we characterize the regulation of IGF1R by E-cadherin and provide evidence that inhibition of IGF1R/insulin receptor (InsR) in E-cadherin deficient breast cancers could potentially serve as an effective therapeutic strategy.	('E-cadherin', 'Gene', (142, 152))	('E-cadherin', 'Gene', '999', (142, 152))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('deficient breast cancers', 'Disease', 'MESH:D001943', (153, 177))	('InsR', 'Gene', (133, 137))	('IGF1R/insulin receptor', 'Gene', '3643', (109, 131))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('deficient breast', 'Phenotype', 'HP:0003187', (153, 169))	('IGF1R', 'Gene', '3480', (49, 54))	('insulin', 'molecular_function', 'GO:0016088', ('115', '122'))	('breast cancers', 'Phenotype', 'HP:0003002', (163, 177))	('E-cadherin', 'Gene', (58, 68))	('E-cadherin', 'Gene', '999', (58, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('IGF1R', 'Gene', (49, 54))	('inhibition', 'Var', (95, 105))	('IGF1R', 'Gene', '3480', (109, 114))	('InsR', 'Gene', '3643', (133, 137))	('cadherin', 'molecular_function', 'GO:0008014', ('60', '68'))	('IGF1R/insulin receptor', 'Gene', (109, 131))	('IGF1R', 'Gene', (109, 114))	('regulation', 'biological_process', 'GO:0065007', ('35', '45'))	('deficient breast cancers', 'Disease', (153, 177))	('cadherin', 'molecular_function', 'GO:0008014', ('144', '152'))
21662	29941485	The median expression values for IGF1 and pIGF1R/InsR (Y1135/1136 [Cell Signaling #3024]) across ER+ IDC and ILC tumors (n=554) were used as cutoffs for Figure 4H-I.	('ILC tumors', 'Disease', 'MESH:D009369', (109, 119))	('ILC tumors', 'Disease', (109, 119))	('IGF1', 'Gene', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('Signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('pIGF1R/InsR', 'Gene', '3643', (42, 53))	('Y1135/1136 [', 'Var', (55, 67))	('IGF1', 'Gene', '3479', (33, 37))	('IGF1', 'Gene', '3479', (43, 47))	('pIGF1R/InsR', 'Gene', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('IGF1', 'Gene', (33, 37))	('ER+ IDC', 'Disease', (97, 104))
21674	29941485	40-50%), however, the knockdown of E-cadherin rescued signaling in both confluency conditions (Fig 1E).	('rescued', 'PosReg', (46, 53))	('E-cadherin', 'Gene', '999', (35, 45))	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('knockdown', 'Var', (22, 31))	('cadherin', 'molecular_function', 'GO:0008014', ('37', '45'))	('signaling', 'MPA', (54, 63))	('E-cadherin', 'Gene', (35, 45))
21680	29941485	Due to the enhanced sensitivity of E-cadherin knockdown cells to IGF1 stimulation, we determined if loss of E-cadherin in MCF-7 and ZR75.1 cells also increased sensitivity to the IGF1R/InsR ATP-competitive small molecule inhibitors, OSI-906 (OSI) and BMS-754807 (BMS).	('ATP', 'Chemical', 'MESH:D000255', (190, 193))	('sensitivity', 'MPA', (20, 31))	('enhanced', 'PosReg', (11, 19))	('IGF1', 'Gene', (65, 69))	('E-cadherin', 'Gene', (108, 118))	('BMS-754807', 'Chemical', 'MESH:C545990', (251, 261))	('loss', 'Var', (100, 104))	('E-cadherin', 'Gene', '999', (108, 118))	('InsR', 'Gene', '3643', (185, 189))	('sensitivity', 'MPA', (160, 171))	('IGF1', 'Gene', '3479', (179, 183))	('E-cadherin', 'Gene', (35, 45))	('E-cadherin', 'Gene', '999', (35, 45))	('cadherin', 'molecular_function', 'GO:0008014', ('37', '45'))	('InsR', 'Gene', (185, 189))	('IGF1R', 'Gene', '3480', (179, 184))	('IGF1', 'Gene', '3479', (65, 69))	('MCF-7', 'CellLine', 'CVCL:0031', (122, 127))	('IGF1', 'Gene', (179, 183))	('IGF1R', 'Gene', (179, 184))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('increased', 'PosReg', (150, 159))
21682	29941485	In addition to 2D adherent culture, ultra-low attachment suspension growth (ULA) was examined, since we observed increased cell viability in E-cadherin knockdown cells under these conditions (Tasdemir et al, manuscript in preparation), possibly due to the reported annoikis resistance of cells lacking E-cadherin expression.	('E-cadherin', 'Gene', '999', (141, 151))	('knockdown', 'Var', (152, 161))	('cadherin', 'molecular_function', 'GO:0008014', ('143', '151'))	('cadherin', 'molecular_function', 'GO:0008014', ('304', '312'))	('cell viability', 'CPA', (123, 137))	('E-cadherin', 'Gene', '999', (302, 312))	('increased', 'PosReg', (113, 122))	('E-cadherin', 'Gene', (302, 312))	('E-cadherin', 'Gene', (141, 151))
21687	29941485	Overall, these data suggest that the loss of E-cadherin enhances breast cancer cell sensitivity to IGF1R/InsR inhibition.	('InsR', 'Gene', (105, 109))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('IGF1R', 'Gene', (99, 104))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('IGF1R', 'Gene', '3480', (99, 104))	('loss', 'Var', (37, 41))	('InsR', 'Gene', '3643', (105, 109))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))	('enhances', 'PosReg', (56, 64))
21688	29941485	We also tested the growth response of MCF-7 siSCR and siCDH1 cells treated with ICI 182,780 (ICI), a selective estrogen receptor downregulator (SERD), and observed no statistical difference in EC50 suggesting that the loss of E-cadherin does not generally sensitize cells to all small molecule drug treatments (Fig S5).	('tested', 'Reg', (8, 14))	('ICI', 'Chemical', 'MESH:C481040', (80, 83))	('MCF-7', 'CellLine', 'CVCL:0031', (38, 43))	('CDH1', 'Gene', (56, 60))	('cadherin', 'molecular_function', 'GO:0008014', ('228', '236'))	('ICI 182,780', 'Chemical', 'MESH:C070081', (80, 91))	('CDH1', 'Gene', '999', (56, 60))	('loss', 'Var', (218, 222))	('E-cadherin', 'Gene', (226, 236))	('E-cadherin', 'Gene', '999', (226, 236))	('downregulator', 'NegReg', (129, 142))	('ICI', 'Chemical', 'MESH:C481040', (93, 96))	('estrogen', 'Chemical', 'MESH:D004967', (111, 119))
21695	29941485	In MCF-7 cells, IGF1 treatment caused a significant decrease in number of fluorescent puncta (p=0.003), suggesting that the interaction between the two proteins needs to be disrupted for proper IGF1R function (Fig 3E-I [high magnification], Fig S6E-H [low magnification]), possibly explaining why siCDH1 cells have an increased IGF1R signaling capacity compared to control cells.	('IGF1R', 'Gene', (194, 199))	('IGF1', 'Gene', (194, 198))	('IGF1R', 'Gene', (328, 333))	('IGF1', 'Gene', (328, 332))	('increased IGF1R', 'Phenotype', 'HP:0030269', (318, 333))	('CDH1', 'Gene', '999', (299, 303))	('IGF1', 'Gene', '3479', (16, 20))	('CDH1', 'Gene', (299, 303))	('interaction', 'Interaction', (124, 135))	('signaling', 'biological_process', 'GO:0023052', ('334', '343'))	('decrease', 'NegReg', (52, 60))	('number of fluorescent puncta', 'MPA', (64, 92))	('increased IGF1', 'Phenotype', 'HP:0030269', (318, 332))	('IGF1', 'Gene', (16, 20))	('IGF1', 'Gene', '3479', (194, 198))	('treatment', 'Var', (21, 30))	('increased', 'PosReg', (318, 327))	('IGF1', 'Gene', '3479', (328, 332))	('MCF-7', 'CellLine', 'CVCL:0031', (3, 8))	('IGF1R', 'Gene', '3480', (194, 199))	('IGF1R', 'Gene', '3480', (328, 333))
21701	29941485	Because knockdown or inhibition of E-cadherin induces hyperactivity of the IGF1R pathway in cell line models, we investigated whether IGF1R pathway activity is also hyperactivated in ILC, a subtype of breast cancer that accounts for 10-15% of all breast cancer cases and is molecularly classified by its genetic loss of E-cadherin.	('ILC', 'Disease', (183, 186))	('genetic loss', 'Disease', (304, 316))	('hyperactivity', 'Disease', 'MESH:D006948', (54, 67))	('IGF1R', 'Gene', (75, 80))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('breast cancer', 'Disease', (247, 260))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cadherin', 'molecular_function', 'GO:0008014', ('322', '330'))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('hyperactivity', 'Disease', (54, 67))	('IGF1R', 'Gene', '3480', (134, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('inhibition', 'NegReg', (21, 31))	('hyperactivated', 'PosReg', (165, 179))	('E-cadherin', 'Gene', (35, 45))	('E-cadherin', 'Gene', '999', (35, 45))	('E-cadherin', 'Gene', (320, 330))	('E-cadherin', 'Gene', '999', (320, 330))	('IGF1R', 'Gene', (134, 139))	('activity', 'MPA', (148, 156))	('cadherin', 'molecular_function', 'GO:0008014', ('37', '45'))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('breast cancer', 'Disease', (201, 214))	('genetic loss', 'Disease', 'MESH:D020022', (304, 316))	('hyperactivity', 'Phenotype', 'HP:0000752', (54, 67))	('knockdown', 'Var', (8, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('IGF1R', 'Gene', '3480', (75, 80))
21727	29941485	In the MM134 tumor we observed a significant decrease (p=0.002) in Ki67 positive nuclei from 47% in the vehicle to 22% in the BMS treated tumor tissue (n=3 or 4; Fig 6A-C).	('MM134', 'Var', (7, 12))	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (138, 143))	('Ki67', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('decrease', 'NegReg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
21730	29941485	Despite a large body of preclinical evidence supporting the use of IGF1R/InsR inhibitors for the treatment of breast cancer, the outcomes of clinical trials testing the efficacy of these drugs in patients thus far have been disappointing.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('IGF1R', 'Gene', (67, 72))	('InsR', 'Gene', '3643', (73, 77))	('IGF1R', 'Gene', '3480', (67, 72))	('inhibitors', 'Var', (78, 88))	('patients', 'Species', '9606', (196, 204))	('InsR', 'Gene', (73, 77))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
21748	29941485	described the requirement for IGF1R internalization via endocytosis for maximal activation of IGF1-induced Akt signaling, showing that inhibition of IGF1R internalization was sufficient to block maximal Akt activation.	('Akt', 'Gene', (203, 206))	('Akt', 'Gene', (107, 110))	('IGF1', 'Gene', (30, 34))	('IGF1R', 'Gene', '3480', (149, 154))	('IGF1', 'Gene', '3479', (94, 98))	('IGF1', 'Gene', '3479', (30, 34))	('internalization', 'MPA', (155, 170))	('IGF1R', 'Gene', (30, 35))	('Akt', 'Gene', '207', (203, 206))	('IGF1', 'Gene', '3479', (149, 153))	('IGF1R', 'Gene', '3480', (30, 35))	('Akt signaling', 'biological_process', 'GO:0043491', ('107', '120'))	('endocytosis', 'biological_process', 'GO:0006897', ('56', '67'))	('inhibition', 'Var', (135, 145))	('Akt', 'Gene', '207', (107, 110))	('IGF1', 'Gene', (149, 153))	('IGF1', 'Gene', (94, 98))	('IGF1R', 'Gene', (149, 154))
21755	29941485	Supporting this concept, our data indicate that the knockdown of E-cadherin in three ER+ breast cancer cell lines not only enhanced IGF1-induced signaling via IGF1R/InsR but also increased sensitivity of the cells to the ligand.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('InsR', 'Gene', (165, 169))	('breast cancer', 'Disease', (89, 102))	('IGF1', 'Gene', '3479', (159, 163))	('knockdown', 'Var', (52, 61))	('increased', 'PosReg', (179, 188))	('ligand', 'molecular_function', 'GO:0005488', ('221', '227'))	('IGF1R', 'Gene', '3480', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('IGF1', 'Gene', '3479', (132, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('67', '75'))	('IGF1R', 'Gene', (159, 164))	('IGF1', 'Gene', (159, 163))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('IGF1', 'Gene', (132, 136))	('enhanced IGF1', 'Phenotype', 'HP:0030269', (123, 136))	('E-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (65, 75))	('enhanced', 'PosReg', (123, 131))	('InsR', 'Gene', '3643', (165, 169))	('sensitivity', 'MPA', (189, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))
21766	29941485	One limitation for the use of IGF1R inhibitors in ILC is the relatively high prevalence of mutations in the PI3K/Akt signaling pathway.	('Akt signaling', 'biological_process', 'GO:0043491', ('113', '126'))	('ILC', 'Disease', (50, 53))	('Akt', 'Gene', '207', (113, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('IGF1R', 'Gene', (30, 35))	('signaling pathway', 'biological_process', 'GO:0007165', ('117', '134'))	('IGF1R', 'Gene', '3480', (30, 35))	('Akt', 'Gene', (113, 116))	('mutations', 'Var', (91, 100))
21772	29941485	Resistance to other upstream kinase inhibitors in tumors harboring activating alterations in PIK3CA/PTEN has been previously observed and therefore, it would be important to screen patients for these alterations before considering use of receptor tyrosine kinase inhibitor therapy.	('PTEN', 'Gene', (100, 104))	('Resistance', 'MPA', (0, 10))	('PIK3CA', 'Gene', '5290', (93, 99))	('PTEN', 'Gene', '5728', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tyrosine', 'Chemical', 'None', (247, 255))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('256', '272'))	('alterations', 'Var', (78, 89))	('patients', 'Species', '9606', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('activating', 'PosReg', (67, 77))	('PIK3CA', 'Gene', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
21774	29941485	recently reported that high levels of insulin promote resistance to PI3K inhibitors in tumors with PIK3CA mutations, and therefore there may also be a role for combinatorial IGF1R and PI3K inhibition.	('promote', 'PosReg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('PIK3CA', 'Gene', '5290', (99, 105))	('insulin', 'molecular_function', 'GO:0016088', ('38', '45'))	('resistance to PI3K inhibitors', 'MPA', (54, 83))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('184', '188'))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('IGF1R', 'Gene', (174, 179))	('mutations', 'Var', (106, 115))	('insulin', 'Gene', (38, 45))	('insulin', 'Gene', '3630', (38, 45))	('IGF1R', 'Gene', '3480', (174, 179))	('PIK3CA', 'Gene', (99, 105))
21776	29941485	In summary, we present a diverse set of data indicating that the loss of E-cadherin enhances IGF1R pathway activity and sensitivity to IGF1R/InsR therapy, specifically in ILC.	('sensitivity', 'MPA', (120, 131))	('E-cadherin', 'Gene', (73, 83))	('enhances', 'PosReg', (84, 92))	('loss', 'Var', (65, 69))	('IGF1R', 'Gene', '3480', (135, 140))	('ILC', 'Disease', (171, 174))	('activity', 'MPA', (107, 115))	('IGF1R', 'Gene', '3480', (93, 98))	('E-cadherin', 'Gene', '999', (73, 83))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('InsR', 'Gene', '3643', (141, 145))	('IGF1R', 'Gene', (93, 98))	('InsR', 'Gene', (141, 145))	('IGF1R', 'Gene', (135, 140))
21784	26266010	Gastric Metastasis of Triple Negative Invasive Lobular Carcinoma Invasive lobular carcinomas are the second most common type (5% to 15%) of invasive breast carcinomas.	('lobular carcinomas', 'Disease', 'MESH:D018275', (74, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('invasive breast carcinomas', 'Disease', (140, 166))	('Triple Negative', 'Var', (22, 37))	('Lobular Carcinoma', 'Disease', (47, 64))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (74, 92))	('breast carcinoma', 'Phenotype', 'HP:0003002', (149, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Lobular Carcinoma', 'Disease', 'MESH:D018275', (47, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (140, 166))	('lobular carcinomas', 'Disease', (74, 92))	('Carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('Lobular Carcinoma', 'Phenotype', 'HP:0030076', (47, 64))	('Gastric', 'Disease', (0, 7))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (74, 91))	('breast carcinomas', 'Phenotype', 'HP:0003002', (149, 166))
21830	26266010	Our case was surgically exposed to partial gastrectomy because as a result of the biopsy pathologists considered the case was gastric adenocarcinoma While forming the diagnostic procedure of breast cancer metastasis to the stomach, immunostaining of CK20 and CK7 is a beneficial modality.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (126, 148))	('CK7', 'Gene', (259, 262))	('gastric adenocarcinoma', 'Disease', (126, 148))	('CK20', 'Gene', '54474', (250, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('breast cancer metastasis to the stomach', 'Disease', 'MESH:D009362', (191, 230))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('CK7', 'Gene', '3855', (259, 262))	('CK20', 'Gene', (250, 254))	('breast cancer metastasis to the stomach', 'Disease', (191, 230))	('immunostaining', 'Var', (232, 246))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
21845	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))
21846	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))	('STK11', 'molecular_function', 'GO:0033868', ('63', '68'))	('CDH1', 'Gene', (57, 61))	('PTEN', 'Gene', '5728', (74, 78))	('TP53', 'Gene', '7157', (44, 48))	('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))
21875	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))	('STK11', 'molecular_function', 'GO:0033868', ('195', '200'))	('BRCA-2', 'Gene', '675', (168, 174))	('STK11', 'Gene', '6794', (195, 200))	('PALB2', 'Gene', '79728', (182, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('BRCA-2', 'Gene', (168, 174))	('BRCA-1', 'Gene', (160, 166))	('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))
22047	29595684	Based on these findings, the patient was diagnosed with T3N0M0 gastric cancer according to the 7th edition of the AJCC staging system.	('patient', 'Species', '9606', (29, 36))	('gastric cancer', 'Disease', (63, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('T3N0M0', 'Var', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
22107	25834613	We compared clinical and histopathological characteristics and the diagnostic performances of MRI and 18F-FDG PET/CT for the primary mass, additional ipsilateral and/or contralateral lesion(s), and axillary lymph node metastasis between the ILC and IDC groups.	('IDC', 'Gene', '4000', (249, 252))	('axillary lymph node metastasis', 'CPA', (198, 228))	('18F-FDG', 'Chemical', 'MESH:D019788', (102, 109))	('IDC', 'Gene', (249, 252))	('MRI', 'Var', (94, 97))
22112	25834613	The sensitivity for ipsilateral lesion(s) was significantly higher with MRI; however, specificity was higher with 18F-FDG PET/CT in both tumor groups.	('tumor', 'Disease', (137, 142))	('18F-FDG PET/CT', 'Var', (114, 128))	('higher', 'PosReg', (60, 66))	('sensitivity', 'MPA', (4, 15))	('ipsilateral lesion', 'Disease', (20, 38))	('ipsilateral lesion', 'Disease', 'MESH:D006053', (20, 38))	('specificity', 'MPA', (86, 97))	('higher', 'PosReg', (102, 108))	('MRI', 'Var', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('18F-FDG', 'Chemical', 'MESH:D019788', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
22113	25834613	There was no significant difference in the diagnostic performance for additional contralateral lesion(s) or axillary lymph node metastasis on MRI or 18F-FDG PET/CT for ILC versus IDC.	('IDC', 'Gene', '4000', (179, 182))	('MRI', 'Var', (142, 145))	('18F-FDG', 'Chemical', 'MESH:D019788', (149, 156))	('IDC', 'Gene', (179, 182))	('ILC', 'Disease', (168, 171))	('axillary lymph node metastasis', 'CPA', (108, 138))
22115	25834613	Although 18F-FDG PET/CT demonstrates lower sensitivity for primary and additional ipsilateral lesions, it shows higher specificity for additional ipsilateral lesions, and could play a complementary role in the staging of ILC as well as IDC.	('IDC', 'Gene', (236, 239))	('ipsilateral lesion', 'Disease', (146, 164))	('IDC', 'Gene', '4000', (236, 239))	('higher', 'PosReg', (112, 118))	('specificity', 'MPA', (119, 130))	('ipsilateral lesion', 'Disease', 'MESH:D006053', (82, 100))	('play', 'Reg', (177, 181))	('ILC', 'Disease', (221, 224))	('ipsilateral lesion', 'Disease', (82, 100))	('18F-FDG', 'Var', (9, 16))	('lower', 'NegReg', (37, 42))	('ipsilateral lesion', 'Disease', 'MESH:D006053', (146, 164))	('18F-FDG', 'Chemical', 'MESH:D019788', (9, 16))	('sensitivity', 'MPA', (43, 54))
22120	25834613	However, the sensitivities of 18F-FDG PET/CT for primary cancer, multiple lesions, and axillary lymph node metastasis are not comparable to those of US or MRI.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('18F-FDG', 'Var', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('18F-FDG', 'Chemical', 'MESH:D019788', (30, 37))
22147	25834613	If a tissue diagnosis was unattainable, follow-up studies were used to evaluate the clinical significance of additional findings on MRI and/or 18F-FDG PET/CT.	('18F-FDG', 'Chemical', 'MESH:D019788', (143, 150))	('MRI', 'Var', (132, 135))	('18F-FDG', 'Var', (143, 150))
22163	25834613	With 18F-FDG PET/CT, the detection rate for ILC (75.0%) was lower than that for IDC (83.6%), but did not achieve statistical significance.	('IDC', 'Gene', (80, 83))	('18F-FDG', 'Chemical', 'MESH:D019788', (5, 12))	('18F-FDG PET/CT', 'Var', (5, 19))	('ILC', 'Disease', (44, 47))	('IDC', 'Gene', '4000', (80, 83))	('lower', 'NegReg', (60, 65))
22166	25834613	The diagnostic performances of MRI and 18F-FDG PET/CT for additional ipsilateral and contralateral lesion(s) and axillary lymph node metastasis are presented in Table 3.	('axillary lymph node metastasis', 'CPA', (113, 143))	('MRI', 'Var', (31, 34))	('18F-FDG', 'Chemical', 'MESH:D019788', (39, 46))
22174	25834613	Comparing the diagnostic performance between MRI and 18F-FDG PET/CT in the ILC group, the sensitivity was significantly higher with MRI (87.5% vs. 0%, p=0.001); however, the specificity was higher with 18F-FDG PET/CT (58.3% vs. 91.7%, p=0.008) (Figure 2).	('18F-FDG', 'Chemical', 'MESH:D019788', (53, 60))	('18F-FDG', 'Chemical', 'MESH:D019788', (202, 209))	('higher', 'PosReg', (120, 126))	('MRI', 'Var', (132, 135))	('18F-FDG PET/CT', 'Var', (202, 216))	('higher', 'PosReg', (190, 196))
22175	25834613	The accuracy for ipsilateral lesion(s) in the ILC group was not significantly different between MRI and 18F-FDG PET/CT (65.6% vs. 68.8%, p=0.790).	('MRI', 'Var', (96, 99))	('ipsilateral lesion', 'Disease', 'MESH:D006053', (17, 35))	('ipsilateral lesion', 'Disease', (17, 35))	('18F-FDG', 'Chemical', 'MESH:D019788', (104, 111))
22176	25834613	The AUC from the ROC analysis was significantly higher for MRI than 18F-FDG PET-CT (0.73 vs. 0.54, p=0.027).	('AUC', 'MPA', (4, 7))	('18F-FDG', 'Chemical', 'MESH:D019788', (68, 75))	('higher', 'PosReg', (48, 54))	('MRI', 'Var', (59, 62))
22177	25834613	Comparing the diagnostic performance between MRI and 18F-FDG PET/CT in the IDC group, the sensitivity was significantly higher with MRI (100.0% vs. 37.5%, p<0.001) (Figure 3); however, the specificity was higher with 18F-FDG PET/CT (66.7% vs. 94.7%, p<0.001).	('18F-FDG', 'Chemical', 'MESH:D019788', (53, 60))	('IDC', 'Gene', (75, 78))	('higher', 'PosReg', (205, 211))	('higher', 'PosReg', (120, 126))	('18F-FDG', 'Chemical', 'MESH:D019788', (217, 224))	('MRI', 'Var', (132, 135))	('18F-FDG PET/CT', 'Var', (217, 231))	('IDC', 'Gene', '4000', (75, 78))
22179	25834613	The AUC from the ROC analysis was significantly higher for MRI than 18F-FDG PET-CT (0.83 vs. 0.66, p=0.008).	('AUC', 'MPA', (4, 7))	('18F-FDG', 'Chemical', 'MESH:D019788', (68, 75))	('higher', 'PosReg', (48, 54))	('MRI', 'Var', (59, 62))
22187	25834613	There was no statistically significant difference between the diagnostic performances of MRI and 18F-FDG PET/CT in the detection of contralateral lesion(s) and axillary lymph node metastasis in either cancer group.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('axillary lymph node metastasis', 'CPA', (160, 190))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('18F-FDG', 'Chemical', 'MESH:D019788', (97, 104))	('MRI', 'Var', (89, 92))
22202	25834613	reported that the sensitivity of 18F-FDG PET/CT for primary breast cancer was 89.6%, which is similar or slightly higher than that of the IDC group in our study.	('breast cancer', 'Disease', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('18F-FDG', 'Var', (33, 40))	('IDC', 'Gene', '4000', (138, 141))	('IDC', 'Gene', (138, 141))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('18F-FDG', 'Chemical', 'MESH:D019788', (33, 40))
22206	25834613	In a semiquantitative assessment of 18F-FDG PET/CT, even when the cutoff value was set to 1.0, the cancer detection rate was lower than that of visual assessment.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('18F-FDG PET/CT', 'Var', (36, 50))	('cancer', 'Disease', (99, 105))	('lower', 'NegReg', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('18F-FDG', 'Chemical', 'MESH:D019788', (36, 43))
22209	25834613	Indeed, there are concerns about the high false-positive rate, overestimation of tumor extent on MRI, and resulting unnecessary mastectomies, but recent studies have shown that preoperative MRI can reduce the re-excision rate without increasing the rate of unnecessary mastectomies.	('reduce', 'NegReg', (198, 204))	('false', 'biological_process', 'GO:0071878', ('42', '47'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('re-excision', 'CPA', (209, 220))	('MRI', 'Var', (190, 193))	('false', 'biological_process', 'GO:0071877', ('42', '47'))	('tumor', 'Disease', (81, 86))
22213	25834613	In the current study, the sensitivities of 18F-FDG PET/CT in detecting additional ipsilateral lesion(s) were 0.0% for ILC and 37.5% for IDC; the specificities were 91.7% and 94.7%, respectively.	('ipsilateral lesion', 'Disease', 'MESH:D006053', (82, 100))	('ILC', 'Disease', (118, 121))	('18F-FDG', 'Chemical', 'MESH:D019788', (43, 50))	('IDC', 'Gene', '4000', (136, 139))	('ipsilateral lesion', 'Disease', (82, 100))	('IDC', 'Gene', (136, 139))	('18F-FDG', 'Var', (43, 50))
22220	25834613	The number of false-positive cases for multiple contralateral lesions was higher on MRI (n=7, 5 IDC and 2 ILC) than 18F-FDG PET/CT (n=3, 3 IDC).	('false', 'biological_process', 'GO:0071878', ('14', '19'))	('IDC', 'Gene', (139, 142))	('18F-FDG', 'Chemical', 'MESH:D019788', (116, 123))	('IDC', 'Gene', '4000', (96, 99))	('IDC', 'Gene', (96, 99))	('false', 'biological_process', 'GO:0071877', ('14', '19'))	('MRI', 'Var', (84, 87))	('IDC', 'Gene', '4000', (139, 142))
22227	25834613	They concluded that 18F-FDG PET/CT cannot replace invasive approaches for axillary staging, but may extend the indications for sentinel lymph node biopsy because of its high specificity and accuracy.	('18F-FDG', 'Var', (20, 27))	('extend', 'PosReg', (100, 106))	('18F-FDG', 'Chemical', 'MESH:D019788', (20, 27))
22228	25834613	In a previous study, the sensitivity and specificity of 18F-FDG PET/CT for axillary lymph node metastasis were reported to be 37.3% and 95.8%, respectively.	('18F-FDG', 'Var', (56, 63))	('18F-FDG', 'Chemical', 'MESH:D019788', (56, 63))	('axillary lymph node metastasis', 'CPA', (75, 105))
22239	25834613	However, 18F-FDG PET/CT demonstrates higher specificity for additional ipsilateral lesions, which could compensate for the lower specificity of MRI.	('ipsilateral lesion', 'Disease', (71, 89))	('higher', 'PosReg', (37, 43))	('18F-FDG', 'Var', (9, 16))	('18F-FDG', 'Chemical', 'MESH:D019788', (9, 16))	('ipsilateral lesion', 'Disease', 'MESH:D006053', (71, 89))
22240	25834613	The diagnostic performance for additional contralateral lesion(s) and axillary lymph node metastasis do not differ significantly between MRI and 18F-FDG PET/CT in the ILC or IDC group.	('MRI', 'Var', (137, 140))	('IDC', 'Gene', '4000', (174, 177))	('IDC', 'Gene', (174, 177))	('18F-FDG', 'Chemical', 'MESH:D019788', (145, 152))	('18F-FDG PET/CT', 'Var', (145, 159))
22272	24633840	Other markers of LN include the cytoplasmic localisation of p120-catenin and cytokeratin-34betaE12.	('cytokeratin-34betaE12', 'Var', (77, 98))	('localisation', 'biological_process', 'GO:0051179', ('44', '56'))	('p120-catenin', 'Gene', '1500', (60, 72))	('p120-catenin', 'Gene', (60, 72))
22279	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))	('HER2', 'Gene', (173, 177))	('E-cadherin', 'Gene', (67, 77))	('E-cadherin', 'Gene', '999', (67, 77))	('HER2', 'Gene', '2064', (173, 177))	('cadherin', 'molecular_function', 'GO:0008014', ('69', '77'))	('higher', 'PosReg', (181, 187))	('expression', 'MPA', (159, 169))	('progesterone receptors', 'Protein', (126, 148))	('absence', 'NegReg', (56, 63))	('lower', 'NegReg', (92, 97))	('expression', 'MPA', (98, 108))
22304	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))	('cadherin', 'molecular_function', 'GO:0008014', ('6', '14'))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('ILC', 'Disease', (140, 143))	('tumour', 'Disease', (54, 60))	('mutations', 'Var', (109, 118))	('E-cadherin', 'Gene', (4, 14))	('E-cadherin', 'Gene', '999', (4, 14))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('low-grade DCIS', 'Disease', (148, 162))
22343	24591794	In the TNM staging classification, LABC is represented by stage IIIA (T0-N2; T1/2 - N2; T3 - N1/2), stage IIIB (T4, N0-2) and stage IIIC disease (any T, N3).	('TNM', 'Gene', '10178', (7, 10))	('T0-N2;', 'Var', (70, 76))	('LABC', 'Disease', (35, 39))	('stage IIIC disease', 'Disease', (126, 144))	('T3 - N1/2', 'Var', (88, 97))	('TNM', 'Gene', (7, 10))	('T4', 'Var', (112, 114))
22365	24591794	Estrogen receptors showed positivity in 66 patients (67.3%), and progesterone receptors in 55 patients (56.1%).	('progesterone receptor', 'Gene', '5241', (65, 86))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (43, 51))	('Estrogen receptors', 'Protein', (0, 18))	('progesterone receptor', 'Gene', (65, 86))	('positivity', 'Var', (26, 36))
22435	21151863	One representative section from each case was also stained with antibodies to basal markers CK5/6 (clone D5/16B4, Dako), CK14 (clone LL002 Noracastra) and CK17 (clone E3, Dako), and luminal markers CK8 (clone 35bH11, Dako) and CK18 (clone DC10, Dako).	('CK8', 'Gene', '3856', (198, 201))	('CK14', 'Gene', (121, 125))	('clone 35bH11', 'Var', (203, 215))	('CK8', 'Gene', (198, 201))	('CK18', 'Gene', (227, 231))	('CK5/6', 'Gene', '3852', (92, 97))	('DC10', 'Gene', (239, 243))	('CK5/6', 'Gene', (92, 97))	('CK18', 'Gene', '3875', (227, 231))	('CK17', 'Gene', '3872', (155, 159))	('DC10', 'Gene', '26269', (239, 243))	('CK14', 'Gene', '3861', (121, 125))	('CK17', 'Gene', (155, 159))
22510	33616312	LOXL1 knockdown also impaired lobular xenograft growth with a coincident decrease in tumor cell proliferation and loss of collagen fiber organization.	('tumor', 'Disease', (85, 90))	('collagen fiber organization', 'CPA', (122, 149))	('collagen', 'molecular_function', 'GO:0005202', ('122', '130'))	('LOXL1', 'Gene', '4016', (0, 5))	('loss', 'NegReg', (114, 118))	('loss of collagen fiber', 'Phenotype', 'HP:0030095', (114, 136))	('LOXL1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('decrease', 'NegReg', (73, 81))	('impaired', 'NegReg', (21, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('knockdown', 'Var', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lobular xenograft growth', 'CPA', (30, 54))
22517	33616312	Also, deletion of CDH1 in ILC may well activate dependence on ROS1 tyrosine kinase signaling (Bajrami et al, 2018).	('CDH1', 'Gene', (18, 22))	('CDH1', 'Gene', '999', (18, 22))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('ROS1', 'Gene', (62, 66))	('deletion', 'Var', (6, 14))	('ROS1', 'Gene', '6098', (62, 66))	('activate', 'PosReg', (39, 47))
22541	29402252	However, in patients undergoing mastectomy, positive SLN leads to ALND.	('patients', 'Species', '9606', (12, 20))	('ALND', 'Chemical', '-', (66, 70))	('ALND', 'MPA', (66, 70))	('SLN', 'Var', (53, 56))	('positive SLN', 'Var', (44, 56))	('leads to', 'Reg', (57, 65))
22636	29402252	However, it must be emphasized that in our study majority of patients, who benefited from one stage axillary procedure were patients with N2/N3 disease and patients with large LN metastases, who will, despite the changes in the axillary treatment, still require ALND as part of the regional treatment of the nodal disease.	('patients', 'Species', '9606', (156, 164))	('ALND', 'Chemical', '-', (262, 266))	('patients', 'Species', '9606', (61, 69))	('N2/N3 disease', 'Var', (138, 151))	('nodal disease', 'Disease', 'MESH:D013611', (308, 321))	('nodal disease', 'Disease', (308, 321))	('metastases', 'Disease', (179, 189))	('metastases', 'Disease', 'MESH:D009362', (179, 189))	('patients', 'Species', '9606', (124, 132))
19826	23833125	All women diagnosed with an invasive breast cancer with a lobular component based on ICD-O codes 8520, 8522, and 8524 assigned by CSS were potentially eligible as lobular cases.	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('invasive breast cancer', 'Disease', (28, 50))	('8520', 'Var', (97, 101))	('8522', 'Var', (103, 107))	('women', 'Species', '9606', (4, 9))	('invasive breast cancer', 'Disease', 'MESH:D001943', (28, 50))	('CSS', 'Chemical', '-', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
19838	23833125	In addition, we assessed whether or not risk estimates differed among women with invasive lobular (ICD-O codes 8520 and 8524) versus invasive ductal-lobular (ICD-O code 8522) carcinomas.	('invasive lobular', 'Disease', (81, 97))	('8524', 'Var', (120, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('carcinomas', 'Disease', (175, 185))	('carcinomas', 'Disease', 'MESH:D002277', (175, 185))	('women', 'Species', '9606', (70, 75))
22826	23833125	Laboratory studies have investigated how disrupting the melavonate pathway may lead to carcinogenesis and have discovered both pro and anti-cancer effects of statins.	('melavonate', 'Chemical', '-', (56, 66))	('disrupting', 'Var', (41, 51))	('melavonate pathway', 'Pathway', (56, 74))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('carcinogenesis', 'Disease', (87, 101))	('lead to', 'Reg', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
22832	23833125	In the WHI cohort while use of hydrophilic statins was not related to breast cancer risk, an 18% (p = 0.02) lower breast cancer incidence was observed among users of lipophilic statins (simvastatin, lovastatin or fluvastatin) compared to statin nonusers.	('lovastatin', 'Chemical', 'MESH:D008148', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (70, 83))	('lower', 'NegReg', (108, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('fluvastatin', 'Chemical', 'MESH:D000077340', (213, 224))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('simvastatin', 'Chemical', 'MESH:D019821', (186, 197))	('lipophilic', 'Var', (166, 176))	('breast cancer', 'Disease', (114, 127))
22849	33921735	Pathological examination with immunohistochemistry staining established the complete diagnostic: pT2pN3aM1 Stage IV breast cancer, luminal B subtype.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('pT2pN3aM1', 'Var', (97, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('luminal', 'Chemical', 'MESH:D010634', (131, 138))	('aM1', 'Species', '408139', (103, 106))
22900	33921735	Biologically, CA15-3 tumor marker value was increased at 4339 U/mL, whilst the rest of the blood tests were normal.	('tumor', 'Disease', (21, 26))	('4339 U/mL', 'Var', (57, 66))	('CA15-3', 'Gene', '4582', (14, 20))	('increased', 'PosReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('CA15-3', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
23022	27000271	Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS).	('OS', 'Chemical', '-', (147, 149))	('Ki67', 'Chemical', '-', (0, 4))	('OS', 'Chemical', '-', (73, 75))	('Ki67', 'Var', (0, 4))	('DFS', 'Disease', (65, 68))
23024	27000271	The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with 'pure' ILC performed worse than 'mixed' histology.	('Ki67', 'Chemical', '-', (53, 57))	('increases', 'PosReg', (58, 67))	('patients', 'Species', '9606', (78, 86))	('pure', 'molecular_function', 'GO:0034023', ('93', '97'))	('DFS rate', 'MPA', (31, 39))	('ILC', 'Disease', (99, 102))	('decreases', 'NegReg', (40, 49))	('Ki67', 'Var', (53, 57))
23025	27000271	Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with 'pure' ILC.	('pure', 'molecular_function', 'GO:0034023', ('197', '201'))	('Ki67', 'Chemical', '-', (63, 67))	('discriminate', 'Reg', (94, 106))	('Ki67', 'Var', (63, 67))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (124, 132))	('ILC', 'Disease', (138, 141))
23029	27000271	With regard to molecular features, the most frequent genetic alteration of ILC is the loss of 16q chromosome, where the E-cadherin gene (CDH1) is located.	('ILC', 'Gene', (75, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('loss of', 'Var', (86, 93))	('E-cadherin', 'Gene', (120, 130))	('E-cadherin', 'Gene', '999', (120, 130))	('CDH1', 'Gene', (137, 141))	('cadherin', 'molecular_function', 'GO:0008014', ('122', '130'))	('CDH1', 'Gene', '999', (137, 141))
23030	27000271	The loss of E-cadherin, a transmembrane glycoprotein that mediates the adhesion between the epithelial cells, promotes invasion and metastatic behavior and is also associated with the process of epithelial to mesenchymal transition.	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('195', '231'))	('transmembrane', 'cellular_component', 'GO:0016021', ('26', '39'))	('E-cadherin', 'Gene', (12, 22))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('associated', 'Reg', (164, 174))	('invasion', 'CPA', (119, 127))	('transmembrane', 'cellular_component', 'GO:0044214', ('26', '39'))	('E-cadherin', 'Gene', '999', (12, 22))	('promotes', 'PosReg', (110, 118))	('epithelial to mesenchymal transition', 'CPA', (195, 231))	('loss', 'Var', (4, 8))
23036	27000271	As the majority of prognostic factors for early ILC, the value of Ki67 derives from the context of trials where the most of patients included are affected by IDC, thereby limiting its clinical utility in the specific context of ILC.	('IDC', 'Gene', '4000', (158, 161))	('IDC', 'Gene', (158, 161))	('Ki67', 'Var', (66, 70))	('Ki67', 'Chemical', '-', (66, 70))	('affected', 'Reg', (146, 154))	('patients', 'Species', '9606', (124, 132))
23037	27000271	Thus, the long-term prognostic role of Ki67 in ILC has not yet been fully established.	('Ki67', 'Chemical', '-', (39, 43))	('ILC', 'Disease', (47, 50))	('Ki67', 'Var', (39, 43))
23077	27000271	The results of the analysis reported herein suggest that the Ki67 assay is able to significantly discriminate the long-term prognosis of patients with primary resected ILC.	('Ki67', 'Var', (61, 65))	('Ki67', 'Chemical', '-', (61, 65))	('discriminate', 'Reg', (97, 109))	('patients', 'Species', '9606', (137, 145))	('primary resected ILC', 'Disease', (151, 171))
23081	27000271	These studies have shown an independent significant association between high Ki67 expression and increased risk of breast cancer relapse and benefit of the addition of adjuvant cytotoxic chemotherapy.	('expression', 'MPA', (82, 92))	('Ki67', 'Gene', (77, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('high', 'Var', (72, 76))	('Ki67', 'Chemical', '-', (77, 81))
23091	27000271	With regard to histology, the multivariate analysis confirms that a high Ki67 (>21 %) is associated with poor prognosis, and the STEPP analysis suggests an interaction against 'pure' ILC, which display to have a worse prognosis in comparison with mixed ductal-lobular, as the Ki67 positivity increases.	('Ki67', 'Var', (73, 77))	('Ki67', 'Chemical', '-', (73, 77))	('pure', 'molecular_function', 'GO:0034023', ('177', '181'))	('interaction', 'Interaction', (156, 167))	('Ki67', 'Chemical', '-', (276, 280))
23092	27000271	The aggressive biological behavior of high Ki67 ILC is also corroborated by the significant association between high Ki67 and other potential prognostic predictors in breast cancer, such as tumor size, lymph-node status, HER2 status, vascular invasion and histological grade (Table 2).	('HER2', 'Gene', (221, 225))	('breast cancer', 'Disease', (167, 180))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('HER2', 'Gene', '2064', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('high Ki67', 'Var', (112, 121))	('tumor', 'Disease', (190, 195))	('Ki67', 'Chemical', '-', (117, 121))	('vascular invasion', 'CPA', (234, 251))	('high Ki67', 'Var', (38, 47))	('Ki67', 'Chemical', '-', (43, 47))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
23093	27000271	In our study, the unfavorable prognostic trend of patients with high Ki67 is not counteracted by the adjuvant chemotherapy received by almost all these patients.	('patients', 'Species', '9606', (50, 58))	('Ki67', 'Chemical', '-', (69, 73))	('Ki67', 'Var', (69, 73))	('high Ki67', 'Var', (64, 73))	('patients', 'Species', '9606', (152, 160))
23095	27000271	Based on the STEPP analysis, the prognostic impact of high Ki67 on 5-year DFS is primarily driven by the very poor outcome of 'pure' ILC patients with highest levels of Ki67.	('high', 'Var', (54, 58))	('Ki67', 'Chemical', '-', (59, 63))	('patients', 'Species', '9606', (137, 145))	('pure', 'molecular_function', 'GO:0034023', ('127', '131'))	('Ki67', 'Gene', (59, 63))	('Ki67', 'Chemical', '-', (169, 173))	("'pure' ILC", 'Disease', (126, 136))
23096	27000271	The few number of these patients represents one of the crucial limitation of our study that allow only to generate a hypothesis concerning the prognostic role of Ki67 in ILC.	('ILC', 'Disease', (170, 173))	('Ki67', 'Var', (162, 166))	('Ki67', 'Chemical', '-', (162, 166))	('patients', 'Species', '9606', (24, 32))
23097	27000271	Despite the retrospective and exploratory nature of the study, the different types and duration of adjuvant treatments, the absence of a central pathology review, our study indicates that Ki67 is able to significantly discriminate the prognosis of patients with ILC, and this effect is more pronounced for patients with pure ILC.	('Ki67', 'Var', (188, 192))	('discriminate', 'Reg', (218, 230))	('patients', 'Species', '9606', (248, 256))	('ILC', 'Disease', (262, 265))	('Ki67', 'Chemical', '-', (188, 192))	('pure', 'molecular_function', 'GO:0034023', ('320', '324'))	('patients', 'Species', '9606', (306, 314))
23098	27000271	In particular, if we derive suggestions for additional studies in the context of local laboratory values, the prognostic analysis of ILC according to Ki67 is able to identify patients with a low-proliferative tumor (Ki67 < 6 %, in general less than 5 %) and patients with a 'true' high-proliferative tumors (Ki67 > 21 %, higher than 20 %).	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('Ki67', 'Chemical', '-', (216, 220))	('low-proliferative tumor', 'Disease', (191, 214))	('Ki67', 'Chemical', '-', (150, 154))	('Ki67', 'Var', (150, 154))	('tumors', 'Disease', (300, 306))	('ILC', 'Disease', (133, 136))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (258, 266))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('Ki67', 'Chemical', '-', (308, 312))	('low-proliferative tumor', 'Disease', 'MESH:D001948', (191, 214))
23187	20550696	However, the association between aberrant MUC1 expression pattern and phenotypic differentiation of breast carcinomas is still unclear.	('MUC1', 'Gene', '4582', (42, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('breast carcinomas', 'Disease', 'MESH:D001943', (100, 117))	('breast carcinomas', 'Disease', (100, 117))	('breast carcinoma', 'Phenotype', 'HP:0003002', (100, 116))	('aberrant', 'Var', (33, 41))	('breast carcinomas', 'Phenotype', 'HP:0003002', (100, 117))	('MUC1', 'Gene', (42, 46))
23188	20550696	In addition to the extracellular mucin production, another unusual presentation in our case is the amplification of HER2 gene in a classical ILC.	('mucin', 'Gene', '100508689', (33, 38))	('HER2', 'Gene', (116, 120))	('amplification', 'Var', (99, 112))	('HER2', 'Gene', '2064', (116, 120))	('extracellular', 'cellular_component', 'GO:0005576', ('19', '32'))	('mucin', 'Gene', (33, 38))
23205	31062375	After adjustment for known covariates, NACT continued to be associated with worse OS (HR 1.38, 95% CI 1.25-1.52).	('NACT', 'Var', (39, 43))	('NACT', 'Chemical', '-', (39, 43))	('worse OS', 'Disease', (76, 84))	('HR', 'Gene', '3164', (86, 88))
23211	31062375	But ILC is also nearly always hormone receptor (HR)-positive, and previous studies have demonstrated that patients with low-grade, HR-positive (HR+) ILC have a poor response to neoadjuvant chemotherapy, experiencing lower rates of pathologic complete response (pCR) than patients with IDC.	('hormone receptor', 'Gene', (30, 46))	('hormone receptor', 'Gene', '3164', (30, 46))	('lower', 'NegReg', (216, 221))	('HR', 'Gene', '3164', (144, 146))	('HR', 'Gene', '3164', (48, 50))	('HR', 'Gene', '3164', (131, 133))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (271, 279))	('low-grade', 'Var', (120, 129))	('ILC', 'Disease', (149, 152))
23242	31062375	NACT resulted in an overall pCR rate of 3.4%, and a higher rate of pCR in the lymph nodes (3.3%) vs the breast (0.9%).	('NACT', 'Chemical', '-', (0, 4))	('pCR', 'Disease', (67, 70))	('NACT', 'Var', (0, 4))	('pCR', 'Disease', (28, 31))
23250	31062375	Among patients who received a combination of chemotherapy and adjuvant endocrine therapy, NACT + endocrine patients had worse survival compared to ACT + endocrine patients (58.4% vs 67.3%, log-rank p<0.001).	('survival', 'MPA', (126, 134))	('patients', 'Species', '9606', (163, 171))	('worse', 'NegReg', (120, 125))	('NACT', 'Chemical', '-', (90, 94))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (107, 115))	('NACT +', 'Var', (90, 96))
23253	31062375	Similar to the overall cohort, NACT was associated with worse survival compared to ACT in both stage II and stage III patients.	('worse', 'NegReg', (56, 61))	('patients', 'Species', '9606', (118, 126))	('NACT', 'Var', (31, 35))	('NACT', 'Chemical', '-', (31, 35))
23254	31062375	After adjustment for known covariates, patients who underwent NACT had worse OS than patients receiving ACT (HR 1.38, 95% CI 1.25-1.52, p<0.001, Table 2).	('HR', 'Gene', '3164', (109, 111))	('patients', 'Species', '9606', (39, 47))	('NACT', 'Chemical', '-', (62, 66))	('patients', 'Species', '9606', (85, 93))	('worse', 'NegReg', (71, 76))	('NACT', 'Var', (62, 66))
23257	31062375	In stage-specific sensitivity analyses, NACT continued to be associated with worse adjusted survival compared to ACT in stage II and III patients (Supplemental Tables 1-2).	('NACT', 'Var', (40, 44))	('patients', 'Species', '9606', (137, 145))	('adjusted survival', 'MPA', (83, 100))	('NACT', 'Chemical', '-', (40, 44))	('worse', 'NegReg', (77, 82))
23258	31062375	In our analysis of node-positive ILC patients, receipt of NACT was associated with worse OS compared to ACT even among those with stage III disease.	('NACT', 'Var', (58, 62))	('worse OS', 'Disease', (83, 91))	('NACT', 'Chemical', '-', (58, 62))	('patients', 'Species', '9606', (37, 45))	('ILC', 'Disease', (33, 36))	('receipt', 'Var', (47, 54))	('stage III disease', 'Disease', (130, 147))	('stage III disease', 'Disease', 'MESH:D058625', (130, 147))
23272	31062375	demonstrated that the 77 patients who received NACT had higher clinical stage at presentation and higher rate of mastectomy (84%) compared to ACT patients.	('mastectomy', 'Disease', (113, 123))	('clinical stage', 'CPA', (63, 77))	('NACT', 'Var', (47, 51))	('patients', 'Species', '9606', (25, 33))	('higher', 'PosReg', (56, 62))	('NACT', 'Chemical', '-', (47, 51))	('patients', 'Species', '9606', (146, 154))
23282	31062375	Overall and positive lymph node yields were similar (NACT 13 and 3 vs ACT 14 and 4), suggesting that NACT rarely obviated ALND or downstaged the axilla.	('obviated', 'NegReg', (113, 121))	('ALND', 'CPA', (122, 126))	('NACT', 'Var', (101, 105))	('NACT', 'Chemical', '-', (101, 105))	('downstaged', 'NegReg', (130, 140))	('NACT', 'Chemical', '-', (53, 57))
23286	31062375	Patients who underwent NACT had worse unadjusted survival compared to patients receiving ACT (77.8% vs 84.7%), and this finding persisted in the adjusted analysis, where NACT conferred a 38% increased risk of death.	('patients', 'Species', '9606', (70, 78))	('death', 'Disease', 'MESH:D003643', (209, 214))	('NACT', 'Chemical', '-', (170, 174))	('death', 'Disease', (209, 214))	('Patients', 'Species', '9606', (0, 8))	('NACT', 'Var', (23, 27))	('NACT', 'Chemical', '-', (23, 27))	('worse', 'NegReg', (32, 37))
23304	31062375	Among node-positive ILC patients in our study, receipt of NACT rarely conferred pCR, was associated with worse survival compared with receipt of ACT, and did not decrease rates of mastectomy or extensive axillary surgery.	('NACT', 'Var', (58, 62))	('conferred', 'Reg', (70, 79))	('survival', 'MPA', (111, 119))	('NACT', 'Chemical', '-', (58, 62))	('rarely', 'NegReg', (63, 69))	('pCR', 'Disease', (80, 83))	('patients', 'Species', '9606', (24, 32))	('worse', 'NegReg', (105, 110))
23381	29774524	alphaE-catenin is a candidate tumor suppressor for the development of E-cadherin-expressing lobular-type breast cancer Although mutational inactivation of E-cadherin (CDH1) is the main driver of invasive lobular breast cancer (ILC), approximately 10-15% of all ILCs retain membrane-localized E-cadherin despite the presence of an apparent non-cohesive and invasive lobular growth pattern.	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('growth pattern', 'biological_process', 'GO:0040007', ('373', '387'))	('invasive lobular breast cancer', 'Disease', (195, 225))	('E-cadherin', 'Gene', '12550', (70, 80))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('E-cadherin', 'Gene', '12550', (292, 302))	('lobular-type breast cancer', 'Disease', 'MESH:D013274', (92, 118))	('E-cadherin', 'Gene', (155, 165))	('alphaE-catenin', 'Gene', (0, 14))	('cadherin', 'molecular_function', 'GO:0008014', ('294', '302'))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('E-cadherin', 'Gene', '12550', (155, 165))	('membrane', 'cellular_component', 'GO:0016020', ('273', '281'))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('tumor', 'Disease', (30, 35))	('mutational inactivation', 'Var', (128, 151))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (204, 225))	('alphaE-catenin', 'Gene', '12385', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('lobular-type breast cancer', 'Phenotype', 'HP:0006625', (92, 118))	('lobular-type breast cancer', 'Disease', (92, 118))	('growth pattern', 'biological_process', 'GO:0007150', ('373', '387'))	('CDH1', 'Gene', (167, 171))	('E-cadherin', 'Gene', (292, 302))	('CDH1', 'Gene', '12550', (167, 171))	('E-cadherin', 'Gene', (70, 80))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (195, 225))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('membrane-localized', 'MPA', (273, 291))
23383	29774524	We found that inactivating somatic CTNNA1 mutations in human breast cancer correlated with lobular and mixed ducto-lobular phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('CTNNA1', 'Gene', (35, 41))	('human', 'Species', '9606', (55, 60))	('correlated', 'Reg', (75, 85))	('lobular', 'Disease', (91, 98))	('inactivating', 'Var', (14, 26))	('mutations', 'Var', (42, 51))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
23385	29774524	Finally, using a transplantation-based conditional mouse model, we demonstrate that inducible inactivation of alpha-catenin instigates acquisition of lobular features and invasive behavior.	('alpha-catenin', 'Protein', (110, 123))	('mouse', 'Species', '10090', (51, 56))	('invasive behavior', 'CPA', (171, 188))	('acquisition', 'CPA', (135, 146))	('inactivation', 'Var', (94, 106))
23386	29774524	We therefore suggest that alpha-catenin represents a bona fide tumor suppressor for the development of lobular-type breast cancer and as such provides an alternative event to E-cadherin inactivation, adherens junction (AJ) dysfunction, and subsequent constitutive actomyosin contraction.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', (63, 68))	('adherens junction', 'cellular_component', 'GO:0005912', ('200', '217'))	('dysfunction', 'Var', (223, 234))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('177', '185'))	('lobular-type breast cancer', 'Disease', 'MESH:D013274', (103, 129))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('lobular-type breast cancer', 'Phenotype', 'HP:0006625', (103, 129))	('inactivation', 'NegReg', (186, 198))	('lobular-type breast cancer', 'Disease', (103, 129))	('E-cadherin', 'Protein', (175, 185))	('actomyosin', 'cellular_component', 'GO:0042641', ('264', '274'))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('63', '79'))
23388	29774524	In contrast to the larger group of invasive ductal carcinoma, not otherwise specified (IDC-NOS), loss of E-cadherin (CDH1) in ILC has been identified as the key underlying cause of tumor development and progression 1, 2.	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (35, 60))	('tumor', 'Disease', (181, 186))	('cadherin', 'molecular_function', 'GO:0008014', ('107', '115'))	('loss', 'Var', (97, 101))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (44, 60))	('CDH1', 'Gene', (117, 121))	('invasive ductal carcinoma', 'Disease', (35, 60))	('CDH1', 'Gene', '12550', (117, 121))	('cause', 'Reg', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
23390	29774524	In ILC, loss of cadherin-based junctions is tolerated because of tumor suppressor inactivation or activation of oncogenes that render mammary tumor-initiating cells resistant to anoikis 2, 5, 6.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('tumor', 'Disease', (65, 70))	('anoikis', 'biological_process', 'GO:0043276', ('178', '185'))	('tumor', 'Disease', (142, 147))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('oncogenes', 'Gene', (112, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('ILC', 'Disease', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('inactivation', 'Var', (82, 94))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
23394	29774524	Interestingly, a minority of ILC cases with a clear lobular phenotype have retained E-cadherin expression without truncating or frame shift mutations or CDH1 promoter methylation, indicating that functional inactivation of the adherens junction must have occurred through means other than somatic loss or epigenetic silencing of E-cadherin.	('adherens junction', 'cellular_component', 'GO:0005912', ('227', '244'))	('methylation', 'biological_process', 'GO:0032259', ('167', '178'))	('E-cadherin', 'Protein', (84, 94))	('ILC', 'Disease', (29, 32))	('cadherin', 'molecular_function', 'GO:0008014', ('331', '339'))	('loss', 'NegReg', (297, 301))	('CDH1', 'Gene', (153, 157))	('CDH1', 'Gene', '12550', (153, 157))	('epigenetic silencing', 'Var', (305, 325))	('cadherin', 'molecular_function', 'GO:0008014', ('86', '94'))	('expression', 'MPA', (95, 105))
23399	29774524	Second, loss of alpha-catenin is a prognostic factor for poor survival of breast and other cancers (reviewed in 20).	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('poor', 'NegReg', (57, 61))	('cancers', 'Disease', (91, 98))	('alpha-catenin', 'Protein', (16, 29))	('loss', 'Var', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast', 'Disease', (74, 80))
23400	29774524	Finally, several studies have identified inactivating CTNNA1 mutations in breast cancer cell lines 21, 22 and a case of diffuse gastric cancer 23.	('breast cancer', 'Disease', (74, 87))	('gastric cancer', 'Disease', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (61, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('CTNNA1', 'Gene', (54, 60))	('inactivating', 'Var', (41, 53))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
23402	29774524	We found that somatic inactivating CTNNA1 mutations are linked to ILC and observed that alpha-catenin loss leads to E-cadherin-expressing invasive cancer cells that depend on constitutive actomyosin contraction for their anchorage independence.	('cadherin', 'molecular_function', 'GO:0008014', ('118', '126'))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('linked', 'Reg', (56, 62))	('actomyosin', 'cellular_component', 'GO:0042641', ('188', '198'))	('CTNNA1', 'Gene', (35, 41))	('invasive cancer', 'Disease', 'MESH:D009362', (138, 153))	('alpha-catenin', 'Protein', (88, 101))	('leads to', 'Reg', (107, 115))	('inactivating', 'Var', (22, 34))	('invasive cancer', 'Disease', (138, 153))	('loss', 'NegReg', (102, 106))	('E-cadherin-expressing', 'Protein', (116, 137))	('ILC', 'Disease', (66, 69))	('mutations', 'Var', (42, 51))
23414	29774524	For inhibition studies, cells were treated with: 0.02 mug/ml C3 transferase (Cytoskeleton Inc, Heerhugowaard, The Netherlands; CT04-A), 10 mum Y27632 (Selleckchem, Huissen, The Netherlands; S1049), 1 mum GSK-429286A (Selleckchem; S1474) or 3 mum blebbistatin (VWR, Radnor, PA, USA; 203390).	('C3 transferase', 'Enzyme', (61, 75))	('GSK', 'molecular_function', 'GO:0050321', ('204', '207'))	('Rad', 'Gene', '56437', (265, 268))	('blebbistatin', 'Chemical', 'MESH:C472645', (246, 258))	('GSK', 'Chemical', '-', (204, 207))	('Y27632', 'Var', (143, 149))	('mug', 'molecular_function', 'GO:0043739', ('54', '57'))	('Cytoskeleton', 'cellular_component', 'GO:0005856', ('77', '89'))	('Rad', 'Gene', (265, 268))
23416	29774524	Primary mouse mammary epithelium cells (MMECs) were obtained from gland numbers 3, 4, and 5 after removal of the intra-mammary lymph nodes of 6- to 8-week-old female WAPcre;Trp53 F/F mice.	('Trp53', 'Gene', '22059', (173, 178))	('F/F', 'Var', (179, 182))	('mice', 'Species', '10090', (183, 187))	('WAP', 'Gene', '22373', (166, 169))	('WAP', 'Gene', (166, 169))	('Trp53', 'Gene', (173, 178))	('mouse', 'Species', '10090', (8, 13))
23425	29774524	After transplantation, the animals were either fed ad libitum with control chow or doxycycline-containing chow (200 mg/kg; A153D00201; Sniff, Soest, Utrecht, The Netherlands).	('200', 'Var', (112, 115))	('doxycycline', 'Chemical', 'MESH:D004318', (83, 94))	('A153D00201', 'Var', (123, 133))
23431	29774524	Because inactivating mutations in alpha-catenin were linked to cancer 21, 23, we performed a survey into the prevalence of CTNNA1 mutations in the publicly-available online databases.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('inactivating mutations', 'Var', (8, 30))	('linked', 'Reg', (53, 59))	('mutations', 'Var', (130, 139))	('alpha-catenin', 'Protein', (34, 47))	('CTNNA1', 'Gene', (123, 129))	('cancer', 'Disease', (63, 69))
23432	29774524	Focusing on breast cancer, we found that a total of 19 unique somatic mutations were reported in the combined METABRIC and TCGA datasets (http://cancergenome.nih.gov) (Table 1 and supplementary material, Figure S1).	('cancer', 'Disease', (145, 151))	('breast cancer', 'Disease', (12, 25))	('mutations', 'Var', (70, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))
23434	29774524	Somatic inactivating CDH1 mutations were reported in five ILC cases (Table 1).	('mutations', 'Var', (26, 35))	('CDH1', 'Gene', (21, 25))	('ILC', 'Disease', (58, 61))	('CDH1', 'Gene', '12550', (21, 25))
23436	29774524	Intriguingly, we found a correlation between low CTNNA1 mRNA expression (< 40%), the presence of wild-type CDH1 alleles, and a lobular, mixed, or ducto-lobular breast cancer phenotype (Table 1).	('lobular breast cancer', 'Phenotype', 'HP:0006625', (152, 173))	('lobular', 'Disease', (127, 134))	('presence', 'Var', (85, 93))	('lobular breast cancer', 'Disease', 'MESH:D013274', (152, 173))	('CDH1', 'Gene', (107, 111))	('CTNNA1', 'Gene', (49, 55))	('CDH1', 'Gene', '12550', (107, 111))	('-lobular breast cancer', 'Phenotype', 'HP:0006625', (151, 173))	('low', 'NegReg', (45, 48))	('lobular breast cancer', 'Disease', (152, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('mixed', 'Disease', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('mRNA expression', 'MPA', (56, 71))
23437	29774524	One ILC case harbored an inactivating CTNNA1 mutation in the presence of a CDH1 mutation but was included due to borderline E-cadherin mRNA expression (39%) and low alpha-catenin expression (27%).	('alpha-catenin expression', 'MPA', (165, 189))	('CTNNA1', 'Gene', (38, 44))	('low', 'NegReg', (161, 164))	('cadherin', 'molecular_function', 'GO:0008014', ('126', '134'))	('mutation', 'Var', (45, 53))	('inactivating', 'Reg', (25, 37))	('CDH1', 'Gene', (75, 79))	('CDH1', 'Gene', '12550', (75, 79))	('mutation', 'Var', (80, 88))
23441	29774524	In conclusion, these publicly available data suggested a correlation between alpha-catenin inactivation and a lobular breast cancer phenotype.	('lobular breast cancer', 'Disease', 'MESH:D013274', (110, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('alpha-catenin', 'Protein', (77, 90))	('inactivation', 'Var', (91, 103))	('lobular breast cancer', 'Disease', (110, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (110, 131))
23445	29774524	Loss of alpha-catenin also induced a non-cohesive growth pattern that prevented confluence and the formation of an epithelial sheet (Figure 2B and supplementary material, Figure S3B).	('S3B', 'Gene', '11778', (178, 181))	('formation', 'biological_process', 'GO:0009058', ('99', '108'))	('growth pattern', 'biological_process', 'GO:0007150', ('50', '64'))	('alpha-catenin', 'Protein', (8, 21))	('S3B', 'Gene', (178, 181))	('non-cohesive growth pattern', 'CPA', (37, 64))	('confluence', 'CPA', (80, 90))	('growth pattern', 'biological_process', 'GO:0040007', ('50', '64'))	('induced', 'Reg', (27, 34))	('prevented', 'NegReg', (70, 79))	('Loss', 'Var', (0, 4))	('formation of an epithelial sheet', 'CPA', (99, 131))
23447	29774524	At the sites of cell-cell adhesion, E-cadherin, beta-catenin, and p120 still localized to the cell membrane, but maturation of the AJ appeared attenuated, which was characterized by aberrant localization of E-cadherin and p120 in distinct puncta and clusters on the plasma membrane (Figure 2C, indicated by arrows).	('attenuated', 'NegReg', (143, 153))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('16', '34'))	('cell membrane', 'cellular_component', 'GO:0005886', ('94', '107'))	('beta-catenin', 'Gene', (48, 60))	('localization', 'biological_process', 'GO:0051179', ('191', '203'))	('E-cadherin', 'Protein', (207, 217))	('cadherin', 'molecular_function', 'GO:0008014', ('38', '46'))	('p120', 'Var', (222, 226))	('localization', 'MPA', (191, 203))	('maturation', 'CPA', (113, 123))	('beta-catenin', 'Gene', '12387', (48, 60))	('cadherin', 'molecular_function', 'GO:0008014', ('209', '217'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('266', '281'))
23451	29774524	Confirming previous studies, we observed that E-cadherin knockout in mammary carcinoma cells leads to cytosolic and nuclear relocalization of p120-catenin and a strong reduction in the expression of alpha-catenin and beta-catenin (supplementary material, Figure S4C).	('reduction', 'NegReg', (168, 177))	('cadherin', 'molecular_function', 'GO:0008014', ('48', '56'))	('beta-catenin', 'Gene', (217, 229))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (69, 86))	('p120-catenin', 'Gene', '12388', (142, 154))	('expression', 'MPA', (185, 195))	('knockout', 'Var', (57, 65))	('E-cadherin', 'Protein', (46, 56))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('beta-catenin', 'Gene', '12387', (217, 229))	('alpha-catenin', 'Protein', (199, 212))	('p120-catenin', 'Gene', (142, 154))	('carcinoma', 'Disease', (77, 86))
23455	29774524	Interestingly, our data indicated that alpha-catenin loss in an ILC cell type is not tolerated, because inducible Ctnna1 knockdown in two independent mouse ILC cell lines resulted in cell death through the induction of apoptosis (Figure 3C-E).	('knockdown', 'Var', (121, 130))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('206', '228'))	('cell death', 'biological_process', 'GO:0008219', ('183', '193'))	('alpha-catenin', 'Protein', (39, 52))	('apoptosis', 'CPA', (219, 228))	('Ctnna1', 'Gene', '12385', (114, 120))	('Ctnna1', 'Gene', (114, 120))	('cell death', 'CPA', (183, 193))	('mouse', 'Species', '10090', (150, 155))
23457	29774524	Given that E-cadherin-mutant ILC depends on Rock activity for anchorage-independent tumor growth and metastasis, we assayed the effect of alpha-catenin loss on Rho-Rock pathway activity.	('cadherin', 'molecular_function', 'GO:0008014', ('13', '21'))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('ILC', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('metastasis', 'CPA', (101, 111))	('tumor', 'Disease', (84, 89))	('E-cadherin-mutant', 'Var', (11, 28))
23461	29774524	Pharmacological inhibition of Rho (C3 transferase), Rock (GSK-429286A and Y-27632), myosin II (blebbistatin), and F-actin (cytochalasin D) all resulted in a robust reduction of anoikis resistance (Figure 4C, D), indicating that, similar to E-cadherin-mutant ILC, Rock-dependent actomyosin contraction underpins anoikis resistance in the absence of alpha-catenin.	('GSK-429286A', 'Var', (58, 69))	('myosin II', 'Disease', 'MESH:C564253', (84, 93))	('anoikis', 'biological_process', 'GO:0043276', ('311', '318'))	('F-actin', 'cellular_component', 'GO:0031941', ('114', '121'))	('GSK', 'molecular_function', 'GO:0050321', ('58', '61'))	('actomyosin', 'cellular_component', 'GO:0042641', ('278', '288'))	('anoikis resistance', 'MPA', (177, 195))	('anoikis', 'biological_process', 'GO:0043276', ('177', '184'))	('blebbistatin', 'Chemical', 'MESH:C472645', (95, 107))	('myosin II', 'Disease', (84, 93))	('reduction', 'NegReg', (164, 173))	('cadherin', 'molecular_function', 'GO:0008014', ('242', '250'))	('Y-27632', 'Var', (74, 81))	('Y-27632', 'Chemical', 'MESH:C108830', (74, 81))	('GSK', 'Chemical', '-', (58, 61))
23477	29774524	Because we occasionally observed ducto-lobular phenotypical features, our findings suggest that loss of alpha-catenin represents an alternative route for the development of lobular-type invasive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('alpha-catenin', 'Protein', (104, 117))	('loss', 'Var', (96, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('lobular-type invasive breast cancer', 'Disease', 'MESH:D013274', (173, 208))	('lobular-type invasive breast cancer', 'Disease', (173, 208))
23479	29774524	Whereas somatic ablation of E-cadherin in the mammary gland results in metastatic mouse ILC 2, 5, 24, inactivation of the AJ through p120 loss induces the formation of invasive high-grade and basal-like IDC 25, 31.	('loss', 'NegReg', (138, 142))	('inactivation', 'Var', (102, 114))	('induces', 'Reg', (143, 150))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('ablation', 'Var', (16, 24))	('p120', 'Var', (133, 137))	('cadherin', 'molecular_function', 'GO:0008014', ('30', '38'))	('mouse', 'Species', '10090', (82, 87))
23482	29774524	Second, although p120 regulates Rho signaling at the cell cortex, it is not directly physically connected to the actin cytoskeleton (for a review see 33), which may explain why loss of p120 in mice (although it leads to inactivation of the AJ and induces metastasis) does not result in a lobular tumor phenotype 25.	('metastasis', 'CPA', (255, 265))	('inactivation', 'NegReg', (220, 232))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('113', '131'))	('cell cortex', 'cellular_component', 'GO:0005938', ('53', '64'))	('lobular tumor', 'Disease', (288, 301))	('mice', 'Species', '10090', (193, 197))	('loss', 'Var', (177, 181))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('lobular tumor', 'Disease', 'MESH:D018275', (288, 301))	('induces', 'PosReg', (247, 254))
23483	29774524	Because p120 (CTNND1) is lost in approximately 30% of all IDC-NOS breast cancers, but mutations and promotor methylation are virtually absent 34, we think that p120 is a tumor progression suppressor that is inactivated at the later stages of non-lobular breast cancer.	('non-lobular breast cancer', 'Disease', (242, 267))	('tumor', 'Disease', (170, 175))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (246, 267))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('IDC-NOS breast cancers', 'Disease', 'MESH:D001943', (58, 80))	('non-lobular breast cancer', 'Disease', 'MESH:D013274', (242, 267))	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('p120', 'Var', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('-lobular breast cancer', 'Phenotype', 'HP:0006625', (245, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('CTNND1', 'Gene', (14, 20))	('CTNND1', 'Gene', '12388', (14, 20))	('lost', 'NegReg', (25, 29))	('p120', 'Var', (8, 12))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('IDC-NOS breast cancers', 'Disease', (58, 80))
23484	29774524	In contrast, bi-allelic inactivating mutations in CTNNA1 have been described in several breast cancer cell lines 21, 35.	('bi-allelic inactivating mutations', 'Var', (13, 46))	('described', 'Reg', (67, 76))	('CTNNA1', 'Gene', (50, 56))	('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))
23485	29774524	Because these cell lines are phenotypically luminal and express membrane-bound wild-type E-cadherin, it strengthened our assumption that specific disruption of the link between E-cadherin, alpha-catenin, and actin may be sufficient to underpin lobular carcinoma etiology.	('cadherin', 'molecular_function', 'GO:0008014', ('91', '99'))	('lobular carcinoma', 'Disease', 'MESH:D018275', (244, 261))	('membrane', 'cellular_component', 'GO:0016020', ('64', '72'))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('E-cadherin', 'Protein', (177, 187))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (244, 261))	('lobular carcinoma', 'Disease', (244, 261))	('link', 'Interaction', (164, 168))	('cadherin', 'molecular_function', 'GO:0008014', ('179', '187'))	('alpha-catenin', 'Protein', (189, 202))	('disruption', 'Var', (146, 156))
23486	29774524	Supporting this is a frame shift mutation in CTNNA1 that was described in a family with hereditary diffuse gastric cancer (HDGC) without detectable E-cadherin defects 23.	('HDGC', 'Disease', (123, 127))	('CTNNA1', 'Gene', (45, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('frame shift mutation', 'Var', (21, 41))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('hereditary diffuse gastric cancer', 'Disease', (88, 121))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (88, 121))	('HDGC', 'Disease', 'MESH:D013274', (123, 127))
23487	29774524	Similar to ILC, HDGC and plasmacytoid bladder cancer development is causally linked to mutational inactivation of E-cadherin 36, 37, again implying that there may be a functional relationship between inactivation of alpha-catenin, cell-intrinsic actomyosin contraction, and the development and progression of ILC.	('E-cadherin', 'Gene', (114, 124))	('HDGC', 'Disease', (16, 20))	('HDGC', 'Disease', 'MESH:D013274', (16, 20))	('actomyosin', 'cellular_component', 'GO:0042641', ('246', '256'))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('linked', 'Reg', (77, 83))	('bladder cancer', 'Disease', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('116', '124'))	('inactivation', 'Var', (200, 212))	('alpha-catenin', 'Protein', (216, 229))	('ILC', 'Disease', (309, 312))	('mutational inactivation', 'Var', (87, 110))
23488	29774524	Despite the low overall prevalence of CTNNA1 mutations in breast cancer, we observed 19 somatic mutations in the publicly available TCGA database BioPortal, of which six cases showed potential inactivating CTNNA1 mutations in the presence of wild-type CDH1.	('mutations', 'Var', (45, 54))	('CTNNA1', 'Gene', (38, 44))	('CTNNA1', 'Gene', (206, 212))	('inactivating', 'NegReg', (193, 205))	('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', (213, 222))	('CDH1', 'Gene', (252, 256))	('mutations', 'Var', (96, 105))	('CDH1', 'Gene', '12550', (252, 256))
23489	29774524	While we have not probed the underlying biochemistry, we hypothesize that the (bio)mechanical forces induced by activation of Rho/Rock-dependent actomyosin contraction upon loss of alpha-catenin can result in extracellular matrix (ECM)/integrin linkage detachment (comparable to the onset of mitosis), which may have substantial consequences for the migration and invasion of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('activation', 'PosReg', (112, 122))	('tumor', 'Disease', (376, 381))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('209', '229'))	('extracellular matrix', 'MPA', (209, 229))	('mitosis', 'biological_process', 'GO:0000278', ('292', '299'))	('alpha-catenin', 'Protein', (181, 194))	('loss', 'Var', (173, 177))	('mitosis', 'Disease', (292, 299))	('result in', 'Reg', (199, 208))	('Rho/Rock-dependent actomyosin', 'Protein', (126, 155))	('mitosis', 'Disease', 'None', (292, 299))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('actomyosin', 'cellular_component', 'GO:0042641', ('145', '155'))
23490	29774524	We therefore envisage that Rho activity is most likely caused by intracellular cytoskeletal tension upon cellular rounding due to the disruption of the E-cadherin linkage to actin, which could potentially induce a positive feedback loop resulting in high Rho-GTP, as has been shown previously by others 38, 39.	('induce', 'Reg', (205, 211))	('disruption', 'Var', (134, 144))	('intracellular', 'cellular_component', 'GO:0005622', ('65', '78'))	('Rho', 'Disease', (27, 30))	('caused', 'Reg', (55, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('154', '162'))	('Rho-GTP', 'MPA', (255, 262))	('E-cadherin linkage', 'Protein', (152, 170))	('actin', 'Protein', (174, 179))	('GTP', 'Chemical', 'MESH:D006160', (259, 262))
23492	29774524	As such, alpha-catenin (like E-cadherin) may represent a tumor suppressor that represents the same gene hypothesis, which states that specific mutations that provide a selective advantage during tumor initiation can also foster tumor progression 40.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor initiation can also foster tumor', 'Disease', 'MESH:D009369', (195, 233))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cadherin', 'molecular_function', 'GO:0008014', ('31', '39'))	('tumor', 'Disease', (228, 233))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))	('tumor', 'Disease', (57, 62))	('mutations', 'Var', (143, 152))	('tumor initiation can also foster tumor', 'Disease', (195, 233))
23496	29774524	Lentiviral integration of the Dox-inducible Ctnna1 knockdown will probably overlap with the cancer-initiating cell that undergoes WAPcre-mediated Trp53 deletion, but it will likely also occur in p53 wild-type cells in the mammary gland.	('p53', 'Gene', (195, 198))	('p53', 'Gene', '22059', (195, 198))	('deletion', 'Var', (152, 160))	('WAP', 'Gene', '22373', (130, 133))	('cancer', 'Disease', (92, 98))	('p53', 'Gene', (148, 151))	('Trp53', 'Gene', (146, 151))	('Ctnna1', 'Gene', (44, 50))	('Ctnna1', 'Gene', '12385', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('p53', 'Gene', '22059', (148, 151))	('Dox', 'Chemical', 'MESH:D004318', (30, 33))	('Trp53', 'Gene', '22059', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('WAP', 'Gene', (130, 133))
23508	29774524	CTNNA1 genomic alterations in human cancer  Figure S2.	('human', 'Species', '9606', (30, 35))	('genomic alterations', 'Var', (7, 26))	('CTNNA1', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
23561	33176745	However, correlations between BRF2 alterations and clinical outcomes in breast cancer are limited.	('alterations', 'Var', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRF2', 'Gene', (30, 34))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
23562	33176745	We conducted this review to analyze BRF2 alterations in genomic data sets housed in Oncomine and cBioPortal to identify potential correlations between BRF2 alterations and clinical outcomes.	('Oncomine', 'Chemical', '-', (84, 92))	('BRF2', 'Gene', (36, 40))	('alterations', 'Var', (41, 52))
23563	33176745	The authors queried both Oncomine and cBioPortal for alterations in BRF2 in human cancers and performed meta-analyses identifying significant correlations between BRF2 and clinical outcomes in invasive breast cancer (IBC).	('BRF2', 'Gene', (163, 167))	('correlations', 'Interaction', (142, 154))	('invasive breast cancer', 'Disease', 'MESH:D001943', (193, 215))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('alterations', 'Var', (53, 64))	('BRF2', 'Gene', (68, 72))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('IBC', 'Chemical', '-', (217, 220))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('invasive breast cancer', 'Disease', (193, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('Oncomine', 'Chemical', '-', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
23566	33176745	Overall survival in IBC patients with BRF2 alterations (21%) is significantly decreased (p = 9.332e-3).	('IBC', 'Chemical', '-', (20, 23))	('IBC', 'Disease', (20, 23))	('patients', 'Species', '9606', (24, 32))	('BRF2', 'Gene', (38, 42))	('alterations', 'Var', (43, 54))	('Overall', 'MPA', (0, 7))	('decreased', 'NegReg', (78, 87))
23567	33176745	IBC patients with BRF2 alterations aged 46 to 50 have a significantly poor survival outcome (p = 7.093e-3).	('poor', 'NegReg', (70, 74))	('IBC', 'Chemical', '-', (0, 3))	('survival', 'MPA', (75, 83))	('alterations', 'Var', (23, 34))	('patients', 'Species', '9606', (4, 12))	('BRF2', 'Gene', (18, 22))
23580	33176745	Atypical RNA pol III transcription is a common feature of many cancer types.	('Atypical', 'Var', (0, 8))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('transcription', 'biological_process', 'GO:0006351', ('21', '34'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('RNA pol III transcription', 'Gene', (9, 34))	('cancer', 'Disease', (63, 69))
23586	33176745	Amplification of BRF2, 8p11.23, and chromosome 8 frequently occurs in somatic breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('Amplification', 'Var', (0, 13))	('occurs', 'Reg', (60, 66))	('BRF2', 'Gene', (17, 21))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))	('breast cancer', 'Disease', (78, 91))
23593	33176745	In this study, we performed a meta-analysis of patient data from both Oncomine and cBioPortal databases to analyze BRF2 alterations in human cancers, with a focus on breast cancer.	('BRF2', 'Gene', (115, 119))	('patient', 'Species', '9606', (47, 54))	('Oncomine', 'Chemical', '-', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('human', 'Species', '9606', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('alterations', 'Var', (120, 131))	('cancers', 'Disease', (141, 148))
23597	33176745	We performed a comprehensive query of the Oncomine Research Edition, a cancer microarray database and web-based data-mining platform containing 715 data sets (86, 733 samples), to determine the frequency of BRF2 mutations, alterations in BRF2 DNA copy number, and BRF2 gene expression in human cancers.	('BRF2', 'Gene', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('human', 'Species', '9606', (288, 293))	('BRF2', 'Gene', (238, 242))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('gene expression', 'biological_process', 'GO:0010467', ('269', '284'))	('cancers', 'Disease', (294, 301))	('cancer', 'Disease', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (212, 221))	('Oncomine', 'Chemical', '-', (42, 50))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('BRF2', 'Gene', (264, 268))
23604	33176745	In our current analysis of BRF2 alterations in IBC, we included the data available in cBioPortal's TCGA, Firehose Legacy data set for analysis consisting of 960 patients with available mutation, CNA, and mRNA microarray expression (z-score threshold + 2.0).	('IBC', 'Chemical', '-', (47, 50))	('mRNA', 'MPA', (204, 208))	('alterations', 'Var', (32, 43))	('patients', 'Species', '9606', (161, 169))	('BRF2', 'Gene', (27, 31))
23605	33176745	BRF2 alterations in the Breast Cancer METABRIC (Nature 2012 & Nature 2016) data set analyzed included patients with mutation, CNA, and mRNA microarray expression (z-score threshold + 2.0).	('Breast Cancer', 'Phenotype', 'HP:0003002', (24, 37))	('Breast Cancer', 'Disease', (24, 37))	('patients', 'Species', '9606', (102, 110))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('alterations', 'Var', (5, 16))	('with', 'Var', (111, 115))	('Breast Cancer', 'Disease', 'MESH:D001943', (24, 37))	('BRF2', 'Gene', (0, 4))
23606	33176745	We queried Oncomine, containing 715 data sets (86,733 samples), to determine the frequency of BRF2 alterations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('BRF2', 'Gene', (94, 98))	('Oncomine', 'Chemical', '-', (11, 19))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('alterations', 'Var', (99, 110))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
23633	33176745	1d), prompted a more detailed look at BRF2 alterations in subtypes of breast cancer (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('BRF2', 'Gene', (38, 42))	('alterations', 'Var', (43, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
23644	33176745	BRF2 copy number events occur most frequently in breast cancer, 5.9%, as compared to other human cancers analyzed (Fig.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('copy number events', 'Var', (5, 23))	('breast cancer', 'Disease', (49, 62))	('BRF2', 'Gene', (0, 4))	('human', 'Species', '9606', (91, 96))
23650	33176745	The estimated BRF2 copy numbers ranged from 0.8 to 9.2 in 2389 patients diagnosed with IDC.	('BRF2', 'Gene', (14, 18))	('IDC', 'Disease', (87, 90))	('copy numbers', 'Var', (19, 31))	('patients', 'Species', '9606', (63, 71))
23672	33176745	In our current analysis of BRF2 in IBC, we included the 960 patients with mutation, CNA, and mRNA microarray expression (z-score threshold + 2.0) data available in cBioPortal's TCGA, Firehose Legacy data set to identify if BRF2 alterations correlate with overall patient survival potentially.	('patient', 'Species', '9606', (263, 270))	('patient', 'Species', '9606', (60, 67))	('patients', 'Species', '9606', (60, 68))	('alterations', 'Var', (228, 239))	('correlate with', 'Reg', (240, 254))	('IBC', 'Chemical', '-', (35, 38))	('BRF2', 'Gene', (223, 227))
23674	33176745	The majority of the BRF2 alterations are amplifications of copy number (7.7%) and an increase in BRF2 mRNA expression (3.85%), but multiple BRF2 alterations (5.31%) co-occur in IBC (data not shown).	('alterations', 'Var', (25, 36))	('mRNA expression', 'MPA', (102, 117))	('copy number', 'MPA', (59, 70))	('BRF2', 'Gene', (20, 24))	('increase', 'PosReg', (85, 93))	('IBC', 'Chemical', '-', (177, 180))	('BRF2', 'Gene', (97, 101))	('IBC', 'Disease', (177, 180))
23675	33176745	The Kaplan-Meier estimate of overall survival was determined by comparing overall patient survival status, by month, in IBC patients with BRF2 alterations (red line) to those without alterations in BRF2 (blue line) (Fig.	('patient', 'Species', '9606', (82, 89))	('IBC', 'Chemical', '-', (120, 123))	('IBC', 'Disease', (120, 123))	('patient', 'Species', '9606', (124, 131))	('BRF2', 'Gene', (138, 142))	('alterations', 'Var', (143, 154))	('patients', 'Species', '9606', (124, 132))
23683	33176745	Figure 5 suggests BRF2 alterations specifically and significantly correlate with overall patient survival in patients with IBC.	('patient', 'Species', '9606', (89, 96))	('patient', 'Species', '9606', (109, 116))	('IBC', 'Chemical', '-', (123, 126))	('patients', 'Species', '9606', (109, 117))	('IBC', 'Disease', (123, 126))	('correlate with', 'Reg', (66, 80))	('alterations', 'Var', (23, 34))	('BRF2', 'Gene', (18, 22))
23684	33176745	No significant decrease in overall survival for patients with alterations in ERBB2 (HER2) (Fig.	('decrease', 'NegReg', (15, 23))	('ERBB2', 'Gene', '2064', (77, 82))	('overall', 'MPA', (27, 34))	('HER2', 'Gene', (84, 88))	('ERBB2', 'Gene', (77, 82))	('HER2', 'Gene', '2064', (84, 88))	('patients', 'Species', '9606', (48, 56))	('alterations', 'Var', (62, 73))
23687	33176745	Patients with BRF2 alterations had a median survival of 111.99 months (p = 9.332e-3) as compared to a median survival of 212.09 months in patients without BRF2 alterations (Fig.	('BRF2', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('alterations', 'Var', (19, 30))	('patients', 'Species', '9606', (138, 146))
23688	33176745	In queries of the IBC (TCGA, Firehose Legacy) data set in the cBioPortal, the Disease/Progression-free Kaplan median months disease-free were not available for patients with BRF2 alterations.	('patients', 'Species', '9606', (160, 168))	('alterations', 'Var', (179, 190))	('BRF2', 'Gene', (174, 178))	('IBC', 'Chemical', '-', (18, 21))
23689	33176745	To elucidate if BRF2 alterations co-occur with alterations in known oncogenes and biomarkers in IBC we analyzed copy-number alteration frequency in breast cancer patients with BRF2 alterations (Fig.	('alterations', 'Var', (181, 192))	('patients', 'Species', '9606', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('IBC', 'Chemical', '-', (96, 99))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('BRF2', 'Gene', (176, 180))
23692	33176745	MYC is frequently amplified in breast cancer and amplification is associated with poor prognosis.	('MYC', 'Gene', (0, 3))	('amplification', 'Var', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('MYC', 'Gene', '4609', (0, 3))
23693	33176745	MYC is amplified in 35.5% of patients with BRF2 alterations, p = 6.638e-6 (Fig.	('MYC', 'Gene', (0, 3))	('patients', 'Species', '9606', (29, 37))	('alterations', 'Var', (48, 59))	('BRF2', 'Gene', (43, 47))	('MYC', 'Gene', '4609', (0, 3))
23694	33176745	The breast cancer biomarkers ERBB2 (HER2), ESR1(ER), PIK3CA are not significantly altered in patients with BRF2 alterations (Fig.	('ESR1', 'Gene', (43, 47))	('BRF2', 'Gene', (107, 111))	('ERBB2', 'Gene', (29, 34))	('ER', 'Gene', '2099', (48, 50))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HER2', 'Gene', (36, 40))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('PIK3CA', 'Gene', '5290', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('ESR1', 'Gene', '2099', (43, 47))	('HER2', 'Gene', '2064', (36, 40))	('breast cancer', 'Disease', (4, 17))	('ER', 'Gene', '2099', (29, 31))	('ER', 'Gene', '2099', (37, 39))	('alterations', 'Var', (112, 123))	('PIK3CA', 'Gene', (53, 59))	('ERBB2', 'Gene', '2064', (29, 34))
23699	33176745	BRF2 alterations tend to co-occur with MYC alterations (p = 0.008), Fig.	('MYC', 'Gene', '4609', (39, 42))	('co-occur', 'Reg', (25, 33))	('alterations', 'Var', (5, 16))	('BRF2', 'Gene', (0, 4))	('MYC', 'Gene', (39, 42))
23700	33176745	6c, we determined if BRF2 alterations also co-occurred or are mutually exclusive with well-established breast cancer biomarkers.	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('alterations', 'Var', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('BRF2', 'Gene', (21, 25))
23701	33176745	BRF2 alterations tend to be mutually exclusive from PIK3CA alterations (p = 0.002), Fig.	('BRF2', 'Gene', (0, 4))	('alterations', 'Var', (5, 16))	('PIK3CA', 'Gene', '5290', (52, 58))	('PIK3CA', 'Gene', (52, 58))
23702	33176745	6a-c, prompted an examination of overall survival for patients with breast invasive carcinoma with concurrent alterations in BRF2 and breast cancer biomarkers which were determined to be either co-occurring or mutually exclusive and statistically significant, Fig.	('breast invasive carcinoma', 'Disease', (68, 93))	('alterations', 'Var', (110, 121))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('patients', 'Species', '9606', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (68, 93))	('BRF2', 'Gene', (125, 129))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
23703	33176745	Kaplan-Meier estimate was determined comparing overall patient survival status, by month, in patients with alterations (red line) to those without alterations (blue line) in PIK3CA (Fig.	('PIK3CA', 'Gene', (174, 180))	('alterations', 'Var', (107, 118))	('PIK3CA', 'Gene', '5290', (174, 180))	('patient', 'Species', '9606', (93, 100))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (93, 101))
23709	33176745	These data suggest co-occurring alterations in BRF2 and MYC significantly decrease overall survival in patients with breast invasive carcinoma.	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (117, 142))	('overall survival', 'MPA', (83, 99))	('decrease', 'NegReg', (74, 82))	('BRF2', 'Gene', (47, 51))	('MYC', 'Gene', (56, 59))	('breast invasive carcinoma', 'Disease', (117, 142))	('alterations', 'Var', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('patients', 'Species', '9606', (103, 111))	('MYC', 'Gene', '4609', (56, 59))
23710	33176745	MYC and ESR1(ER) alterations tend to co-occur in breast invasive carcinoma (p < 0.001), Fig.	('co-occur', 'Reg', (37, 45))	('MYC', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('breast invasive carcinoma', 'Disease', (49, 74))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (49, 74))	('ESR1', 'Gene', '2099', (8, 12))	('ESR1', 'Gene', (8, 12))	('MYC', 'Gene', '4609', (0, 3))	('alterations', 'Var', (17, 28))	('ER', 'Gene', '2099', (13, 15))
23711	33176745	The overall survival for alterations in MYC alone were significant as previously reported (Fig.	('alterations', 'Var', (25, 36))	('MYC', 'Gene', '4609', (40, 43))	('MYC', 'Gene', (40, 43))
23713	33176745	Next, we investigated if age of first IBC diagnosis correlated with BRF2 alterations and overall survival outcome as BRF2 alterations significantly correlated with poor survival (p = 9.332e-3), Fig.	('alterations', 'Var', (122, 133))	('poor survival', 'MPA', (164, 177))	('BRF2', 'Gene', (117, 121))	('IBC', 'Chemical', '-', (38, 41))
23715	33176745	The overall Kaplan-Meier estimate was determined by comparing overall patient survival status, by month, in patients with BRF2 alterations (red line) to those without BRF2 alterations (blue line) by selected age ranges.	('patient', 'Species', '9606', (70, 77))	('BRF2', 'Gene', (122, 126))	('patient', 'Species', '9606', (108, 115))	('alterations', 'Var', (127, 138))	('patients', 'Species', '9606', (108, 116))
23716	33176745	12% of women aged 35 < X < 40 (n = 59), had alterations in BRF2, classified as amplification in IBC, and have an overall decrease in patient survival (p = 0.032), Fig.	('patient survival', 'CPA', (133, 149))	('patient', 'Species', '9606', (133, 140))	('IBC', 'Chemical', '-', (96, 99))	('BRF2', 'Gene', (59, 63))	('alterations', 'Var', (44, 55))	('decrease', 'NegReg', (121, 129))	('women', 'Species', '9606', (7, 12))
23717	33176745	In patients aged 40 < X < 45 (n = 81), BRF2 is altered (17%) and these alterations are overwhelmingly amplifications in IBC and correlated with overall patient survival (p = 0.0123), Fig.	('BRF2', 'Gene', (39, 43))	('IBC', 'Chemical', '-', (120, 123))	('patient', 'Species', '9606', (3, 10))	('IBC', 'Disease', (120, 123))	('alterations', 'Var', (71, 82))	('patients', 'Species', '9606', (3, 11))	('correlated with', 'Reg', (128, 143))	('altered', 'Reg', (47, 54))	('patient', 'Species', '9606', (152, 159))
23718	33176745	13% of patients aged 45 < X < 50 (n = 121) have amplifications in BRF2 in both IBC and invasive lobular carcinoma (ILC), Fig.	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (87, 113))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('amplifications', 'Var', (48, 62))	('IBC', 'Chemical', '-', (79, 82))	('IBC', 'Disease', (79, 82))	('BRF2', 'Gene', (66, 70))	('patients', 'Species', '9606', (7, 15))	('invasive lobular carcinoma', 'Disease', (87, 113))
23721	33176745	However, in our analysis of women with BRF2 alterations (13%) aged 50 < X < 55 (n = 119) showed no significant decrease in overall survival, Fig.	('BRF2', 'Gene', (39, 43))	('overall survival', 'MPA', (123, 139))	('alterations', 'Var', (44, 55))	('women', 'Species', '9606', (28, 33))	('decrease', 'NegReg', (111, 119))
23722	33176745	Survival in women with BRF2 alterations (17%) aged 55 < X < 60 (n = 118) were unaffected (p = 0.305), data not shown.	('women', 'Species', '9606', (12, 17))	('BRF2', 'Gene', (23, 27))	('alterations', 'Var', (28, 39))
23724	33176745	Further, BRF2 alterations may be useful as an age-related prognostic marker for women, aged 35 < X < 50, with a first-time diagnosis of IBC or ILC.	('alterations', 'Var', (14, 25))	('women', 'Species', '9606', (80, 85))	('BRF2', 'Gene', (9, 13))	('IBC', 'Chemical', '-', (136, 139))	('IBC', 'Disease', (136, 139))	('ILC', 'Disease', (143, 146))
23727	33176745	Using the cBioPortal we queried for BRF2 alteration in the two available metastatic breast cancer data sets: Metastatic Breast Cancer (INSERM, PLoS Med 2016) and the Metastatic Breast Cancer Project (Provisional, October 2018).	('Breast Cancer', 'Phenotype', 'HP:0003002', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('BRF2', 'Gene', (36, 40))	('Breast Cancer', 'Disease', (120, 133))	('Breast Cancer', 'Disease', 'MESH:D001943', (177, 190))	('ER', 'Gene', '2099', (138, 140))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('alteration', 'Var', (41, 51))	('Breast Cancer', 'Disease', 'MESH:D001943', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Breast Cancer', 'Phenotype', 'HP:0003002', (177, 190))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('Breast Cancer', 'Disease', (177, 190))	('breast cancer', 'Disease', (84, 97))
23729	33176745	In these metastatic breast cancer data sets, BRF2 alterations are predominately amplifications, 14.57%.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('alterations', 'Var', (50, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('BRF2', 'Gene', (45, 49))
23730	33176745	BRF2 alterations were identified in subtypes of metastatic breast invasive carcinoma, including IDL, IBC, breast mixed ductal and lobular carcinoma, and IBC NOS, Fig.	('IBC', 'Disease', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('lobular carcinoma', 'Disease', (130, 147))	('breast invasive carcinoma', 'Disease', (59, 84))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (130, 147))	('breast mixed ductal', 'Disease', (106, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('IDL', 'Disease', (96, 99))	('alterations', 'Var', (5, 16))	('BRF2', 'Gene', (0, 4))	('IBC', 'Chemical', '-', (101, 104))	('lobular carcinoma', 'Disease', 'MESH:D018275', (130, 147))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (59, 84))	('IBC', 'Disease', (101, 104))	('IBC', 'Chemical', '-', (153, 156))
23733	33176745	The highest frequency of BRF2 alterations, 33%, occur in women with metastatic breast cancer aged 45 < x < 50, Fig.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('women', 'Species', '9606', (57, 62))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('BRF2', 'Gene', (25, 29))	('alterations', 'Var', (30, 41))
23736	33176745	MYC and BRF2 alterations specifically co-occur in women aged 45 < x < 50 (p = 0.053) with metastatic breast cancer, Fig.	('MYC', 'Gene', (0, 3))	('BRF2', 'Gene', (8, 12))	('co-occur', 'Reg', (38, 46))	('women', 'Species', '9606', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('MYC', 'Gene', '4609', (0, 3))	('alterations', 'Var', (13, 24))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
23738	33176745	Interestingly, deletions in BRF2 have been identified in the 33% of women aged 45 < x < 50, Fig.	('BRF2', 'Gene', (28, 32))	('women', 'Species', '9606', (68, 73))	('deletions', 'Var', (15, 24))	('identified', 'Reg', (43, 53))
23740	33176745	The data presented in this study agree with previous data demonstrating that 8p deletions have been linked to advanced tumor stage, MYC amplification, inversely associated with ER receptor expression, and shortened overall survival.	('tumor', 'Disease', (119, 124))	('associated', 'Reg', (161, 171))	('8p deletions', 'Var', (77, 89))	('expression', 'MPA', (189, 199))	('MYC', 'Gene', (132, 135))	('ER', 'Gene', '2099', (177, 179))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('amplification', 'Var', (136, 149))	('overall', 'MPA', (215, 222))	('inversely', 'NegReg', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('shortened', 'NegReg', (205, 214))	('MYC', 'Gene', '4609', (132, 135))
23741	33176745	Further analysis of the patients with BRF2 deletions had clinical data available, which is correlative.	('deletions', 'Var', (43, 52))	('BRF2', 'Gene', (38, 42))	('patients', 'Species', '9606', (24, 32))
23742	33176745	For example, all these patients with BRF2 deletions are ages 45 < x < 50, self-reported race as white, were diagnosed as III high grade (poorly differentiated) and had negative ER and PR status per the medical record (MedR) diagnostic.	('PR', 'Gene', '5241', (184, 186))	('patients', 'Species', '9606', (23, 31))	('BRF2', 'Gene', (37, 41))	('deletions', 'Var', (42, 51))	('ER', 'Gene', '2099', (177, 179))
23747	33176745	Together, these data suggest additional studies are warranted to determine if tamoxifen treatment would be beneficial in patients with IBC and BRF2 alterations.	('tamoxifen', 'Chemical', 'MESH:D013629', (78, 87))	('alterations', 'Var', (148, 159))	('BRF2', 'Gene', (143, 147))	('IBC', 'Chemical', '-', (135, 138))	('patients', 'Species', '9606', (121, 129))	('IBC', 'Disease', (135, 138))
23753	33176745	Together, these data prompted a more detailed analysis of BRF2 alterations in IBC.	('IBC', 'Disease', (78, 81))	('alterations', 'Var', (63, 74))	('BRF2', 'Gene', (58, 62))	('IBC', 'Chemical', '-', (78, 81))
23760	33176745	The cytogenetic location of BRF2 is 8p11.23 and amplification of the short arm of chromosome 8 is a frequent feature of breast cancer cell lines and tumors.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('short arm', 'Phenotype', 'HP:0009824', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('BRF2', 'Gene', (28, 32))	('amplification', 'Var', (48, 61))
23761	33176745	In this study, we demonstrate that BRF2 is amplified in 5.9% of all breast cancers and 6.9% of all ductal breast carcinomas queried (Fig.	('BRF2', 'Gene', (35, 39))	('breast carcinomas', 'Disease', 'MESH:D001943', (106, 123))	('breast carcinomas', 'Disease', (106, 123))	('breast cancers', 'Disease', 'MESH:D001943', (68, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('breast cancers', 'Disease', (68, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast carcinomas', 'Phenotype', 'HP:0003002', (106, 123))	('amplified', 'Var', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('breast carcinoma', 'Phenotype', 'HP:0003002', (106, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))
23764	33176745	In this analysis, the estimated BRF2 copy numbers ranged from 0.8 to 9.2 in 2389 patients diagnosed with IDC, Fig.	('BRF2', 'Gene', (32, 36))	('copy numbers', 'Var', (37, 49))	('IDC', 'Disease', (105, 108))	('patients', 'Species', '9606', (81, 89))
23768	33176745	As such, we then queried for BRF2 alterations and clinical outcomes, specifically overall patient survival.	('patient', 'Species', '9606', (90, 97))	('alterations', 'Var', (34, 45))	('BRF2', 'Gene', (29, 33))
23769	33176745	A query of the TCGA Firehose Legacy data set in the cBioPortal for BRF2 alterations and patient overall survival status demonstrated a statistically significant correlation, Fig.	('patient', 'Species', '9606', (88, 95))	('BRF2', 'Gene', (67, 71))	('alterations', 'Var', (72, 83))
23770	33176745	Notably, in patients with BRF2 alterations, 21%, overall survival was drastically decreased, p = 9.332e-3, Fig.	('alterations', 'Var', (31, 42))	('patients', 'Species', '9606', (12, 20))	('BRF2', 'Gene', (26, 30))	('overall', 'CPA', (49, 56))	('decreased', 'NegReg', (82, 91))
23774	33176745	5d) showed no correlation with overall survival in the same invasive breast cancer data set we examined for BRF2 alterations.	('invasive breast cancer', 'Disease', 'MESH:D001943', (60, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('alterations', 'Var', (113, 124))	('invasive breast cancer', 'Disease', (60, 82))	('BRF2', 'Gene', (108, 112))
23775	33176745	Overall survival was dramatically decreased in breast cancer patients with co-occurring alterations in BRF2 and MYC, p = 5.299e-3, Fig.	('breast cancer', 'Disease', (47, 60))	('decreased', 'NegReg', (34, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('MYC', 'Gene', '4609', (112, 115))	('patients', 'Species', '9606', (61, 69))	('alterations', 'Var', (88, 99))	('Overall survival', 'CPA', (0, 16))	('BRF2', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('MYC', 'Gene', (112, 115))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
23780	33176745	However, a separate query of the Breast Cancer METABRIC data set in the cBioPortal for BRF2 alterations and overall survival was correlative.	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Breast Cancer', 'Disease', 'MESH:D001943', (33, 46))	('alterations', 'Var', (92, 103))	('Breast Cancer', 'Phenotype', 'HP:0003002', (33, 46))	('BRF2', 'Gene', (87, 91))	('Breast Cancer', 'Disease', (33, 46))
23781	33176745	In patients aged 55-60, BRF2 was altered in 16% (36 of 229 patients) and median months survival in patients with alterations in BRF2 was 143.13 and 213.20, in patients with no alterations, p = 6.47e-3 (Supplemental Table 1).	('patients', 'Species', '9606', (99, 107))	('altered', 'Reg', (33, 40))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (59, 67))	('alterations', 'Var', (113, 124))	('patients', 'Species', '9606', (159, 167))	('BRF2', 'Gene', (128, 132))
23783	33176745	Further query of the Breast Cancer METABRIC, for patients aged 55-60 with BRF2 alterations, ER positive status (n = 170) correlated with a decrease in overall survival, p = 7.87e-3, whereas ER negative status (n = 59) did not, p = 0.516 (Supplemental Table 1).	('alterations', 'Var', (79, 90))	('BRF2', 'Gene', (74, 78))	('ER', 'Gene', '2099', (190, 192))	('Breast Cancer', 'Phenotype', 'HP:0003002', (21, 34))	('Breast Cancer', 'Disease', (21, 34))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('patients', 'Species', '9606', (49, 57))	('overall survival', 'MPA', (151, 167))	('ER', 'Gene', '2099', (92, 94))	('Breast Cancer', 'Disease', 'MESH:D001943', (21, 34))	('decrease', 'NegReg', (139, 147))
23785	33176745	All patients with BRF2 alterations were coded as postmenopausal in the METABRIC) data set which differed from patients with BRF2 alterations in the TCGA, Firehose Legacy data set.	('patients', 'Species', '9606', (110, 118))	('BRF2', 'Gene', (18, 22))	('alterations', 'Var', (23, 34))	('patients', 'Species', '9606', (4, 12))
23786	33176745	Our study presents data suggesting BRF2 alterations in patients aged 35 to 50 correlates with overall survival (Fig.	('BRF2', 'Gene', (35, 39))	('overall survival', 'MPA', (94, 110))	('correlates with', 'Reg', (78, 93))	('alterations', 'Var', (40, 51))	('patients', 'Species', '9606', (55, 63))
23788	33176745	The decrease in overall survival in patients, 46-50, classified as ER- and with BRF2 alterations, correlated with postmenopausal status, p = 1.377e-4 (data not shown).	('BRF2', 'Gene', (80, 84))	('patients', 'Species', '9606', (36, 44))	('overall survival', 'MPA', (16, 32))	('decrease', 'NegReg', (4, 12))	('postmenopausal status', 'Phenotype', 'HP:0008209', (114, 135))	('ER', 'Gene', '2099', (67, 69))	('alterations', 'Var', (85, 96))
23791	33176745	A larger study of BRF2 alterations and ER status in breast cancer is needed to determine correlative value.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ER', 'Gene', '2099', (39, 41))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('alterations', 'Var', (23, 34))	('BRF2', 'Gene', (18, 22))
23799	33176745	Recently, it has been hypothesized that an oncogenic event, such as the mutation of c-MYC, is required to facilitate an aberrant increase in RNA pol III activity for the initiation and progression in a model of breast cancer.	('c-MYC', 'Gene', '4609', (84, 89))	('c-MYC', 'Gene', (84, 89))	('RNA pol III', 'Enzyme', (141, 152))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('RNA', 'cellular_component', 'GO:0005562', ('141', '144'))	('activity', 'MPA', (153, 161))	('increase', 'PosReg', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('mutation', 'Var', (72, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('breast cancer', 'Disease', (211, 224))
23800	33176745	There is evidence that MYC amplifies transcription of RNA pol III genes when RNA pol III genes are hypomethylated in breast cancer, specifically the nc886 gene, a short noncoding RNA, which has been shown to be occupied by BRF1 and deregulated in cancer.	('MYC', 'Gene', '4609', (23, 26))	('cancer', 'Disease', (247, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('BRF1', 'Gene', (223, 227))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('transcription', 'biological_process', 'GO:0006351', ('37', '50'))	('breast cancer', 'Disease', (117, 130))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('hypomethylated', 'Var', (99, 113))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('MYC', 'Gene', (23, 26))	('cancer', 'Disease', (124, 130))	('nc886', 'Gene', '100126299', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('RNA', 'cellular_component', 'GO:0005562', ('179', '182'))	('BRF1', 'Gene', '2972', (223, 227))	('nc886', 'Gene', (149, 154))
23803	33176745	In this study, we demonstrate MYC and BRF2 alterations co-occur in breast invasive carcinoma, p = 0.008 (Fig.	('MYC', 'Gene', '4609', (30, 33))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (67, 92))	('co-occur', 'Reg', (55, 63))	('BRF2', 'Gene', (38, 42))	('alterations', 'Var', (43, 54))	('MYC', 'Gene', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('breast invasive carcinoma', 'Disease', (67, 92))
23806	33176745	8f) and co-occurring MYC and BRF2 alterations significantly decreased overall survival, p = 5.299e-3 (Fig.	('decreased', 'NegReg', (60, 69))	('overall survival', 'MPA', (70, 86))	('BRF2', 'Gene', (29, 33))	('MYC', 'Gene', '4609', (21, 24))	('alterations', 'Var', (34, 45))	('MYC', 'Gene', (21, 24))
23864	27446447	qPCR was performed in duplex reactions, mixing TaqMan FAM-labelled probes for human egfl7 (Hs00211952_m1) or for ICAM-1 (Hs00164932.m1) with the normalizing beta2-microglobulin (B2M) VIC-labelled probe in the same tube and processed in a StepOne machine.	('egfl7', 'Gene', (84, 89))	('beta2-microglobulin', 'Gene', (157, 176))	('B2M', 'Gene', (178, 181))	('B2M', 'Gene', '567', (178, 181))	('Hs00164932.m1', 'Var', (121, 134))	('Hs00211952_m1', 'Var', (91, 104))	('beta2-microglobulin', 'Gene', '567', (157, 176))	('human', 'Species', '9606', (78, 83))
23865	27446447	Data were expressed as 2-DeltaDeltaCq where DeltaCq=Cq of gene-Cq of B2M, and DeltaDeltaCq=DeltaCq sample-DeltaCq control.	('B2M', 'Gene', (69, 72))	('B2M', 'Gene', '567', (69, 72))	('gene-Cq', 'Var', (58, 65))	('DeltaDeltaCq=DeltaCq', 'Var', (78, 98))	('DeltaCq=Cq', 'Var', (44, 54))
23888	27446447	Cuzick's tests for trend demonstrated that when the ICAM-1 score increased, the egfl7 score decreased (Fig.	('increased', 'PosReg', (65, 74))	('rat', 'Species', '10116', (32, 35))	('ICAM-1', 'Gene', (52, 58))	('egfl7 score', 'MPA', (80, 91))	('decreased', 'NegReg', (92, 101))	('score', 'Var', (59, 64))
23890	27446447	In order to assess which gene between ICAM-1 and egfl7 regulated the expression of the other one, we deregulated either egfl7 or ICAM-1 in human primary endothelial cells by RNA interference and checked for the expression of the other gene.	('deregulated', 'Var', (101, 112))	('egfl7', 'Gene', (120, 125))	('RNA', 'cellular_component', 'GO:0005562', ('174', '177'))	('RNA interference', 'MPA', (174, 190))	('RNA interference', 'biological_process', 'GO:0016246', ('174', '190'))	('human', 'Species', '9606', (139, 144))	('ICAM-1', 'Gene', (129, 135))
23916	27446447	As a matter of fact, targeting egfl7 has been shown to increase tumor blood vessel damage and to enhance the tumor response to anti-VEGF treatment in various murine models but the effects on the infiltration of immune cells into the tumors has not been assessed.	('increase', 'PosReg', (55, 63))	('VEGF', 'Gene', (132, 136))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('murine', 'Species', '10090', (158, 164))	('VEGF', 'Gene', '22339', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor blood vessel damage', 'Disease', 'MESH:D009383', (64, 89))	('tumor', 'Disease', (233, 238))	('tumor blood vessel damage', 'Disease', (64, 89))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('egfl7', 'Gene', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (64, 69))	('rat', 'Species', '10116', (201, 204))	('tumors', 'Disease', (233, 239))	('targeting', 'Var', (21, 30))	('enhance', 'PosReg', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (109, 114))
23917	27446447	Whether an anti-egfl7 therapy would increase the efficiency of immunotherapies in treating cancer remains to be assessed.	('anti-egfl7', 'Gene', (11, 21))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('increase', 'PosReg', (36, 44))	('anti-egfl7', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
23972	26515602	BRCA1/2 mutations) that would result in suboptimal outcomes; ii) older patients (perticularly those diagnosed after 79 years) may have significantly shorter life expectancy, and they are more likely to develop multiple complications during chemotherapy or endocrine therapy than younger patients; iii) older patients might be treated with significantly less standard adjuvant radiotherapy, chemotherapy or hormone therapy, for instance, they may receive reduced treatment cycles and dosage, shorter duration of long-term endocrine therapy.	('BRCA1/2', 'Gene', '672;675', (0, 7))	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (308, 316))	('patients', 'Species', '9606', (287, 295))	('mutations', 'Var', (8, 17))	('shorter', 'NegReg', (149, 156))	('BRCA1/2', 'Gene', (0, 7))
23996	26515602	This study was limited to women 18 years or older who had a pathologic diagnosis of T1-4, N0-3, M0 (AJCC) pure lobular breast cancer.	('N0-3', 'Var', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (111, 132))	('women', 'Species', '9606', (26, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('T1-4', 'Var', (84, 88))	('pure', 'molecular_function', 'GO:0034023', ('106', '110'))	('lobular breast cancer', 'Disease', (111, 132))	('lobular breast cancer', 'Disease', 'MESH:D013274', (111, 132))
24032	33609943	(left breast at 11 o'clock): IHC: E-cadherin (-), ER (3 +, 65 %), PR (3 +, 80 %), HER-2 (3 +), Ki67 (+, 8%), CK5 / 6 (myoepithelial +).	('HER-2', 'Gene', '2064', (82, 87))	('HER-2', 'Gene', (82, 87))	('E-cadherin', 'Gene', '999', (34, 44))	('E-cadherin', 'Gene', (34, 44))	('cadherin', 'molecular_function', 'GO:0008014', ('36', '44'))	('CK5', 'Var', (109, 112))	('PR', 'Gene', '140738', (66, 68))
24048	33609943	Studies have shown that IPLC has a higher frequency of ERBB2 mutations, which is considered as a target of anti ERBB2 drugs.	('ERBB2', 'Gene', '2064', (112, 117))	('ERBB2', 'Gene', (112, 117))	('mutations', 'Var', (61, 70))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))
24049	33609943	Besides, the IRS2 mutation found by Zhu Sha et al.	('IRS2', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('IRS2', 'Gene', '8660', (13, 17))
24051	33609943	Some studies have shown that in the multivariate model, polymorphic histology has nothing to do with the reduction of DFS (Disease-Free Survival), nor does it affect DSS (Disease-Specific Survival).	('DFS', 'Disease', 'None', (118, 121))	('reduction', 'NegReg', (105, 114))	('DSS', 'MPA', (166, 169))	('DSS', 'Chemical', '-', (166, 169))	('polymorphic histology', 'Var', (56, 77))	('DFS', 'Disease', (118, 121))
24071	27400234	In line with this observation, in vitro experiments demonstrated reduced proliferation and migration rates (~20%) in HCC1806 cells following NDRG2 silencing.	('NDRG2', 'Gene', '57447', (141, 146))	('reduced', 'NegReg', (65, 72))	('proliferation', 'CPA', (73, 86))	('NDRG2', 'Gene', (141, 146))	('migration rates', 'CPA', (91, 106))	('HCC1806', 'CellLine', 'CVCL:1258', (117, 124))	('silencing', 'Var', (147, 156))
24085	27400234	Recent studies indicated decreased NDRG2 expression due to promoter DNA-hypermethylation, underlining a possible tumor suppressive role of NDRG2 in breast carcinogenesis.	('DNA-hypermethylation', 'biological_process', 'GO:0044026', ('68', '88'))	('promoter DNA-hypermethylation', 'Var', (59, 88))	('tumor', 'Disease', (113, 118))	('NDRG2', 'Gene', '57447', (35, 40))	('NDRG2', 'Gene', '57447', (139, 144))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('expression', 'MPA', (41, 51))	('NDRG2', 'Gene', (35, 40))	('decreased', 'NegReg', (25, 34))	('breast carcinogenesis', 'Disease', (148, 169))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('NDRG2', 'Gene', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (148, 169))
24090	27400234	Moreover, NDRG2 knockdown in the basal A breast cancer cell line HCC1806 caused a reduced proliferation and migration rate while NDRG2 over-expression in basal A-like BT20 breast cancer cells, lacking endogenous NDRG2 expression, resulted in an increased cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('reduced', 'NegReg', (82, 89))	('NDRG2', 'Gene', (212, 217))	('migration rate', 'CPA', (108, 122))	('NDRG2', 'Gene', '57447', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cell proliferation', 'CPA', (255, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('NDRG2', 'Gene', '57447', (10, 15))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('breast cancer', 'Disease', (172, 185))	('HCC1806', 'CellLine', 'CVCL:1258', (65, 72))	('NDRG2', 'Gene', (129, 134))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('NDRG2', 'Gene', (10, 15))	('proliferation', 'CPA', (90, 103))	('breast cancer', 'Disease', (41, 54))	('increased', 'PosReg', (245, 254))	('knockdown', 'Var', (16, 25))	('over-expression', 'PosReg', (135, 150))	('NDRG2', 'Gene', '57447', (212, 217))	('cell proliferation', 'biological_process', 'GO:0008283', ('255', '273'))
24130	27400234	SI00656096, 5'-AAGGGTATGGACCTACGTGAA-3' and Hs_NDRG2_6 FlexiTube siRNA, Cat.	('Cat', 'molecular_function', 'GO:0004096', ('72', '75'))	('NDRG2', 'Gene', '57447', (47, 52))	('NDRG2', 'Gene', (47, 52))	('SI00656096', 'Var', (0, 10))
24131	27400234	After 48 h treatment cells were splitted and re-transfected with siRNA to guarantee efficient NDRG2 knock-down.	('NDRG2', 'Gene', '57447', (94, 99))	('knock-down', 'Var', (100, 110))	('NDRG2', 'Gene', (94, 99))
24170	27400234	For all following experiments, cells were treated with siRNAs for 144 h to assure an efficient NDRG2 protein knockdown.	('protein', 'Protein', (101, 108))	('knockdown', 'Var', (109, 118))	('NDRG2', 'Gene', '57447', (95, 100))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('NDRG2', 'Gene', (95, 100))
24174	27400234	In HCC1806 cells proliferation was significantly (P = 0.007) reduced by siRNA knockdown of NDRG2 compared to cells treated with control siRNA (Fig 4B and 4C).	('proliferation', 'CPA', (17, 30))	('knockdown', 'Var', (78, 87))	('HCC1806', 'CellLine', 'CVCL:1258', (3, 10))	('NDRG2', 'Gene', '57447', (91, 96))	('NDRG2', 'Gene', (91, 96))	('reduced', 'NegReg', (61, 68))
24175	27400234	Of interest, in BT20 cells, we observed that in a bulk of transiently transfected cells, i.e., a part of non-transfected BT20 cells may be present, NDRG2 re-expression led to a significant (P = 0.042) increased cell growth by 38%, compared with the mock-transfected cells 96 h after plating (S3C Fig).	('increased', 'PosReg', (201, 210))	('NDRG2', 'Gene', (148, 153))	('cell growth', 'CPA', (211, 222))	('re-expression', 'Var', (154, 167))	('cell growth', 'biological_process', 'GO:0016049', ('211', '222'))	('NDRG2', 'Gene', '57447', (148, 153))
24178	27400234	While the motility of BT20 cells was not clearly altered by NDRG2 overexpression (data not shown), loss of NDRG2 expression inhibits cell migration of basal-type HCC1806 cells, i.e.	('HCC1806', 'CellLine', 'CVCL:1258', (162, 169))	('inhibits', 'NegReg', (124, 132))	('NDRG2', 'Gene', (107, 112))	('NDRG2', 'Gene', '57447', (60, 65))	('cell migration of basal-type HCC1806 cells', 'CPA', (133, 175))	('loss', 'Var', (99, 103))	('NDRG2', 'Gene', '57447', (107, 112))	('NDRG2', 'Gene', (60, 65))	('cell migration', 'biological_process', 'GO:0016477', ('133', '147'))
24196	27400234	Again, TCGA data analyses confirmed our results by indicating a frequent hypermethylation in primary tumor tissue and, accordingly, demonstrated an inverse correlation (r = -0.548, P<0.001) of NDRG2 methylation and mRNA expression indicating promoter hypermethylation as the molecular cause of the NDRG2 loss particularly in luminal and HER2-enriched breast cancer.	('NDRG2', 'Gene', (298, 303))	('mRNA expression', 'MPA', (215, 230))	('HER2-enriched breast cancer', 'Disease', (337, 364))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('NDRG2', 'Gene', '57447', (193, 198))	('HER2-enriched breast cancer', 'Disease', 'MESH:D001943', (337, 364))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('promoter hypermethylation', 'Var', (242, 267))	('NDRG2', 'Gene', '57447', (298, 303))	('loss', 'NegReg', (304, 308))	('luminal', 'Disease', (325, 332))	('methylation', 'Var', (199, 210))	('NDRG2', 'Gene', (193, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (351, 364))	('methylation', 'biological_process', 'GO:0032259', ('199', '210'))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
24209	27400234	Since basal-type tumors frequently metastasize to the brain, one may speculate that high expression of NDRG2 as well as WNT/beta-catenin signaling molecules, known to have an important putative role in the development and maintenance of normal brain tissue, facilitate metastasis of basal tumors.	('facilitate', 'PosReg', (258, 268))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('basal tumors', 'Phenotype', 'HP:0002671', (283, 295))	('high', 'Var', (84, 88))	('beta-catenin', 'Gene', (124, 136))	('basal-type tumors', 'Disease', (6, 23))	('NDRG2', 'Gene', (103, 108))	('basal-type tumors', 'Disease', 'MESH:D002280', (6, 23))	('metastasis of basal tumors', 'Disease', (269, 295))	('beta-catenin', 'Gene', '1499', (124, 136))	('metastasis of basal tumors', 'Disease', 'MESH:D009362', (269, 295))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('NDRG2', 'Gene', '57447', (103, 108))
24211	27400234	Since biological evidence supporting this hypothesis was lacking, the present study aimed to proof the relevance of NDRG2 in basal-type breast cancer in two independent transient basal A-type in vitro cell models: BT20 and HCC1806 belong to the basal A subtype while published MDA-MB-231 cell models, showing a tumor suppressive function of NDRG2, belongs to the basal B subtype.	('basal-type breast cancer', 'Disease', (125, 149))	('NDRG2', 'Gene', '57447', (341, 346))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('NDRG2', 'Gene', (341, 346))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('NDRG2', 'Gene', '57447', (116, 121))	('HCC1806', 'Var', (223, 230))	('HCC1806', 'CellLine', 'CVCL:1258', (223, 230))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('basal-type breast cancer', 'Disease', 'MESH:D001943', (125, 149))	('tumor', 'Disease', (311, 316))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (277, 287))	('BT20', 'Var', (214, 218))	('NDRG2', 'Gene', (116, 121))
24220	27400234	In parallel to the abundant NDRG2 expression in basal-type primary breast cancer, we observed a clear tumor suppressive impact mediated by NDRG2 knockdown in metastatic, basal A-like HCC1806.	('NDRG2', 'Gene', (28, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('knockdown', 'Var', (145, 154))	('NDRG2', 'Gene', '57447', (139, 144))	('primary breast cancer', 'Disease', 'MESH:D001943', (59, 80))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('primary breast cancer', 'Disease', (59, 80))	('NDRG2', 'Gene', (139, 144))	('HCC1806', 'CellLine', 'CVCL:1258', (183, 190))	('NDRG2', 'Gene', '57447', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
24221	27400234	In fact, cell proliferation in HCC1806 cells was effectively suppressed by NDRG2 knockdown.	('cell proliferation', 'biological_process', 'GO:0008283', ('9', '27'))	('suppressed', 'NegReg', (61, 71))	('NDRG2', 'Gene', '57447', (75, 80))	('knockdown', 'Var', (81, 90))	('HCC1806', 'CellLine', 'CVCL:1258', (31, 38))	('cell proliferation', 'CPA', (9, 27))	('NDRG2', 'Gene', (75, 80))
24294	30197937	In addition, molecular differences in ILC and IDC may contribute to the increased number of LNs at the time of surgery that we observed in this patient cohort.	('LNs', 'Disease', (92, 95))	('contribute', 'Reg', (54, 64))	('patient', 'Species', '9606', (144, 151))	('molecular differences', 'Var', (13, 34))	('ILC', 'Gene', (38, 41))	('IDC', 'Gene', '4000', (46, 49))	('IDC', 'Gene', (46, 49))
24300	30197937	In patients found to have pathologic stage IIIA or greater disease (AJCC version 7: T3N1, N2-N3, or T4) a recommendation of PMRT is often made, which is consistent with a high level of evidence (category 1) and uniform National Comprehensive Cancer Network consensus that intervention is appropriate.	('T3N1', 'Var', (84, 88))	('Cancer', 'Disease', 'MESH:D009369', (242, 248))	('Cancer', 'Phenotype', 'HP:0002664', (242, 248))	('N2-N3', 'Var', (90, 95))	('patients', 'Species', '9606', (3, 11))	('Cancer', 'Disease', (242, 248))
24374	28863134	In the ER+/PR+ and ER+/PR- subgroups, the prognosis of IDC were better than that for ILC, regardless of OS or DSS(Table 3).	('OS', 'Chemical', '-', (104, 106))	('ER+/PR-', 'Var', (19, 26))	('DSS', 'Chemical', '-', (110, 113))	('IDC', 'Gene', '4000', (55, 58))	('ER+/PR+', 'Var', (7, 14))	('IDC', 'Gene', (55, 58))
24375	28863134	For the OS of the ILC cohort, the risk of death in the patients with ER+/PR- (purple dotted line) tumors was 50% higher than those with ER+/PR+(red dotted line) tumors(HR: 1.549;P<0.0001), and was 40% higher than those with the ER-/PR+ (black dotted line) tumors(HR:1.399;P<0.0001).	('tumors', 'Disease', (98, 104))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (256, 262))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('death', 'Disease', 'MESH:D003643', (42, 47))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('OS', 'Chemical', '-', (8, 10))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('ER+/PR-', 'Var', (69, 76))	('higher', 'PosReg', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('higher', 'PosReg', (113, 119))	('death', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('patients', 'Species', '9606', (55, 63))	('tumors', 'Disease', (256, 262))
24378	28863134	The ER+/PR+ subgroup(red solid line) showed a survival advantage in DSS over the ER-/PR+ subgroup (black solid line)(ER-/PR+ vs. ER+/PR+,HR: 1.926;P<0.0001) and ER+/PR-(purple solid line)(ER+/PR- vs. ER+/PR+,HR: 1.685;P<0.0001), which seemed to be more pronounced than that in the ILC group.	('DSS', 'Chemical', '-', (68, 71))	('survival advantage', 'CPA', (46, 64))	('DSS', 'Disease', (68, 71))	('ER+/PR-', 'Var', (161, 168))
24383	28863134	The ER+PR- subgroup in ILC cohort had the worst survival with respect to OS and DSS(P<0.0001).The ER-/PR+ subgroups in the ILC and IDC cohorts had similar survivals as the ER+/PR- subgroup in the IDC cohort regarding DSS, and seemed to have an advantage in survival over that demonstrated in the OS curve.	('ER-/PR+', 'Var', (98, 105))	('IDC', 'Gene', (131, 134))	('OS', 'Chemical', '-', (296, 298))	('DSS', 'Chemical', '-', (217, 220))	('OS', 'Chemical', '-', (73, 75))	('IDC', 'Gene', '4000', (196, 199))	('ILC', 'Disease', (123, 126))	('IDC', 'Gene', (196, 199))	('DSS', 'MPA', (217, 220))	('DSS', 'Chemical', '-', (80, 83))	('IDC', 'Gene', '4000', (131, 134))
24384	28863134	These results meant that when ER and PR were expressed together at a different level, the clinical outcome differed between the subgroups in ILC and IDC, and the ER+/PR- subgroup in the ILC had the worst prognosis.	('ILC', 'Disease', (141, 144))	('differed', 'Reg', (107, 115))	('IDC', 'Gene', '4000', (149, 152))	('IDC', 'Gene', (149, 152))	('ER+/PR-', 'Var', (162, 169))
24430	28863134	The ILC patients with hormone receptor status ER+/PR-had a poorer survival than the other groups.	('hormone receptor', 'Gene', '3164', (22, 38))	('survival', 'MPA', (66, 74))	('poorer', 'NegReg', (59, 65))	('hormone receptor', 'Gene', (22, 38))	('ILC', 'Disease', (4, 7))	('ER+/PR-had', 'Var', (46, 56))	('patients', 'Species', '9606', (8, 16))
24447	26729235	Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC.	('CDH1', 'Gene', '999', (13, 17))	('PI3K', 'molecular_function', 'GO:0016303', ('29', '33'))	('PI3K pathway', 'Pathway', (29, 41))	('ILC', 'Disease', (89, 92))	('Mutations', 'Var', (0, 9))	('frequent', 'Reg', (55, 63))	('CDH1', 'Gene', (13, 17))
24448	26729235	We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('PD-1', 'Gene', '5133', (105, 109))	('ILCs', 'Disease', (35, 39))	('regulation', 'biological_process', 'GO:0065007', ('84', '94'))	('chromosomes', 'Var', (308, 319))	('CTLA-4', 'Gene', (114, 120))	('PD-L1', 'Gene', (98, 103))	('Epithelial to Mesenchymal Transition', 'biological_process', 'GO:0001837', ('252', '288'))	('gain', 'PosReg', (300, 304))	('Epithelial to Mesenchymal Transition', 'CPA', (252, 288))	('PD-L1', 'Gene', '29126', (98, 103))	('up-regulation', 'PosReg', (81, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('342', '352'))	('CTLA-4', 'Gene', '1493', (114, 120))	('EMT', 'biological_process', 'GO:0001837', ('290', '293'))	('loss', 'NegReg', (334, 338))	('PD-1', 'Gene', (105, 109))
24465	26729235	To explore the biology of invasive lobular carcinomas (ILCs), we performed comprehensive molecular profiling of 144 untreated tissue samples from primary ILC tumours with 6.8 years median clinical follow-up (Additional file 1) using (i) targeted DNA sequencing to study somatic variants on a set of 613 genes (518 protein kinases and 95 additional cancer genes, Additional file 2); (ii) SNP6 arrays to study somatic copy number alteration (CNA) profiles; (iii) DNA microarrays to study gene expression and (iv) reverse-phase protein arrays (RPPA) to measure the expression of 168 selected proteins and phospho-proteins (Additional file 3).	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('DNA', 'cellular_component', 'GO:0005574', ('461', '464'))	('protein', 'cellular_component', 'GO:0003675', ('525', '532'))	('gene expression', 'biological_process', 'GO:0010467', ('486', '501'))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (35, 52))	('clinical', 'Species', '191496', (188, 196))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (35, 53))	('cancer', 'Disease', (348, 354))	('ILC tumours', 'Disease', 'MESH:D009369', (154, 165))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('variants', 'Var', (278, 286))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (26, 53))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('DNA', 'cellular_component', 'GO:0005574', ('246', '249'))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('expression', 'MPA', (562, 572))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('invasive lobular carcinomas', 'Disease', (26, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('protein', 'cellular_component', 'GO:0003675', ('314', '321'))	('ILC tumours', 'Disease', (154, 165))
24480	26729235	Genomic profiling was performed to identify mutations in kinases and breast cancer genes that contribute to the development of ILC.	('kinases', 'Gene', (57, 64))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('ILC', 'Disease', (127, 130))	('mutations', 'Var', (44, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('contribute', 'Reg', (94, 104))
24483	26729235	As expected, CDH1 mutants show lower expression at both the mRNA (Wilcoxon p = 2.4e-5) and protein (Wilcoxon p = 8.9e-4) levels (Figure S11).	('CDH1', 'Gene', '999', (13, 17))	('mutants', 'Var', (18, 25))	('lower', 'NegReg', (31, 36))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('S11', 'Gene', '6267', (136, 139))	('expression', 'MPA', (37, 47))	('CDH1', 'Gene', (13, 17))	('S11', 'Gene', (136, 139))
24486	26729235	The PI3K pathway was mutated in 46% of the tumours, with mutations in AKT1 (5.1%), PIK3R3 (2.9%), PTEN (1.4%), PIK3CB (1.4%), PIK3CG (1.4%), PIK3CD (1.4%) and PIK3CA that tended to be mutually exclusive (Figure S12).	('AKT1', 'Gene', '207', (70, 74))	('mutations', 'Var', (57, 66))	('PIK3CD', 'Gene', (141, 147))	('tumours', 'Disease', (43, 50))	('PIK3CA', 'Gene', '5290', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('AKT1', 'Gene', (70, 74))	('PTEN', 'Gene', (98, 102))	('PI3K pathway', 'Pathway', (4, 16))	('S12', 'Gene', '6268', (211, 214))	('PIK3CG', 'Gene', (126, 132))	('PIK3CG', 'Gene', '5294', (126, 132))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('PIK3R3', 'Gene', '8503', (83, 89))	('PIK3CA', 'Gene', (159, 165))	('PIK3CB', 'Gene', (111, 117))	('PIK3CD', 'Gene', '5293', (141, 147))	('PIK3CB', 'Gene', '5291', (111, 117))	('PIK3R3', 'Gene', (83, 89))	('S12', 'Gene', (211, 214))
24487	26729235	Most ERBB2 mutations occur in the HR subtype (Fig.	('ERBB2', 'Gene', '2064', (5, 10))	('mutations', 'Var', (11, 20))	('occur', 'Reg', (21, 26))	('ERBB2', 'Gene', (5, 10))
24488	26729235	GATA3 mutations are enriched in the IR subtype, even though not significantly so (Fig.	('GATA3', 'Gene', '2625', (0, 5))	('mutations', 'Var', (6, 15))	('GATA3', 'Gene', (0, 5))	('IR subtype', 'Disease', (36, 46))
24496	26729235	More specifically we selected cell lines with inactivating mutations in CDH1 (E-cadherin) and CTNNA1 (alpha-catenin) resulting in inactivation of the complex these proteins belong to.	('CTNNA1', 'Gene', (94, 100))	('CDH1', 'Gene', (72, 76))	('E-cadherin', 'Gene', (78, 88))	('complex these', 'MPA', (150, 163))	('inactivating mutations', 'Var', (46, 68))	('CTNNA1', 'Gene', '1495', (94, 100))	('inactivation', 'MPA', (130, 142))	('E-cadherin', 'Gene', '999', (78, 88))	('CDH1', 'Gene', '999', (72, 76))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))
24503	26729235	Tumours with a high number of non-silent somatic mutations were associated with poor survival (Figure S18), with an adjusted Hazard Ratio of 1.26 (95% CI 1.10 to 1.45).	('S18', 'Gene', '6222', (102, 105))	('poor', 'NegReg', (80, 84))	('S18', 'Gene', (102, 105))	('non-silent somatic mutations', 'Var', (30, 58))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
24505	26729235	Two had an FDR < 1%: a higher level of eIF4B was associated with poor survival, (Figure S19A, adjusted Hazard Ratio 10.35, 95% CI 2.5 to 42.88) while a higher level of histone H2AX was associated with better survival (Figure S19B, adjusted Hazard Ratio 0.3376, 95% CI 0.16 to 0.73).	('S19B', 'Var', (225, 229))	('S19A', 'Mutation', 'p.S19A', (88, 92))	('eIF4', 'cellular_component', 'GO:0008304', ('39', '43'))	('eIF4B', 'Gene', (39, 44))	('S19B', 'SUBSTITUTION', 'None', (225, 229))	('eIF4B', 'Gene', '1975', (39, 44))	('histone H2AX', 'Gene', '3014', (168, 180))	('poor', 'NegReg', (65, 69))	('histone H2AX', 'Gene', (168, 180))
24507	26729235	5B): patients with high mutation rate show poor survival while patients with low eIF4B level exhibit good survival (Fig.	('eIF4', 'cellular_component', 'GO:0008304', ('81', '85'))	('patients', 'Species', '9606', (5, 13))	('low eIF4B', 'Phenotype', 'HP:0045044', (77, 86))	('eIF4B', 'Gene', (81, 86))	('mutation', 'Var', (24, 32))	('patients', 'Species', '9606', (63, 71))	('eIF4B', 'Gene', '1975', (81, 86))
24513	26729235	When we investigated the influence of therapy, the patients with low mutation rate and high eIF4B appeared on the Kaplan-Meier plot to be highly responsive to anti-hormonal therapy (Figure S22).	('responsive', 'MPA', (145, 155))	('eIF4B', 'Gene', (92, 97))	('high', 'Var', (87, 91))	('eIF4', 'cellular_component', 'GO:0008304', ('92', '96'))	('patients', 'Species', '9606', (51, 59))	('eIF4B', 'Gene', '1975', (92, 97))
24514	26729235	Even though the small size of the subsets precludes significance to be achieved in statistical tests, this result suggests that high eIF4B could increase proliferation, leading to poor survival, but this can be effectively controlled by anti-hormonal therapy.	('poor', 'NegReg', (180, 184))	('eIF4B', 'Gene', (133, 138))	('increase', 'PosReg', (145, 153))	('high', 'Var', (128, 132))	('proliferation', 'CPA', (154, 167))	('eIF4B', 'Gene', '1975', (133, 138))	('eIF4', 'cellular_component', 'GO:0008304', ('133', '137'))
24517	26729235	Similar to the recent TCGA study, we found that ILCs frequently carry mutations that inactivate CDH1 and that activate the PI3K pathway.	('CDH1', 'Gene', (96, 100))	('mutations', 'Var', (70, 79))	('inactivate', 'NegReg', (85, 95))	('CDH1', 'Gene', '999', (96, 100))	('activate', 'PosReg', (110, 118))	('PI3K pathway', 'Pathway', (123, 135))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))
24519	26729235	We also found low frequency mutations in a number of signalling molecules including ERBB2, MAP3K1, and MAP2K4 and low frequency inactivating mutations in TP53 and the transcription factor GATA3, which is critically important for ER signalling.	('ERBB2', 'Gene', (84, 89))	('signalling', 'biological_process', 'GO:0023052', ('53', '63'))	('signalling', 'biological_process', 'GO:0023052', ('232', '242'))	('GATA3', 'Gene', '2625', (188, 193))	('MAP3K', 'molecular_function', 'GO:0004709', ('91', '96'))	('MAP2K4', 'Gene', (103, 109))	('TP53', 'Gene', (154, 158))	('MAP3K1', 'Gene', (91, 97))	('TP53', 'Gene', '7157', (154, 158))	('MAP3K1', 'Gene', '4214', (91, 97))	('MAP2K4', 'Gene', '6416', (103, 109))	('transcription', 'biological_process', 'GO:0006351', ('167', '180'))	('transcription factor', 'molecular_function', 'GO:0000981', ('167', '187'))	('MAP2K', 'molecular_function', 'GO:0004708', ('103', '108'))	('GATA3', 'Gene', (188, 193))	('ERBB2', 'Gene', '2064', (84, 89))	('mutations', 'Var', (28, 37))	('inactivating', 'NegReg', (128, 140))
24555	26729235	Variants found back in the tumour sample and not in the normal are validated mutations (VALIDATED); variants found in both the tumour and the normal samples are rare germline variants (SNP); variants not found back in the tumour samples are false positive calls (ABSENT); finally some variants were tested but the experiment failed (FAILED).	('tumour', 'Disease', 'MESH:D009369', (222, 228))	('Variants', 'Var', (0, 8))	('tumour', 'Disease', (222, 228))	('variants', 'Var', (100, 108))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('false', 'biological_process', 'GO:0071878', ('241', '246'))	('tumour', 'Disease', (27, 33))	('variants', 'Var', (191, 199))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('false', 'biological_process', 'GO:0071877', ('241', '246'))	('tumour', 'Disease', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))
24569	26963620	Analyzed parameters were: age, tumor size, axillary lymph node (N), distant metastasis (M), histological grade (HG), estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Ki-67, p53 and BCL2 ILC of non-lactating women showed a larger (p = 0.009), lymph node involvement (p = 0.051) and distant metastasis (p = 0.060).	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BCL2', 'molecular_function', 'GO:0015283', ('208', '212'))	('androgen receptor', 'Gene', (169, 186))	('p53', 'Gene', (200, 203))	('tumor', 'Disease', (31, 36))	('distant metastasis', 'CPA', (308, 326))	('BCL2', 'Gene', '596', (208, 212))	('p53', 'Gene', '7157', (200, 203))	('distant metastasis', 'CPA', (68, 86))	('Ki-67', 'Var', (193, 198))	('androgen receptor', 'Gene', '367', (169, 186))	('women', 'Species', '9606', (234, 239))	('BCL2', 'Gene', (208, 212))	('lymph node involvement', 'CPA', (269, 291))
24592	26963620	ER and PR were assessed according to the Allred score as negative (scores 0-2) and positive (score 3-8), and positivity thresholds for p53 and Ki-67 were 20% and 15%, respectively.	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('Ki-67', 'Var', (143, 148))
24607	26963620	We found absence of lactation was associated with larger tumors, more axillary lymph node involvement and distant metastases, which reflect a poorer outcome.	('metastases', 'Disease', (114, 124))	('lactation', 'Disease', (20, 29))	('absence', 'Var', (9, 16))	('lactation', 'Disease', 'MESH:D007775', (20, 29))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('lactation', 'biological_process', 'GO:0007595', ('20', '29'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('more', 'PosReg', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
24619	19768562	Promoter Methylation and the Detection of Breast Cancer Mammographic screening has been shown to reduce breast cancer mortality in women over the age of 50 years, and to a lesser extent in younger women.	('women', 'Species', '9606', (131, 136))	('Breast Cancer', 'Phenotype', 'HP:0003002', (42, 55))	('women', 'Species', '9606', (197, 202))	('Promoter Methylation', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('Breast Cancer', 'Disease', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('Breast Cancer', 'Disease', 'MESH:D001943', (42, 55))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('reduce', 'NegReg', (97, 103))
24621	19768562	Silencing of tumor suppressor genes through promoter hypermethylation is known to be a frequent and early event in carcinogenesis.	('promoter hypermethylation', 'Var', (44, 69))	('tumor suppressor', 'Gene', (13, 29))	('Silencing', 'NegReg', (0, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('tumor suppressor', 'Gene', '7248', (13, 29))	('carcinogenesis', 'Disease', (115, 129))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
24624	19768562	In this paper we review the current literature on promoter hypermethylation changes and breast cancer and discuss issues that remain to be addressed in order for the potential of these markers to augment the sensitivity of screening mammography.	('promoter hypermethylation changes', 'Var', (50, 83))	('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))
24638	19768562	Cancer initiation and progression is driven by the accumulation of inherited or acquired DNA mutations.	('DNA', 'Gene', (89, 92))	('Cancer initiation', 'Disease', 'MESH:D009369', (0, 17))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('inherited', 'Var', (67, 76))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('Cancer initiation', 'Disease', (0, 17))
24639	19768562	Though these modifications may all show potential for early detection of cancer, this review focuses exclusively on DNA methylation.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('DNA methylation', 'biological_process', 'GO:0006306', ('116', '131'))	('modifications', 'Var', (13, 26))
24643	19768562	While global hypomethylation is thought to play a role in carcinogenesis primarily by increasing genetic instability, local hypermethylation alters gene expression.	('global hypomethylation', 'Var', (6, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('gene expression', 'biological_process', 'GO:0010467', ('148', '163'))	('alters', 'Reg', (141, 147))	('carcinogenesis', 'Disease', (58, 72))	('genetic instability', 'MPA', (97, 116))	('increasing', 'PosReg', (86, 96))	('gene expression', 'MPA', (148, 163))	('local hypermethylation', 'Var', (118, 140))
24644	19768562	Silencing of tumor suppressor genes through promoter hypermethylation is known to be a common event in carcinogenesis, thought to provide a selective growth advantage to tumor cells and contributing to the overall genetic instability of the tumor.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor suppressor', 'Gene', '7248', (13, 29))	('tumor', 'Disease', (241, 246))	('growth advantage', 'CPA', (150, 166))	('promoter hypermethylation', 'Var', (44, 69))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor suppressor', 'Gene', (13, 29))	('Silencing', 'NegReg', (0, 9))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('tumor', 'Disease', (170, 175))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('carcinogenesis', 'Disease', (103, 117))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
24645	19768562	This hypermethylation appears to be an early event in carcinogenesis, and occurs at least as frequently as genetic mutations in somatic cells so that hundreds of genes may be inactivated by DNA methylation in a single cancer.	('carcinogenesis', 'Disease', 'MESH:D063646', (54, 68))	('methylation', 'Var', (194, 205))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('inactivated', 'NegReg', (175, 186))	('cancer', 'Disease', (218, 224))	('carcinogenesis', 'Disease', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('DNA', 'cellular_component', 'GO:0005574', ('190', '193'))	('DNA methylation', 'biological_process', 'GO:0006306', ('190', '205'))
24646	19768562	A large number of studies of breast cancer tissue have been conducted showing the frequent methylation of genes involved in cell cycle regulation: p16INK4A, p14ARF, p15, CCDN2, DAPK; DNA repair: MGMT, hMLH1; transformation: GSTP1; signal transduction: RARbeta2, APC, ERbeta; and adhesion and metastasis: CDH1, CDH13.	('p14ARF', 'Gene', '1029', (157, 163))	('CDH13', 'Gene', '1012', (310, 315))	('CDH1', 'Gene', (310, 314))	('APC', 'Disease', 'MESH:D011125', (262, 265))	('MGMT', 'Gene', (195, 199))	('APC', 'Disease', (262, 265))	('RARbeta', 'Gene', '5915', (252, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('ERbeta', 'Gene', '2100', (267, 273))	('RARbeta', 'Gene', (252, 259))	('ERbeta', 'Gene', (267, 273))	('p14ARF', 'Gene', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('breast cancer', 'Disease', (29, 42))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('CDH1', 'Gene', '999', (304, 308))	('CDH13', 'Gene', (310, 315))	('DAPK', 'Gene', (177, 181))	('GSTP1', 'Gene', '2950', (224, 229))	('methylation', 'Var', (91, 102))	('MGMT', 'molecular_function', 'GO:0003908', ('195', '199'))	('p15', 'Gene', (165, 168))	('CDH1', 'Gene', (304, 308))	('DNA repair', 'biological_process', 'GO:0006281', ('183', '193'))	('GSTP1', 'Gene', (224, 229))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('124', '145'))	('hMLH1', 'Gene', (201, 206))	('MGMT', 'Gene', '4255', (195, 199))	('DAPK', 'Gene', '1612', (177, 181))	('hMLH1', 'Gene', '4292', (201, 206))	('signal transduction', 'biological_process', 'GO:0007165', ('231', '250'))	('p16INK4A', 'Gene', (147, 155))	('p15', 'Gene', '1030', (165, 168))	('APC', 'cellular_component', 'GO:0005680', ('262', '265'))	('CDH1', 'Gene', '999', (310, 314))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('p16INK4A', 'Gene', '1029', (147, 155))
24652	19768562	It was first recognized that tumors were the origin of some circulating DNA during the mid-nineties when it was found that it was possible to detect cancer-associated mutations (N-ras, k-ras), micro-satellite instability and loss of heterozygosity (LOH) identical to that seen in the tumor.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('micro-satellite instability', 'Var', (193, 220))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('N-ras', 'Gene', '4893', (178, 183))	('N-ras', 'Gene', (178, 183))	('loss of heterozygosity', 'Var', (225, 247))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumors', 'Disease', (29, 35))	('tumor', 'Disease', (284, 289))	('cancer', 'Disease', (149, 155))	('k-ras', 'Gene', '3845', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('k-ras', 'Gene', (185, 190))	('tumor', 'Disease', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
24653	19768562	DNA alterations, including both mutations and epigenetic modifications, have also been detected in patients with small and in situ lesions.	('detected', 'Reg', (87, 95))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('patients', 'Species', '9606', (99, 107))	('situ lesions', 'Disease', 'MESH:D002278', (126, 138))	('mutations', 'Var', (32, 41))	('situ lesions', 'Disease', (126, 138))	('epigenetic modifications', 'Var', (46, 70))
24655	19768562	A number of studies illustrate the potential for the use of methylation markers in the early detection of a variety of cancers including prostate, bladder, gastric, renal, ovarian, colorectal, cervical, lung, liver and breast.	('breast', 'Disease', (219, 225))	('ovarian', 'Disease', (172, 179))	('methylation', 'Var', (60, 71))	('lung', 'Disease', (203, 207))	('prostate', 'Disease', (137, 145))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('colorectal', 'Disease', 'MESH:D015179', (181, 191))	('liver', 'Disease', (209, 214))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cervical', 'Disease', (193, 201))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('bladder', 'Disease', (147, 154))	('gastric', 'Disease', (156, 163))	('colorectal', 'Disease', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('renal', 'Disease', (165, 170))
24656	19768562	Studies in lung cancer have found that aberrant DNA methylation is detectable as early as 3 years prior to diagnosis in the sputum of subjects exposed to carcinogens (uranium miners and smokers).	('DNA', 'Protein', (48, 51))	('miners', 'Species', '265634', (175, 181))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('DNA methylation', 'biological_process', 'GO:0006306', ('48', '63'))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('aberrant', 'Var', (39, 47))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
24660	19768562	Studies have also shown that aberrant methylation events occur early on in breast cancer development, and are detectable in tissue from in situ carcinomas (both lobular and ductal) and early stage breast cancer (stages 0 and I).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('stage breast cancer', 'Disease', (191, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('methylation', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('stage breast cancer', 'Disease', 'MESH:D001943', (191, 210))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('situ carcinomas', 'Disease', 'MESH:D002278', (139, 154))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('situ carcinomas', 'Disease', (139, 154))
24680	19768562	Eighty-five percent of breast cancers and 70% of fibroadenomas had methylation of at least one of the genes in the panel with half of the cases having methylation in three or more genes.	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('fibroadenomas', 'Disease', 'MESH:D018226', (49, 62))	('breast cancers', 'Phenotype', 'HP:0003002', (23, 37))	('breast cancers', 'Disease', 'MESH:D001943', (23, 37))	('fibroadenomas', 'Disease', (49, 62))	('breast cancers', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('methylation', 'Var', (67, 78))
24683	19768562	Further, using three of these same genes (RARbeta2, RASSF1A and CCND2), in a study of 36 BBD, 21 in situ carcinoma and 45 invasive carcinoma, Pu et al found there was an increase in the frequency of promoter hypermethylation from benign (42% had methylation of at least one of the three genes) to in situ carcinoma (76%) and invasive carcinoma (96%).	('methylation', 'Var', (246, 257))	('invasive carcinoma', 'Disease', 'MESH:D009361', (325, 343))	('situ carcinoma', 'Disease', 'MESH:D002278', (300, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('methylation', 'biological_process', 'GO:0032259', ('246', '257'))	('RASSF1A', 'Gene', '11186', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('RASSF1A', 'Gene', (52, 59))	('situ carcinoma', 'Disease', 'MESH:D002278', (100, 114))	('situ carcinoma', 'Disease', (300, 314))	('invasive carcinoma', 'Disease', (122, 140))	('invasive carcinoma', 'Disease', 'MESH:D009361', (122, 140))	('CCND2', 'Gene', (64, 69))	('CCND2', 'Gene', '894', (64, 69))	('situ carcinoma', 'Disease', (100, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('RARbeta', 'Gene', '5915', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('RARbeta', 'Gene', (42, 49))	('invasive carcinoma', 'Disease', (325, 343))	('promoter', 'MPA', (199, 207))
24707	19768562	Thus, promoter methylation may not be specific to cancer per se, but rather part of an accumulation of changes in DNA that occur over the course of a lifetime, eventually contributing to tumor development.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('promoter', 'MPA', (6, 14))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('contributing to', 'Reg', (171, 186))	('DNA', 'Gene', (114, 117))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('changes', 'Var', (103, 110))
24709	19768562	Promoter hypermethylation has been identified as a potential marker and been shown to be able to detect established breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('Promoter hypermethylation', 'Var', (0, 25))
24715	19768562	In a recent study, methylation results using a nested QMSP method (QAMA) on DNA obtained from micro-dissected cells from formalin-fixed and paraffin-embedded tumor tissues (n=13) was found to have a good correlation with sequencing results (R=0.982).	('tumor', 'Disease', (158, 163))	('methylation', 'Var', (19, 30))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('formalin', 'Chemical', 'MESH:D005557', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('paraffin', 'Chemical', 'MESH:D010232', (140, 148))
24718	19768562	Methylation of these genes can be found in many other forms of cancer and is not specific to breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('breast cancer', 'Disease', (93, 106))	('found', 'Reg', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (63, 69))
24719	19768562	There are genes however, that may have an increased role in breast cancer specifically, such as GSTP1; which is known to be involved in hormone related cancers, BRCA1; a known player in the family history of breast cancer such that patients with methylated BRCA1 having a similar phenotype to those with BRCA1 mutations and ERS1 and its associated genes because of the known role of estrogen in breast carcinogenesis.	('BRCA1', 'Gene', '672', (304, 309))	('BRCA1', 'Gene', '672', (161, 166))	('methylated', 'Var', (246, 256))	('BRCA1', 'Gene', (304, 309))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('BRCA1', 'Gene', '672', (257, 262))	('BRCA1', 'Gene', (161, 166))	('cancers', 'Disease', (152, 159))	('mutations', 'Var', (310, 319))	('breast carcinogenesis', 'Disease', (395, 416))	('BRCA1', 'Gene', (257, 262))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('GSTP1', 'Gene', '2950', (96, 101))	('breast cancer', 'Disease', (60, 73))	('GSTP1', 'Gene', (96, 101))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (395, 416))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('breast cancer', 'Disease', (208, 221))
24726	19768562	A number of cancer-related genes have been found to be frequently methylated in breast cancer.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('methylated', 'Var', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
24733	19768562	Studies in well defined populations, including appropriate controls and larger numbers are needed to further evaluate the potential of DNA methylation to improve current breast cancer screening strategies.	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('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))	('DNA methylation', 'biological_process', 'GO:0006306', ('135', '150'))	('methylation', 'Var', (139, 150))
24734	18720524	Differential Patterns of Allelic Loss in Estrogen Receptor-Positive Infiltrating Lobular and Ductal Breast Cancer The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct.	('ILC', 'Gene', (186, 189))	('carcinoma', 'Disease', (224, 233))	('Ductal Breast Cancer', 'Disease', 'MESH:D001943', (93, 113))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lobular', 'Disease', (177, 184))	('Breast Cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('Allelic Loss', 'Var', (25, 37))	('carcinoma', 'Disease', 'MESH:D002277', (224, 233))	('Estrogen Receptor', 'Gene', '2099', (41, 58))	('IDC', 'Gene', '4000', (219, 222))	('IDC', 'Gene', (219, 222))	('Estrogen Receptor', 'Gene', (41, 58))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('ILC', 'Gene', '10850', (186, 189))	('breast cancer', 'Disease', (162, 175))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('Ductal Breast Cancer', 'Disease', (93, 113))
24736	18720524	We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p.	('IDC tumors', 'Disease', (100, 110))	('IDC tumors', 'Disease', 'MESH:D009369', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('single nucleotide polymorphisms', 'Var', (9, 40))	('ILC and IDC', 'Gene', '10850;4000', (92, 103))
24737	18720524	Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156).	('ILC', 'Gene', '10850', (82, 85))	('IDC', 'Gene', (9, 12))	('ILC', 'Gene', (82, 85))	('LOH', 'Var', (48, 51))	('IDC', 'Gene', '4000', (9, 12))
24738	18720524	By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors.	('ILC tumors', 'Disease', (173, 183))	('higher', 'PosReg', (112, 118))	('LOH', 'Var', (132, 135))	('IDC tumors', 'Disease', (71, 81))	('IDC tumors', 'Disease', 'MESH:D009369', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ILC tumors', 'Disease', 'MESH:D009369', (173, 183))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
24742	18720524	LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q.	('ILC', 'Gene', '10850', (81, 84))	('IDC', 'Gene', '4000', (99, 102))	('ILC', 'Gene', (81, 84))	('IDC', 'Gene', '4000', (61, 64))	('higher', 'Disease', (48, 54))	('LOH', 'Var', (0, 3))	('IDC', 'Gene', (99, 102))	('IDC', 'Gene', (61, 64))	('IDC tumors', 'Disease', 'MESH:D009369', (61, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('IDC tumors', 'Disease', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('common', 'Reg', (38, 44))
24752	18720524	One of the most common alterations in breast cancer is allelic imbalance or loss of heterozygosity (LOH).	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('loss of heterozygosity', 'Var', (76, 98))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('imbalance', 'Phenotype', 'HP:0002172', (63, 72))
24779	18720524	Seventy tumor samples were assayed with fluorescent primers (Operon Technologies, Alameda, CA) and standard PCR reactions, for the following STR markers in these chromosomal locations: 2q34.35 (D17S1322 and D17S932), 16q22.1 (D16S767 and D17S932), and 17q21 (D2S2319 and D16S767).	('D16S767', 'Var', (226, 233))	('D16S767', 'Var', (271, 278))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('D2S2319', 'Var', (259, 266))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('D17S932', 'Var', (238, 245))	('tumor', 'Disease', (8, 13))	('D17S932', 'Var', (207, 214))	('D17S1322', 'Var', (194, 202))
24784	18720524	Two-sample t statistics were used to assess the significance of the mean differences of FAL between ductal and lobular subtypes and following stratification by the categorized DI (diploid/near diploid versus aneuploid), mitotic rate (low versus intermediate or high), and tumor size T1a/T1b (<=2.0 cm), T1c (2.1-5.0 cm), and T2/T3, (>5.0 cm).	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('T1a/T1b', 'Var', (283, 290))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))
24801	18720524	The concordances in LOH calls by Map 10K array and STR were: BRCA1 (D17S1322) 89%, (D17S932) 85%; CDH1 (D16S767) 100%, (D17S932) 100%; BARD1 (D2S2319) 100%, (D16S767) 100%; and ESR1 (D16S496) 96%.	('BARD1', 'Gene', (135, 140))	('D2S2319', 'Var', (142, 149))	('BRCA1', 'Gene', (61, 66))	('CDH1', 'Gene', '999', (98, 102))	('BRCA1', 'Gene', '672', (61, 66))	('Map 10', 'Gene', '54627', (33, 39))	('D17S1322', 'Var', (68, 76))	('D16S767', 'Var', (104, 111))	('D17S932) 100', 'Var', (120, 132))	('ESR1', 'Gene', '2099', (177, 181))	('Map 10', 'Gene', (33, 39))	('BARD1', 'Gene', '580', (135, 140))	('D16S767', 'Var', (158, 165))	('CDH1', 'Gene', (98, 102))	('ESR1', 'Gene', (177, 181))	('D17S932', 'Var', (84, 91))
24816	18720524	We observed the majority of LOH events to be associated with no copy number change (89 and 82%), for ILC and IDC respectively, with a lower percentage associated with copy number loss (11 and 17%), and dramatically lower with copy number gain (0.14 and 0.53%) for these six chromosomal arms, suggesting that the mechanism for the majority of observed LOH, associated with no copy number change, on these six chromosomal arms is the result of an initial deletion of one allele followed by reduplication of the remaining allele.	('deletion', 'Var', (453, 461))	('copy', 'Var', (167, 171))	('copy', 'Var', (226, 230))	('ILC and IDC', 'Gene', '10850;4000', (101, 112))	('lower', 'NegReg', (215, 220))
24826	18720524	We observed a significant difference (P < 0.001) in the genome-wide FAL between low versus inter/high mitotic rate IDC tumors, whereas ILC tumors stratified by mitotic rate did not show this difference (P = 0.400) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('IDC tumors', 'Disease', (115, 125))	('IDC tumors', 'Disease', 'MESH:D009369', (115, 125))	('low', 'Var', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ILC tumors', 'Disease', 'MESH:D009369', (135, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ILC tumors', 'Disease', (135, 145))
24832	18720524	Two chromosomal arms (7p and 12q) showed significant differences (P < 0.05) in FAL between diploid ILC and IDC.	('diploid', 'Var', (91, 98))	('differences', 'Reg', (53, 64))	('ILC and IDC', 'Gene', '10850;4000', (99, 110))	('FAL', 'MPA', (79, 82))
24833	18720524	Five chromosomal arms (8p, 13q, 16q, 20p, and 20q) showed significant difference (P < 0.05) in FAL between aneuploid ILC and IDC (Table 3).	('ILC and IDC', 'Gene', '10850;4000', (117, 128))	('FAL', 'MPA', (95, 98))	('aneuploid', 'Var', (107, 116))	('difference', 'Reg', (70, 80))
24834	18720524	Identification of differences in LOH frequency and locations between ILC and IDC tumors measured by both whole genome and chromosomal arm FAL is most dramatic when comparing tumors with increased tumor size, mitotic rate, and ploidy.	('tumors', 'Disease', (81, 87))	('tumor', 'Disease', (196, 201))	('IDC tumors', 'Disease', 'MESH:D009369', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('ploidy', 'Var', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('mitotic rate', 'CPA', (208, 220))	('ILC and IDC', 'Gene', '10850;4000', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('IDC tumors', 'Disease', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
24838	18720524	Hierarchical clustering was performed using the 544 SNPs showing differential LOH to evaluate common patterns of LOH events and their association with tumor characteristics such as histology, grade, tumor size, mitotic rate, and ploidy (Fig.	('tumor', 'Disease', (199, 204))	('mitotic rate', 'CPA', (211, 223))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('ploidy', 'Var', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
24846	18720524	Tumors in this group had an overall lower frequency of LOH in these 544 SNPs but virtually all showed LOH in 16q and a subset additionally had LOH in 8p.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('LOH', 'Var', (102, 105))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
24850	18720524	We identified genomic regions with a high frequency of LOH (>=50% FAL) in ILC and IDC tumors and show that there are several regions with an overall high frequency of LOH regardless of subtype (11q, 16q, and 17p) (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('LOH', 'Var', (55, 58))	('ILC and IDC', 'Gene', '10850;4000', (74, 85))	('IDC tumors', 'Disease', (82, 92))	('IDC tumors', 'Disease', 'MESH:D009369', (82, 92))
24851	18720524	Previous studies have reported allelic imbalance in regions on these chromosomal arms and suggested that they are components of early events in breast cancer formation.	('formation', 'biological_process', 'GO:0009058', ('158', '167'))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('allelic imbalance', 'Var', (31, 48))	('imbalance', 'Phenotype', 'HP:0002172', (39, 48))	('reported', 'Reg', (22, 30))
24860	18720524	The loss of E-cadherin protein expression in ILC tumors has been linked to LOH, mutation, hypermethylation, and transcriptional regulation.	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('E-cadherin', 'Gene', (12, 22))	('hypermethylation', 'Var', (90, 106))	('linked', 'Reg', (65, 71))	('LOH', 'Disease', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('E-cadherin', 'Gene', '999', (12, 22))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('ILC tumors', 'Disease', 'MESH:D009369', (45, 55))	('expression', 'MPA', (31, 41))	('ILC tumors', 'Disease', (45, 55))	('loss', 'NegReg', (4, 8))	('mutation', 'Var', (80, 88))
24869	18720524	IDC tumors had significantly higher frequencies of LOH at the SNPs on 8p with and without stratification of tumors.	('IDC tumors', 'Disease', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('LOH', 'Var', (51, 54))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('IDC tumors', 'Disease', 'MESH:D009369', (0, 10))
24870	18720524	Loss on 8p was identified in earlier studies using CGH and microsatellite markers in IDC tumors and proposed this location to be a potential site of tumor suppressor genes.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Loss', 'NegReg', (0, 4))	('tumor suppressor', 'biological_process', 'GO:0051726', ('149', '165'))	('tumor', 'Disease', (149, 154))	('microsatellite markers', 'Var', (59, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('149', '165'))	('IDC tumors', 'Disease', (85, 95))	('IDC tumors', 'Disease', 'MESH:D009369', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
24872	18720524	Perturbation of the protein expression, often associated with allelic imbalance, of one or more of these genes in IDC may contribute to the initiation and maintenance of increased numbers of genomic alterations associated with aneuploidy.	('protein expression', 'MPA', (20, 38))	('aneuploidy', 'Disease', (227, 237))	('imbalance', 'Phenotype', 'HP:0002172', (70, 79))	('aneuploidy', 'Disease', 'MESH:D000782', (227, 237))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('IDC', 'Gene', '4000', (114, 117))	('IDC', 'Gene', (114, 117))	('Perturbation', 'Var', (0, 12))
24874	18720524	Similar to 8p, 5q showed more frequent LOH in IDC than ILC, both with and without stratification into size and mitotic-rate categories.	('LOH', 'Var', (39, 42))	('ILC', 'Gene', '10850', (55, 58))	('ILC', 'Gene', (55, 58))	('IDC', 'Gene', '4000', (46, 49))	('IDC', 'Gene', (46, 49))
24875	18720524	Other studies have also identified genomic alterations on 5q to be associated primarily with ER-negative IDC breast tumors.	('breast tumors', 'Phenotype', 'HP:0100013', (109, 122))	('IDC', 'Gene', (105, 108))	('genomic alterations', 'Var', (35, 54))	('breast tumors', 'Disease', 'MESH:D001943', (109, 122))	('ER', 'Gene', '2099', (93, 95))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('associated', 'Reg', (67, 77))	('breast tumors', 'Disease', (109, 122))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('IDC', 'Gene', '4000', (105, 108))
24876	18720524	The IDC tumors in Group 1 with LOH at 5q could represent a small subset of ER-positive IDC tumors with genomic profiles that are more similar to ER-negative IDC tumors.	('IDC tumors', 'Disease', 'MESH:D009369', (157, 167))	('IDC tumors', 'Disease', 'MESH:D009369', (4, 14))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('IDC tumors', 'Disease', (87, 97))	('IDC tumors', 'Disease', 'MESH:D009369', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ER', 'Gene', '2099', (145, 147))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ER', 'Gene', '2099', (75, 77))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('LOH at 5q', 'Var', (31, 40))	('IDC tumors', 'Disease', (4, 14))	('IDC tumors', 'Disease', (157, 167))
24878	18720524	Two genes involved in DNA damage response and integrity, XRCC4 (5q14.2) and APC (5q22.2) neighbor individual SNPs with significantly different frequency of LOH by histological subtype and may contribute to genomic instability in this subset of IDC tumors.	('XRCC4', 'Gene', '7518', (57, 62))	('XRCC4', 'Gene', (57, 62))	('DNA damage response', 'biological_process', 'GO:0006974', ('22', '41'))	('IDC tumors', 'Disease', (244, 254))	('IDC tumors', 'Disease', 'MESH:D009369', (244, 254))	('5q22.2', 'Var', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('contribute', 'Reg', (192, 202))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('APC', 'cellular_component', 'GO:0005680', ('76', '79'))	('APC', 'Disease', 'MESH:D011125', (76, 79))	('APC', 'Disease', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
24881	18720524	We observed a higher percentage of LOH across 16q in ILC (86%) and low-grade IDC tumors (82%) compared to (77%) for inter/high grade IDC.	('ILC', 'Gene', (53, 56))	('IDC', 'Gene', '4000', (133, 136))	('IDC', 'Gene', (77, 80))	('IDC', 'Gene', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('LOH across 16q', 'Var', (35, 49))	('IDC tumors', 'Disease', (77, 87))	('IDC tumors', 'Disease', 'MESH:D009369', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('IDC', 'Gene', '4000', (77, 80))	('ILC', 'Gene', '10850', (53, 56))
24925	32930928	The MRI group had slightly larger tumours, were more likely to have axillary lymph node involvement and multifocal tumours, and more often underwent mastectomy as the final surgical procedure.	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('tumours', 'Disease', (115, 122))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('MRI', 'Var', (4, 7))	('multifocal tumours', 'Disease', 'MESH:D009369', (104, 122))	('multifocal tumours', 'Disease', (104, 122))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('underwent', 'Reg', (139, 148))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('mastectomy', 'Disease', (149, 159))	('axillary lymph node involvement', 'CPA', (68, 99))	('tumours', 'Disease', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
24972	32930928	Future studies should investigate the effect on prognosis by comparing patients in whom MRI findings led to a change in treatment plan with those without treatment change and/or patients without MRI.	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (178, 186))	('led to', 'Reg', (101, 107))	('change', 'Reg', (110, 116))	('MRI', 'Var', (88, 91))
24983	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))
24984	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))
24990	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))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('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))
24995	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))
25031	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))
25045	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))	('more', 'PosReg', (34, 38))	('breast cancers', 'Disease', (6, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('higher', 'PosReg', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))
25046	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))
25047	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))
25048	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))
25053	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))	('breast cancers', 'Disease', 'MESH:D001943', (103, 117))	('DBT', 'Var', (58, 61))	('breast cancers', 'Disease', (103, 117))	('FFDM', 'Chemical', '-', (145, 149))	('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))
25057	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.	('FFDM', 'Chemical', '-', (216, 220))	('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))	('lobular cancer', 'Phenotype', 'HP:0030076', (106, 120))	('FFDM', 'Chemical', '-', (73, 77))
25081	28132393	A significantly lower risk of positive surgical margins after breast-conserving surgery was only seen in patients with lobular cancer who had undergone MRI as compared to those without MRI (OR 0.59, 95% CI 0.44-0.79, p = 0.0003) and, consequently, a lower risk of secondary mastectomy (OR 0.61, 95% CI 0.42-0.88, p = 0.0088).	('lobular cancer', 'Disease', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (105, 113))	('secondary mastectomy', 'Disease', (264, 284))	('lobular cancer', 'Disease', 'MESH:D013274', (119, 133))	('MRI', 'Var', (152, 155))	('lobular cancer', 'Phenotype', 'HP:0030076', (119, 133))	('lower', 'NegReg', (16, 21))
25082	28132393	Patients who underwent MRI were almost four times more likely to be diagnosed with CBC (OR 3.55, 95% CI 3.01-4.17, p < 0.0001).	('Patients', 'Species', '9606', (0, 8))	('MRI', 'Var', (23, 26))	('CBC', 'cellular_component', 'GO:0005846', ('83', '86'))	('CBC', 'Disease', (83, 86))
25087	28132393	According to the 2012 Dutch Breast Cancer guidelines, the use of breast MRI can be considered preoperatively in invasive breast cancers for the following indications: (1) when the aim is to perform BCT and a tumor size discrepancy is observed between physical examination, mammography and/or ultrasound, or (2) in patients with ILC (unless the tumor is unifocal in a highly reliable mammogram), especially when the patients are young women.	('Breast Cancer', 'Disease', (28, 41))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('Breast Cancer', 'Phenotype', 'HP:0003002', (28, 41))	('tumor', 'Disease', (344, 349))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', (208, 213))	('invasive breast cancers', 'Disease', 'MESH:D001943', (112, 135))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('women', 'Species', '9606', (434, 439))	('patients', 'Species', '9606', (314, 322))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('breast cancers', 'Phenotype', 'HP:0003002', (121, 135))	('discrepancy', 'Var', (219, 230))	('invasive breast cancers', 'Disease', (112, 135))	('patients', 'Species', '9606', (415, 423))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('ILC', 'Disease', (328, 331))	('Breast Cancer', 'Disease', 'MESH:D001943', (28, 41))
25116	28132393	Other subgroups which were more likely to undergo breast MRI were those with a clinical tumor size of 2 to 5 cm (cT2) and tumors larger than 5 cm (cT3) or cT4 (when compared to cT1).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('cT1', 'Gene', '1489', (177, 180))	('cT3', 'Gene', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cT1', 'Gene', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cT2', 'Gene', '386757', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cT2', 'Gene', (113, 116))	('cT3', 'Gene', '285782', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('breast MRI', 'Disease', (50, 60))	('cT4', 'Var', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (122, 127))
25123	28132393	For ILC patients, the use of breast MRI resulted in a difference between positive surgical margins of 5.0% for those with breast MRI versus 7.0% for those without.	('ILC', 'Disease', (4, 7))	('breast MRI', 'Var', (122, 132))	('patients', 'Species', '9606', (8, 16))
25130	28132393	Patients who underwent breast MRI were almost four times more frequently diagnosed with contralateral breast cancer (Table 2), compared to those in whom breast MRI was not performed (3.9% vs. 1.3% cases, respectively: OR 3.55, 95% CI 3.01-4.17).	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('breast MRI', 'Var', (23, 33))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (88, 115))	('contralateral breast cancer', 'Disease', (88, 115))	('Patients', 'Species', '9606', (0, 8))	('diagnosed', 'Reg', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
25158	28132393	In our study, patients that underwent breast MRI had an almost fourfold increased risk of having contralateral breast cancer compared to those in whom breast MRI was not performed (3.9 vs. 1.3%, respectively, Table 1).	('contralateral breast cancer', 'Disease', 'MESH:D001943', (97, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast MRI', 'Var', (38, 48))	('contralateral breast cancer', 'Disease', (97, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('patients', 'Species', '9606', (14, 22))
25180	25385074	These data imply that the primary adhesion defect in ILC underlies a secondary stromal-epithelial disconnect between hormonal signaling and tumor growth, suggesting in turn that this peritumoral feedback defect could reduce both the antimetastatic (adjuvant) and tumorilytic (palliative) efficacy of cytotoxic therapies for such tumors.	('tumors', 'Disease', (329, 335))	('tumors', 'Disease', 'MESH:D009369', (329, 335))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumors', 'Phenotype', 'HP:0002664', (329, 335))	('defect', 'Var', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('reduce', 'NegReg', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (263, 268))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (329, 334))	('tumor', 'Disease', (140, 145))
25184	25385074	Compared to IDCs, ILCs tend to be larger and lower grade; less FDG-avid on PET scanning; less often associated with vascular invasion, angiogenic growth factor expression or stromal reaction; more often node-positive and metastatic, especially to bone or serosal surfaces; and more resistant to chemotherapy despite less frequent TP53 gene mutations.	('angiogenic', 'MPA', (135, 145))	('IDC', 'Gene', (12, 15))	('stromal reaction', 'CPA', (174, 190))	('TP53', 'Gene', (330, 334))	('IDC', 'Gene', '4000', (12, 15))	('associated', 'Reg', (100, 110))	('metastatic', 'CPA', (221, 231))	('FDG', 'Gene', (63, 66))	('FDG', 'Gene', '23583', (63, 66))	('mutations', 'Var', (340, 349))	('vascular invasion', 'CPA', (116, 133))	('node-positive', 'CPA', (203, 216))	('TP53', 'Gene', '7157', (330, 334))	('less', 'NegReg', (58, 62))
25187	25385074	This ILC adhesion defect is constitutive, often reflecting frameshift mutations of the CDH1 gatekeeper tumor suppressor gene that cause truncation of the E-cadherin extracellular domain, together with loss of heterozygosity for the wild-type allele.	('frameshift mutations', 'Var', (59, 79))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cadherin', 'molecular_function', 'GO:0008014', ('156', '164'))	('CDH1', 'Gene', (87, 91))	('tumor', 'Disease', (103, 108))	('truncation', 'MPA', (136, 146))	('gatekeeper', 'Species', '111938', (92, 102))	('CDH1', 'Gene', '999', (87, 91))	('ILC', 'Disease', (5, 8))	('E-cadherin', 'Gene', (154, 164))	('E-cadherin', 'Gene', '999', (154, 164))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('extracellular', 'cellular_component', 'GO:0005576', ('165', '178'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
25191	25385074	An increasing number of reports have highlighted that the apparently favorable ('luminal-like') phenotype of ILC tumors - namely, low nuclear grade, high ER-positivity, absent HER2, CCND1 and TOP2A amplification, and low growth rates - fails to translate into survival benefit relative to IDCs, whether stage-matched or not.	('TOP2A', 'Gene', (192, 197))	('HER2', 'Gene', (176, 180))	('high ER-positivity', 'Var', (149, 167))	('ILC tumors', 'Disease', 'MESH:D009369', (109, 119))	('ILC tumors', 'Disease', (109, 119))	('HER2', 'Gene', '2064', (176, 180))	('CCND1', 'Gene', '595', (182, 187))	('low growth', 'Phenotype', 'HP:0001510', (217, 227))	('low', 'NegReg', (130, 133))	('absent', 'NegReg', (169, 175))	('IDC', 'Gene', '4000', (289, 292))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('IDC', 'Gene', (289, 292))	('TOP2A', 'Gene', '7153', (192, 197))	('CCND1', 'Gene', (182, 187))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
25205	25385074	HER2 IHC assays used in HK and AUS samples were A0485 (Dako) and 4B5 (Ventana) respectively.	('A0485', 'Var', (48, 53))	('HER2', 'Gene', (0, 4))	('4B5', 'Var', (65, 68))	('HER2', 'Gene', '2064', (0, 4))
25224	25385074	ILC tumors in both cohorts were more often ER-positive (p <=0.001), HER2-negative (p <0.02) and low-Ki67 (p <=0.002) than the corresponding IDC tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('ILC tumors', 'Disease', 'MESH:D009369', (0, 10))	('HER2', 'Gene', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('Ki67', 'Chemical', '-', (100, 104))	('HER2', 'Gene', '2064', (68, 72))	('ILC tumors', 'Disease', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('low-Ki67', 'Var', (96, 104))	('IDC tumors', 'Disease', (140, 150))	('IDC tumors', 'Disease', 'MESH:D009369', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('ER-positive', 'Reg', (43, 54))
25227	25385074	A direct correlation between Ki67 and either tumor size, lymph node metastasis, or HER2 status was evident in both ILC and IDC cohorts when combined.	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('ILC', 'Disease', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('IDC', 'Gene', '4000', (123, 126))	('IDC', 'Gene', (123, 126))	('tumor', 'Disease', (45, 50))	('lymph node metastasis', 'CPA', (57, 78))	('HER2', 'Gene', (83, 87))	('Ki67', 'Var', (29, 33))	('Ki67', 'Chemical', '-', (29, 33))	('HER2', 'Gene', '2064', (83, 87))
25231	25385074	Regarded by many as the most critical single molecular prognosticator in breast cancer, even when compared with costlier multigene expression profiling, the Ki67 proliferative index is at once a negative correlate of disease-free survival and overall survival and a strong predictor of initial response to chemotherapy - although these inferences can only be applied to IDC at present.	('Ki67', 'Chemical', '-', (157, 161))	('Ki67', 'Var', (157, 161))	('negative', 'NegReg', (195, 203))	('disease-free survival', 'CPA', (217, 238))	('IDC', 'Gene', '4000', (370, 373))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('IDC', 'Gene', (370, 373))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('overall survival', 'CPA', (243, 259))
25233	25385074	Consistent with this possibility, it is now recognised that breast cancers such as IDC and ILC evolve via multiple pathways involving different combinations of molecular variables such as TP53 gene mutations (commoner in IDC than ILC; see above) and/or mTOR pathway activation (commoner in ILC than IDC; see below).	('activation', 'PosReg', (266, 276))	('IDC', 'Gene', '4000', (221, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('breast cancers', 'Disease', 'MESH:D001943', (60, 74))	('breast cancers', 'Disease', (60, 74))	('IDC', 'Gene', (221, 224))	('mutations', 'Var', (198, 207))	('IDC', 'Gene', '4000', (299, 302))	('IDC', 'Gene', (299, 302))	('TP53', 'Gene', '7157', (188, 192))	('breast cancers', 'Phenotype', 'HP:0003002', (60, 74))	('ILC', 'Disease', (91, 94))	('mTOR', 'Gene', (253, 257))	('IDC', 'Gene', '4000', (83, 86))	('IDC', 'Gene', (83, 86))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('mTOR', 'Gene', '2475', (253, 257))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TP53', 'Gene', (188, 192))
25239	25385074	E-cadherin downregulation is not specific to ILC, as it also occurs during progression to high-Ki67 IDC tumors such as basaloid and triple-negative subtypes, reflecting dynamic epigenetic trans-repression of CDH1 at the invasive tumor front as part of epithelial-mesenchymal transition (EMT).	('Ki67', 'Chemical', '-', (95, 99))	('epithelial-mesenchymal transition', 'CPA', (252, 285))	('IDC tumors', 'Disease', (100, 110))	('IDC tumors', 'Disease', 'MESH:D009369', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('EMT', 'biological_process', 'GO:0001837', ('287', '290'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('252', '285'))	('invasive tumor', 'Disease', 'MESH:D009369', (220, 234))	('invasive tumor', 'Disease', (220, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('epigenetic', 'Var', (177, 187))	('CDH1', 'Gene', (208, 212))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('E-cadherin', 'Gene', (0, 10))	('downregulation', 'NegReg', (11, 25))	('CDH1', 'Gene', '999', (208, 212))	('E-cadherin', 'Gene', '999', (0, 10))
25247	25385074	The ER + IDC pathway tends to be activated by early mutations affecting the anti-apoptotic (pro-survival) PI3K signaling pathway; the commonest such mutation affects the PTEN gatekeeper gene, permitting secondary ER-alpha and ER-beta upregulation, leading in turn to Snail induction, EMT-related TGF-beta and Wnt pathway activation, BRCA1/2 and/or TP53 inactivation.	('IDC', 'Gene', (9, 12))	('EMT-related', 'CPA', (284, 295))	('ER-beta', 'Gene', '2100', (226, 233))	('activation', 'PosReg', (321, 331))	('ER-alpha', 'Gene', (213, 221))	('ER-beta', 'Gene', (226, 233))	('TP53', 'Gene', (348, 352))	('EMT', 'biological_process', 'GO:0001837', ('284', '287'))	('ER-alpha', 'Gene', '2099', (213, 221))	('TGF-beta', 'Gene', '7040', (296, 304))	('PTEN', 'Gene', (170, 174))	('BRCA1/2', 'Gene', (333, 340))	('Snail', 'Gene', '6615', (267, 272))	('pro-survival', 'biological_process', 'GO:0043066', ('92', '104'))	('TGF-beta', 'Gene', (296, 304))	('PTEN', 'Gene', '5728', (170, 174))	('TP53', 'Gene', '7157', (348, 352))	('gatekeeper', 'Species', '111938', (175, 185))	('mutation', 'Var', (149, 157))	('PI3K', 'molecular_function', 'GO:0016303', ('106', '110'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('106', '120'))	('upregulation', 'PosReg', (234, 246))	('signaling pathway', 'biological_process', 'GO:0007165', ('111', '128'))	('IDC', 'Gene', '4000', (9, 12))	('inactivation', 'NegReg', (353, 365))	('Snail', 'Gene', (267, 272))
25249	25385074	When the EMT transactivator Twist is co-expressed with Snail, TGF-beta-dependent E-cadherin downregulation supervenes, with low E-cadherin and high Ki67 marking an especially poor-prognostic breast cancer subgroup.	('TGF-beta', 'Gene', (62, 70))	('high Ki67', 'Var', (143, 152))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('downregulation', 'NegReg', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Snail', 'Gene', '6615', (55, 60))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('E-cadherin', 'Gene', (81, 91))	('E-cadherin', 'Gene', '999', (81, 91))	('Ki67', 'Chemical', '-', (148, 152))	('low', 'NegReg', (124, 127))	('TGF-beta', 'Gene', '7040', (62, 70))	('E-cadherin', 'Gene', (128, 138))	('E-cadherin', 'Gene', '999', (128, 138))	('cadherin', 'molecular_function', 'GO:0008014', ('130', '138'))	('EMT', 'biological_process', 'GO:0001837', ('9', '12'))	('Snail', 'Gene', (55, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
25252	25385074	As noted above, the defining adhesion defect of ILC selectively impairs apoptosis/anoikis while simultaneously selecting for both ER-alpha overexpression and PI3K pathway upregulation via secondary mechanisms such as increased PTEN proteolysis or activating PIK3CA mutations.	('mutations', 'Var', (265, 274))	('activating', 'PosReg', (247, 257))	('PI3K', 'molecular_function', 'GO:0016303', ('158', '162'))	('PIK3CA', 'Gene', (258, 264))	('PI3K pathway', 'Pathway', (158, 170))	('overexpression', 'PosReg', (139, 153))	('PTEN', 'Gene', (227, 231))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('increased', 'PosReg', (217, 226))	('PTEN', 'Gene', '5728', (227, 231))	('proteolysis', 'biological_process', 'GO:0006508', ('232', '243'))	('ER-alpha', 'Gene', (130, 138))	('PIK3CA', 'Gene', '5290', (258, 264))	('upregulation', 'PosReg', (171, 183))	('ER-alpha', 'Gene', '2099', (130, 138))	('impairs', 'NegReg', (64, 71))	('apoptosis/anoikis', 'CPA', (72, 89))	('anoikis', 'biological_process', 'GO:0043276', ('82', '89'))	('defect', 'Var', (38, 44))
25255	25385074	This is consistent with work showing that loss of the Wnt5a tumor suppressor protein is associated with shortened survival and ER/PR-negativity in IDC but not in ILC, supporting a stronger role for Wnt activation, EMT, and ER/PR loss in IDC than in ILC.	('Wnt5a', 'Gene', (54, 59))	('EMT', 'biological_process', 'GO:0001837', ('214', '217'))	('loss', 'Var', (42, 46))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('IDC', 'Gene', '4000', (147, 150))	('Wnt5a', 'Gene', '7474', (54, 59))	('IDC', 'Gene', '4000', (237, 240))	('IDC', 'Gene', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('IDC', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('shortened', 'NegReg', (104, 113))	('survival', 'CPA', (114, 122))	('ER/PR-negativity', 'MPA', (127, 143))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
25262	25385074	Second, the histologic subset of ILC is itself heterogeneous, being divisible into additional non-classic ILC variants such as solid, alveolar, and pleomorphic which are associated with higher Ki67 status and poorer prognosis; given the relatively small size of this study, we cannot exclude that our conclusions may be only applicable to the classical ILC subgroup.	('pleomorphic', 'Var', (148, 159))	('solid', 'Disease', (127, 132))	('Ki67', 'Chemical', '-', (193, 197))	('alveolar', 'Disease', (134, 142))
25266	25385074	In contrast, recent literature has generated a consensus figure of Ki67 = 14% as a qualitative numerical cut-off point to distinguish "faster" from "slower" breast tumors as part of a continuous distribution.	('Ki67', 'Chemical', '-', (67, 71))	('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))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('Ki67', 'Var', (67, 71))
25267	25385074	Moreover, we would argue that there is an arbitrary dimension to all such cut-offs - consider, for example, that a 13% Ki67 tumor's biology is likely to differ more from a 4% Ki67 tumor than from a 15% Ki67 tumor, irrespective of which cutoff convention is used for study purposes.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('Ki67', 'Var', (119, 123))	('Ki67', 'Chemical', '-', (202, 206))	('Ki67', 'Chemical', '-', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('Ki67', 'Chemical', '-', (119, 123))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', (180, 185))	('differ', 'Reg', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
25272	25385074	Recent advances in understanding of the events involved in ILC progression, and their distinction from the EMT/Wnt cascades occurring in IDC, raise the hypothesis that mTOR inhibitors could prove effective in restoring hormone- and/or chemosensitivity to refractory advanced ILC tumors, as well as plausibly improving adjuvant survival outcomes for higher-risk ILCs being treated with these drug classes.	('mTOR', 'Gene', (168, 172))	('inhibitors', 'Var', (173, 183))	('hormone-', 'MPA', (219, 227))	('mTOR', 'Gene', '2475', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('IDC', 'Gene', '4000', (137, 140))	('improving', 'PosReg', (308, 317))	('ILC tumors', 'Disease', 'MESH:D009369', (275, 285))	('IDC', 'Gene', (137, 140))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('ILC tumors', 'Disease', (275, 285))	('restoring', 'PosReg', (209, 218))	('EMT', 'biological_process', 'GO:0001837', ('107', '110'))
25289	23573438	Breast carcinoma metastases in endometrium and myometrium were confirmed histopathologically and immunohistochemically with positivity of pancytokeratin and gross cystic disease fluid protein-15 (GCDFP-15) and negativity of Melan A, CD 10, caldesmon, and alpha-fetoprotein (AFP) (Figure 2).	('AFP', 'Gene', (274, 277))	('CD 10', 'Gene', (233, 238))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('alpha-fetoprotein', 'Gene', '174', (255, 272))	('Breast carcinoma', 'Phenotype', 'HP:0003002', (0, 16))	('AFP', 'Gene', '174', (274, 277))	('Melan A', 'Gene', '2315', (224, 231))	('gross cystic disease fluid protein-15', 'Gene', '5304', (157, 194))	('CD 10', 'molecular_function', 'GO:0004245', ('233', '238'))	('Melan A', 'Gene', (224, 231))	('positivity', 'Var', (124, 134))	('alpha-fetoprotein', 'Gene', (255, 272))	('GCDFP-15', 'Gene', '5304', (196, 204))	('Breast carcinoma', 'Disease', (0, 16))	('CD 10', 'Gene', '4311', (233, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (7, 16))	('GCDFP-15', 'Gene', (196, 204))	('gross cystic disease fluid protein-15', 'Gene', (157, 194))
25349	31849525	The estimated hazard ratio for the ITT population showed a benefit of CMF (HR=0.74, 95% CI=0.44-1.27), but the difference was not statistically significant (p=0.278).	('benefit', 'PosReg', (59, 66))	('CMF', 'Var', (70, 73))	('CMF', 'Chemical', 'MESH:C034456', (70, 73))
25360	31849525	According to the ASCO recommendations, clinicians may use uPA/PAI-1 to guide their decisions on adjuvant systemic chemotherapy in ER/PR positive, HER2 negative, and pN0 breast cancers.	('pN0', 'Var', (165, 168))	('HER2', 'Gene', '2064', (146, 150))	('PR', 'Gene', '5241', (133, 135))	('ER', 'Gene', '2099', (147, 149))	('uPA', 'molecular_function', 'GO:0008243', ('58', '61'))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('uPA', 'Gene', (58, 61))	('breast cancers', 'Phenotype', 'HP:0003002', (169, 183))	('PAI-1', 'Gene', '5054', (62, 67))	('uPA', 'Gene', '5328', (58, 61))	('PAI-1', 'Gene', (62, 67))	('breast cancers', 'Disease', 'MESH:D001943', (169, 183))	('breast cancers', 'Disease', (169, 183))	('ER', 'Gene', '2099', (130, 132))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('HER2', 'Gene', (146, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
25408	31849525	Interestingly, in the whole population, only 5.8% of the patients with grade 3 tumors had a low RS (<=11) and all patients in the small group with Ki67 >= 40% and PR <= 20 had an RS > 25.	('PR', 'Gene', '5241', (163, 165))	('patients', 'Species', '9606', (57, 65))	('Ki67', 'Var', (147, 151))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
25412	31849525	Based on three prospective studies using archived samples, the INCa recommendations attributed a IIB LOE to the prognostic value of Oncotype DX  in ER+ pN0 or pN+ breast cancer.	('breast cancer', 'Disease', (163, 176))	('ER', 'Gene', '2099', (148, 150))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('LOE', 'NegReg', (101, 104))	('Oncotype DX', 'Var', (132, 143))
25416	31849525	In case of pN+ breast cancer, they did not recommend the test to guide the treatment decision because of the potential benefit of chemotherapy in this subgroup (IIB LOE).	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('pN+', 'Var', (11, 14))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
25423	31849525	The Microarray In Node-negative and 1 to 3 Positive Lymph Node Disease may Avoid ChemoTherapy (MINDACT) trial was a prospective randomized trial including 6693 women with pN0 or pN+ (up to 3 nodes), and T1, T2, or operable T3 tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('women', 'Species', '9606', (160, 165))	('pN+', 'Var', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('pN0', 'Var', (171, 174))
25445	31849525	The ASCO issued updated guidelines after the results of the MINDACT trial: they considered that Mammaprint  may be used in ER/PR positive, HER2-, pN0 or pN+ (1 to 3 positive nodes) breast cancer with high clinical risk with a IA LOE.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('HER2', 'Gene', (139, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('breast cancer', 'Disease', (181, 194))	('pN+', 'Var', (153, 156))	('HER2', 'Gene', '2064', (139, 143))	('pN0', 'Var', (146, 149))	('PR', 'Gene', '5241', (126, 128))	('ER', 'Gene', '2099', (123, 125))	('ER', 'Gene', '2099', (140, 142))
25480	31849525	According to the ASCO recommendations, the PAM50 ROR score may be used in ER/PR positive, HER2 negative, pN0 breast cancer to guide decision on adjuvant chemotherapy with a IB LOE.	('HER2', 'Gene', (90, 94))	('ROR', 'Gene', (49, 52))	('breast cancer', 'Disease', (109, 122))	('HER2', 'Gene', '2064', (90, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('ROR', 'Gene', '100885779', (49, 52))	('pN0', 'Var', (105, 108))	('PR', 'Gene', '5241', (77, 79))	('ER', 'Gene', '2099', (91, 93))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ER', 'Gene', '2099', (74, 76))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
25492	31849525	The five biomarkers evaluated showed their clinical validity to identify patients with HR+ HER2- and pN0 or pN+ breast cancers at low or high risk of recurrence.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('HR+', 'Var', (87, 90))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('pN0', 'Var', (101, 104))	('HER2', 'Gene', (91, 95))	('HER2', 'Gene', '2064', (91, 95))	('breast cancers', 'Phenotype', 'HP:0003002', (112, 126))	('pN+ breast cancers', 'Disease', (108, 126))	('pN+ breast cancers', 'Disease', 'MESH:D001943', (108, 126))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
25543	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))
25635	33674614	For those with cortical thickening, rounded morphology, loss of fatty hilum, or asymmetry versus those without, mean tumor deposit size was 1.3 cm vs. 0.6 cm, 1.3 cm vs. 0.7 cm, 1.3 cm vs. 0.7 cm, and 1.2 cm vs. 0.5 cm, respectively (all p < 0.006).	('asymmetry', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('loss', 'NegReg', (56, 60))	('tumor', 'Disease', (117, 122))	('cortical thickening', 'CPA', (15, 34))	('rounded morphology', 'CPA', (36, 54))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
25663	33674614	The ILC subtypes in these patients were pleomorphic in 2 (66.7%) and classic in 1 (33.3%).	('ILC', 'Disease', (4, 7))	('pleomorphic', 'Var', (40, 51))	('patients', 'Species', '9606', (26, 34))
25680	33674614	However, the literature reports higher MRI accuracy in patients with HER2 positive or triple-negative tumors, which are more commonly treated with chemotherapy.	('HER2', 'Gene', '2064', (69, 73))	('tumors', 'Disease', (102, 108))	('higher', 'PosReg', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('triple-negative', 'Var', (86, 101))	('patients', 'Species', '9606', (55, 63))	('HER2', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('MRI', 'MPA', (39, 42))
25713	27925203	NBCs were found to harbour a median of 4.5 (range 1-11) somatic mutations, similar to that of luminal B breast cancers (median=3, range 0-17) but significantly higher than that of luminal A breast cancers (median=3, range 0-18, p=0.02).	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('higher', 'PosReg', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancers', 'Phenotype', 'HP:0003002', (190, 204))	('luminal A breast cancers', 'Disease', 'MESH:D001943', (180, 204))	('luminal A breast cancers', 'Disease', (180, 204))	('breast cancers', 'Phenotype', 'HP:0003002', (104, 118))	('mutations', 'Var', (64, 73))	('luminal B breast cancers', 'Disease', 'MESH:D001943', (94, 118))	('luminal B breast cancers', 'Disease', (94, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
25715	27925203	NBCs less frequently harboured PIK3CA mutations than common forms of ER+/HER2, luminal A and invasive lobular carcinomas (p<0.05) and displayed a significantly higher frequency of somatic mutations affecting ARID1A (17% versus 2%, p<0.05) and the transcription factors FOXA1 (17% versus 2%, p=0.01) and TBX3 (17% versus 3%, p<0.05) than common-type ER+/HER2- breast cancers.	('higher', 'PosReg', (160, 166))	('PIK3', 'Gene', (31, 35))	('cancers', 'Phenotype', 'HP:0002664', (366, 373))	('TBX3', 'Gene', '6926', (303, 307))	('PIK3', 'Gene', '5294', (31, 35))	('ARID1A', 'Gene', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('FOXA1', 'Gene', '3169', (269, 274))	('transcription', 'biological_process', 'GO:0006351', ('247', '260'))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (93, 120))	('FOXA1', 'Gene', (269, 274))	('HER2- breast cancers', 'Disease', (353, 373))	('mutations', 'Var', (38, 47))	('TBX3', 'Gene', (303, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('invasive lobular carcinomas', 'Disease', (93, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('breast cancers', 'Phenotype', 'HP:0003002', (359, 373))	('harboured', 'Reg', (21, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (359, 372))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (102, 119))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (102, 120))	('HER2- breast cancers', 'Disease', 'MESH:D001943', (353, 373))
25716	27925203	Compared to common forms of luminal breast cancers, NBCs display a distinctive repertoire of somatic mutations featuring lower frequency of TP53 and PIK3CA mutations, and enrichment for FOXA1, TBX3 mutations, and akin to neuroendocrine tumours from other sites, ARID1A mutations.	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('PIK3', 'Gene', (149, 153))	('PIK3', 'Gene', '5294', (149, 153))	('TBX3', 'Gene', (193, 197))	('neuroendocrine tumours', 'Disease', 'MESH:D018358', (221, 243))	('neuroendocrine tumours', 'Disease', (221, 243))	('mutations', 'Var', (198, 207))	('luminal breast cancers', 'Disease', 'MESH:D001943', (28, 50))	('breast cancers', 'Phenotype', 'HP:0003002', (36, 50))	('FOXA1', 'Gene', '3169', (186, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('mutations', 'Var', (156, 165))	('ARID1A', 'Gene', (262, 268))	('FOXA1', 'Gene', (186, 191))	('tumours', 'Phenotype', 'HP:0002664', (236, 243))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('TBX3', 'Gene', '6926', (193, 197))	('luminal breast cancers', 'Disease', (28, 50))
25733	27925203	The aims of this study were to investigate whether NBCs harbour mutations affecting the genes most frequently mutated in breast cancer, and if these cancers would display a repertoire of somatic mutations affecting the genes most frequently mutated in breast cancer and DNA repair-related genes that is distinct from that of common forms of luminal (ER+/HER2-) breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('DNA', 'cellular_component', 'GO:0005574', ('270', '273'))	('DNA repair', 'biological_process', 'GO:0006281', ('270', '280'))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (64, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (361, 374))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('breast cancer', 'Disease', (252, 265))	('cancers', 'Disease', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('breast cancer', 'Disease', 'MESH:D001943', (361, 374))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('breast cancer', 'Disease', (361, 374))	('DNA repair-related', 'Gene', (270, 288))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('breast cancer', 'Disease', (121, 134))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
25741	27925203	Genes affected by mutations were further annotated according to their presence in three cancer gene datasets, Kandoth et al, the Cancer Gene Census and Lawrence et al.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Cancer', 'Disease', (129, 135))	('Cancer', 'Disease', 'MESH:D009369', (129, 135))	('Cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (18, 27))
25753	27925203	Targeted capture MPS was performed at a median depth of 568x (448x-754x) and resulted in the identification of a median of 4.5 somatic mutations affecting the 254 genes tested (range 1 - 11).	('MPS', 'Disease', (17, 20))	('mutations', 'Var', (135, 144))	('MPS', 'Disease', 'MESH:D009084', (17, 20))	('48x-7', 'STRUCTURAL_ABNORMALITY', 'None', (63, 68))
25754	27925203	A re-analysis of the 240 ER+/HER2-, 209 luminal A and 111 luminal B from the TCGA breast cancer study revealed a median of three somatic mutations (range 0 - 18 for ER+/HER2- and luminal A, range 0 - 17 for luminal B) affecting the exons of the 254 genes included in our targeted panel.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('ER+/HER2-', 'Var', (165, 174))	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('affecting', 'Reg', (218, 227))
25756	27925203	Whilst the frequency of somatic mutations was comparable between NBCs and ER+/HER2-, luminal B breast cancers and invasive lobular carcinomas from the TCGA, as also highlighted by the interquartile range and highest and lowest value of number of mutations excluding outliers (Figure 2), there was a significantly higher number of somatic mutations affecting these 254 genes in NBCs than in the luminal A breast cancers from TCGA (p=0.02, Mann-Whitney U test; Figure 2).	('luminal A breast cancers', 'Disease', (394, 418))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('breast cancers', 'Phenotype', 'HP:0003002', (404, 418))	('luminal A breast cancers', 'Disease', 'MESH:D001943', (394, 418))	('luminal B breast cancers', 'Disease', 'MESH:D001943', (85, 109))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (123, 141))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (123, 140))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (114, 141))	('higher', 'Reg', (313, 319))	('luminal B breast cancers', 'Disease', (85, 109))	('cancers', 'Phenotype', 'HP:0002664', (411, 418))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('invasive lobular carcinomas', 'Disease', (114, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('mutations', 'Var', (338, 347))	('breast cancers', 'Phenotype', 'HP:0003002', (95, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (404, 417))
25758	27925203	The most frequently mutated cancer genes in NBCs were GATA3, FOXA1, TBX3 and ARID1A (all mutated in three of 18 cases, 17%), followed by PIK3CA, AKT1 and CDH1 (all mutated in two of 18 cases, 11%, Figure 3, Supplementary Table S4).	('CDH1', 'Gene', (154, 158))	('TBX3', 'Gene', '6926', (68, 72))	('CDH1', 'Gene', '999', (154, 158))	('PIK3', 'Gene', '5294', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TBX3', 'Gene', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mutated', 'Var', (89, 96))	('cancer', 'Disease', (28, 34))	('PIK3', 'Gene', (137, 141))	(', FOXA1', 'Gene', '3169', (59, 66))	(', AKT1', 'Gene', '207', (143, 149))
25759	27925203	As expected, the lobular carcinoma (CMNE24T) was one of the two cases harbouring a CDH1 mutation; in this case, the E806K missense CDH1 mutation was coupled with LOH of the wild-type allele and predicted to be clonal (i.e.	('CDH1', 'Gene', (83, 87))	('lobular carcinoma', 'Disease', 'MESH:D018275', (17, 34))	('E806K', 'Mutation', 'rs376922615', (116, 121))	('CM', 'Disease', 'MESH:D009202', (36, 38))	('CDH1', 'Gene', (131, 135))	('CDH1', 'Gene', '999', (83, 87))	('lobular carcinoma', 'Disease', (17, 34))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (17, 34))	('CDH1', 'Gene', '999', (131, 135))	('E806K missense', 'Var', (116, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
25763	27925203	In this case, the R598Q missense CDH1 mutation was also coupled with LOH of the wild-type allele, however was predicted to be subclonal (present in 16% of cancer cells; Supplementary Table S4), potentially explaining the lack of overt lobular differentiation.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('CDH1', 'Gene', (33, 37))	('R598Q missense', 'Var', (18, 32))	('CDH1', 'Gene', '999', (33, 37))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('R598Q', 'Mutation', 'rs780759537', (18, 23))
25764	27925203	Sanger sequencing analysis of selected mutations resulted in a validation rate of 100% (26/26) and confirmed the presence of the FOXA1, ARID1A, GATA3, CDH1, AKT1, PIK3CA, KIT, HUWE1, TBX3, KMT2C and SPEN somatic mutations (Supplementary Figure S2).	('CDH1', 'Gene', (151, 155))	('FOXA1', 'Gene', '3169', (129, 134))	('PIK3', 'Gene', '5294', (163, 167))	('AKT1', 'Gene', (157, 161))	('mutations', 'Var', (39, 48))	('HUWE1', 'Gene', (176, 181))	('PIK3', 'Gene', (163, 167))	('KIT', 'molecular_function', 'GO:0005020', ('171', '174'))	(', GATA3', 'Gene', '2625', (142, 149))	('FOXA1', 'Gene', (129, 134))	('KIT', 'Gene', (171, 174))	('KMT2C', 'Gene', (189, 194))	('HUWE1', 'Gene', '10075', (176, 181))	('TBX3', 'Gene', '6926', (183, 187))	('TBX3', 'Gene', (183, 187))	('SPEN', 'Gene', (199, 203))
25765	27925203	When compared with immunohistochemically defined ER+/HER2- breast carcinomas from TCGA (n=240), NBCs less frequently harboured PIK3CA mutations than common type ER+/HER2- breast cancers (11% versus 42%, p=0.01, Fisher's exact test, Table 2), and displayed a significantly higher frequency of somatic mutations affecting the chromatin remodelling gene ARID1A (17% versus 2%, p=0.01, Fisher's exact test), akin to pulmonary carcinoids, and the transcription factors FOXA1 and TBX3 (17% versus 2% and 17% versus 3%, p=0.01 and p=0.03, respectively, Fisher's exact tests).	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinoids', 'Phenotype', 'HP:0100570', (422, 432))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast carcinomas', 'Phenotype', 'HP:0003002', (59, 76))	('ARID1A', 'Gene', (351, 357))	('HER2- breast cancers', 'Disease', (165, 185))	('breast cancers', 'Phenotype', 'HP:0003002', (171, 185))	('chromatin', 'cellular_component', 'GO:0000785', ('324', '333'))	('pulmonary carcinoids', 'Phenotype', 'HP:0030445', (412, 432))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('FOXA1', 'Gene', '3169', (464, 469))	('harboured', 'Reg', (117, 126))	('mutations', 'Var', (134, 143))	('transcription', 'biological_process', 'GO:0006351', ('442', '455'))	('FOXA1', 'Gene', (464, 469))	('mutations', 'Var', (300, 309))	('TBX3', 'Gene', '6926', (474, 478))	('HER2- breast cancers', 'Disease', 'MESH:D001943', (165, 185))	('PIK3', 'Gene', (127, 131))	('pulmonary carcinoids', 'Disease', (412, 432))	('PIK3', 'Gene', '5294', (127, 131))	('breast carcinomas', 'Disease', 'MESH:D001943', (59, 76))	('breast carcinomas', 'Disease', (59, 76))	('pulmonary carcinoids', 'Disease', 'MESH:D002276', (412, 432))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('324', '345'))	('TBX3', 'Gene', (474, 478))
25766	27925203	TP53 was significantly less frequently mutated in NBCs than in ER+/HER2- breast carcinomas from TCGA (0% versus 22%, p=0.01, Fisher's exact test).	('NBCs', 'Disease', (50, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('TP53', 'Gene', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('less', 'NegReg', (23, 27))	('mutated', 'Var', (39, 46))	('breast carcinomas', 'Disease', 'MESH:D001943', (73, 90))	('breast carcinomas', 'Disease', (73, 90))	('breast carcinomas', 'Phenotype', 'HP:0003002', (73, 90))
25768	27925203	NBCs displayed a repertoire of somatic mutations that was intermediate between those of luminal A and luminal B breast cancers, with a significantly higher frequency of FOXA1, ARID1A and DCHS2 mutations in NBCs (all mutated in 17% of cases) than in both luminal A (2%, 2%, 1%, respectively, p<0.05, Fisher's exact tests) and luminal B breast cancers (2%, 3% and 2%, respectively, p<0.05, Fisher's exact tests; Table 2, Figure 4).	('luminal B breast cancers', 'Disease', 'MESH:D001943', (102, 126))	('luminal B breast cancers', 'Disease', (325, 349))	('mutations', 'Var', (193, 202))	('ARID1A', 'Gene', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('higher', 'PosReg', (149, 155))	('luminal B breast cancers', 'Disease', (102, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (342, 349))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancers', 'Phenotype', 'HP:0003002', (112, 126))	('DCHS2', 'Gene', '54798', (187, 192))	('breast cancers', 'Phenotype', 'HP:0003002', (335, 349))	('FOXA1', 'Gene', '3169', (169, 174))	('luminal B breast cancers', 'Disease', 'MESH:D001943', (325, 349))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (335, 348))	('FOXA1', 'Gene', (169, 174))	('DCHS2', 'Gene', (187, 192))
25769	27925203	In addition, PIK3CA mutations were significantly less frequent in NBCs (11%) than in luminal A cancers (46% p<0.01, Fisher's exact test), whereas none of the NBCs displayed TP53 mutations as compared to 32% of luminal B cancers (p<0.01, Fisher's exact test) and 11% of luminal A cancers (p=0.23, Fisher's exact test; Table 2, Figure 4).	('luminal A cancers', 'Disease', 'MESH:D009369', (269, 286))	('PIK3', 'Gene', '5294', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('luminal A cancers', 'Disease', 'MESH:D009369', (85, 102))	('TP53', 'Gene', (173, 177))	('less', 'NegReg', (49, 53))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('luminal A cancers', 'Disease', (269, 286))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('luminal A cancers', 'Disease', (85, 102))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('mutations', 'Var', (20, 29))	('luminal B cancers', 'Disease', (210, 227))	('luminal B cancers', 'Disease', 'MESH:D006509', (210, 227))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('NBCs', 'Disease', (66, 70))	('mutations', 'Var', (178, 187))	('PIK3', 'Gene', (13, 17))
25770	27925203	Conversely, TBX3 and HUWE1 were more frequently found to be mutated in NBCs (17% and 11%, respectively) than in luminal A breast cancers (2% and 1%, p<0.05, Fisher's exact tests, Table 2, Figure 4).	('TBX3', 'Gene', '6926', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('NBCs', 'Disease', (71, 75))	('TBX3', 'Gene', (12, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('HUWE1', 'Gene', (21, 26))	('HUWE1', 'Gene', '10075', (21, 26))	('mutated', 'Var', (60, 67))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('luminal A breast cancers', 'Disease', 'MESH:D001943', (112, 136))	('luminal A breast cancers', 'Disease', (112, 136))
25773	27925203	These subgroup analyses highlighted that FOXA1, TBX3 and DCHS2 were significantly more frequently mutated in IDCs with neuroendocrine differentiation versus any of the three subgroups from TCGA (all 20% in NBCs versus 2% in ER+/HER2- and luminal A and 2%, 4%, 2% in luminal B breast cancers, respectively, p<0.05, Fisher's exact tests).	('FOXA1', 'Gene', '3169', (41, 46))	('luminal B breast cancers', 'Disease', 'MESH:D001943', (266, 290))	('luminal B breast cancers', 'Disease', (266, 290))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('FOXA1', 'Gene', (41, 46))	('IDCs', 'Disease', (109, 113))	('NBCs', 'Disease', (206, 210))	('TBX3', 'Gene', '6926', (48, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('mutated', 'Var', (98, 105))	('breast cancers', 'Phenotype', 'HP:0003002', (276, 290))	('DCHS2', 'Gene', (57, 62))	('DCHS2', 'Gene', '54798', (57, 62))	('TBX3', 'Gene', (48, 52))
25774	27925203	In addition, the lower frequencies of PIK3CA mutations (13% versus 42% in ER+/HER2-, p=0.03, and 47% in luminal A breast cancers from TCGA, p=0.01, Fisher's exact test) and the lack of TP53 mutations (0% versus 25% in ER+/HER2-, p=0.02, and 33% in luminal B, p<0.01, Fisher's exact test) in IDCs with neuroendocrine differentiation remained statistically significant.	('mutations', 'Var', (45, 54))	('PIK3', 'Gene', (38, 42))	('luminal A breast cancers', 'Disease', 'MESH:D001943', (104, 128))	('TP53', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('luminal A breast cancers', 'Disease', (104, 128))	('PIK3', 'Gene', '5294', (38, 42))	('breast cancers', 'Phenotype', 'HP:0003002', (114, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
25775	27925203	Given that some genes found to be recurrently mutated in NBCs, such as FOXA1 and TBX3, have been recently described as part of the molecular determinants of invasive lobular carcinomas, we endeavoured to assess whether similarities could be found between our cohort of NBCs and lobular carcinomas from TCGA in terms of mutations affecting the exons of the 254 genes included in the targeted panel employed in this study.	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('carcinomas', 'Phenotype', 'HP:0030731', (286, 296))	('FOXA1', 'Gene', '3169', (71, 76))	('TBX3', 'Gene', '6926', (81, 85))	('TBX3', 'Gene', (81, 85))	('NBCs and lobular carcinomas', 'Disease', 'MESH:D018275', (269, 296))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (278, 295))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (278, 296))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (157, 184))	('FOXA1', 'Gene', (71, 76))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (166, 183))	('mutations', 'Var', (319, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('invasive lobular carcinomas', 'Disease', (157, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (166, 184))
25776	27925203	In addition to the statistically significant higher frequency of CDH1 mutations in invasive lobular carcinomas than in NBCs (63% versus 11%, p<0.01, Fisher's exact test, Table 2, Figure 4), we observed that NBCs less frequently harboured PIK3CA mutations (11% versus 48%, p<0.01, Fisher's exact test, Table 2) and more frequently displayed DCHS2, MACF1 and CTCF mutations (17%, 11%, 11%) than invasive lobular carcinomas (1%, 1%, 0% Fisher's exact tests, Table 2, Figure 4).	('PIK3', 'Gene', '5294', (238, 242))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (92, 109))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (92, 110))	('displayed', 'Reg', (330, 339))	('MACF1', 'Gene', '23499', (347, 352))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (402, 419))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (402, 420))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (393, 420))	('DCHS2', 'Gene', '54798', (340, 345))	('mutations', 'Var', (245, 254))	('MACF1', 'Gene', (347, 352))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (83, 110))	('CTCF', 'Gene', (357, 361))	('harboured', 'Reg', (228, 237))	('mutations', 'Var', (70, 79))	('invasive lobular carcinomas', 'Disease', (393, 420))	('DCHS2', 'Gene', (340, 345))	('CDH1', 'Gene', '999', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (410, 419))	('less', 'NegReg', (212, 216))	('invasive lobular carcinomas', 'Disease', (83, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('CDH1', 'Gene', (65, 69))	('mutations', 'Var', (362, 371))	('carcinomas', 'Phenotype', 'HP:0030731', (410, 420))	('PIK3', 'Gene', (238, 242))
25779	27925203	In addition, FOXA1 and ERBB4 gene amplifications were found in one case each (Table 4).	('ERBB4', 'Gene', (23, 28))	('amplifications', 'Var', (34, 48))	('found', 'Reg', (54, 59))	('ERBB4', 'Gene', '2066', (23, 28))	(', FOXA1', 'Gene', '3169', (11, 18))
25791	27925203	Here we have demonstrated that NBCs harbour a repertoire of somatic mutations distinct from that of common types of ER+/HER2- breast cancer, and that the constellation of somatic mutations in NBCs appears to be intermediate between that reported for PAM50-defined luminal A and luminal B breast cancers from TCGA.	('NBCs', 'Gene', (192, 196))	('breast cancers', 'Phenotype', 'HP:0003002', (288, 302))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('luminal A', 'Disease', (264, 273))	('cancers', 'Phenotype', 'HP:0002664', (295, 302))	('luminal B breast cancers', 'Disease', 'MESH:D001943', (278, 302))	('mutations', 'Var', (68, 77))	('breast cancer', 'Disease', 'MESH:D001943', (288, 301))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (288, 301))	('luminal B breast cancers', 'Disease', (278, 302))
25798	27925203	In addition, the lobular NBC harboured a CDH1 mutation and concurrent 1q gain and 16q loss, akin to classic invasive lobular carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('loss', 'NegReg', (86, 90))	('invasive lobular carcinomas', 'Disease', (108, 135))	('gain', 'PosReg', (73, 77))	('CDH1', 'Gene', '999', (41, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (117, 134))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (108, 135))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (117, 135))	('mutation', 'Var', (46, 54))	('CDH1', 'Gene', (41, 45))	('16q', 'CPA', (82, 85))
25801	27925203	This subset of NBCs harboured a relatively simple constellation of copy number alterations and a low prevalence of concurrent 1q gain and 16q losses, lacked TP53 mutations, and less frequently harboured PIK3CA mutations than common forms of ER+/HER2- and PAM50-defined luminal A breast cancers.	('TP53', 'Gene', (157, 161))	('losses', 'NegReg', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))	('mutations', 'Var', (210, 219))	('PIK3', 'Gene', (203, 207))	('lacked', 'NegReg', (150, 156))	('luminal A breast cancers', 'Disease', 'MESH:D001943', (269, 293))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('breast cancers', 'Phenotype', 'HP:0003002', (279, 293))	('luminal A breast cancers', 'Disease', (269, 293))	('PIK3', 'Gene', '5294', (203, 207))	('constellation of copy number alterations', 'Disease', 'MESH:D004408', (50, 90))	('gain', 'PosReg', (129, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (279, 292))	('constellation of copy number alterations', 'Disease', (50, 90))
25807	27925203	Indeed, NBCs were enriched for mutations affecting the transcription factors FOXA1 and TBX3, which have been reported to be more frequently mutated in lobular than ductal carcinomas of no special type.	('ductal carcinomas', 'Disease', (164, 181))	('mutations', 'Var', (31, 40))	('lobular', 'Disease', (151, 158))	('FOXA1', 'Gene', '3169', (77, 82))	('TBX3', 'Gene', (87, 91))	('TBX3', 'Gene', '6926', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('FOXA1', 'Gene', (77, 82))	('ductal carcinomas', 'Disease', 'MESH:D044584', (164, 181))	('transcription', 'biological_process', 'GO:0006351', ('55', '68'))
25808	27925203	Although one of the CDH1 mutations found in the NBCs analysed here was found in an invasive lobular carcinoma with neuroendocrine differentiation, the TBX3 and FOXA1 somatic mutations were detected in NBCs of subtypes other than invasive lobular carcinoma.	('lobular carcinoma', 'Phenotype', 'HP:0030076', (92, 109))	('mutations', 'Var', (25, 34))	('invasive lobular carcinoma', 'Disease', (83, 109))	('and FOXA1', 'Gene', '3169', (156, 165))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (238, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (83, 109))	('CDH1', 'Gene', '999', (20, 24))	('invasive lobular carcinoma', 'Disease', (229, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('TBX3', 'Gene', '6926', (151, 155))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (229, 255))	('TBX3', 'Gene', (151, 155))	('found in', 'Reg', (71, 79))	('and FOXA1', 'Gene', (156, 165))	('detected', 'Reg', (189, 197))	('CDH1', 'Gene', (20, 24))
25814	27925203	Furthermore, the lack of TP53 mutations in the NBCs analysed here is consistent with previous observations in regards to the prevalence of TP53 mutations in non-small cell neuroendocrine carcinomas from other anatomical sites.	('TP53', 'Gene', (25, 29))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (172, 197))	('neuroendocrine carcinomas', 'Disease', (172, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('mutations', 'Var', (30, 39))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (172, 197))
25818	27925203	In addition, the repertoire of somatic mutations found in TD-NBCs appears to be more heterogeneous than that of NBCs defined based on morphology and immunohistochemically-assessed expression of neuroendocrine markers.	('TD-NBCs', 'Disease', (58, 65))	('TD-NBCs', 'Disease', 'MESH:C566844', (58, 65))	('mutations', 'Var', (39, 48))
25819	27925203	Despite these limitations, tumours included in the 'NBC-enriched cluster' were found to differ from the remaining ER+/HER2- breast cancers on the basis of mutations affecting PIK3CA, TP53, ARID1A and FOXA1, consistent with the results obtained through the analysis of NBCs.	('PIK3', 'Gene', (175, 179))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('HER2- breast cancers', 'Disease', (118, 138))	('mutations', 'Var', (155, 164))	('breast cancers', 'Phenotype', 'HP:0003002', (124, 138))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('PIK3', 'Gene', '5294', (175, 179))	('HER2- breast cancers', 'Disease', 'MESH:D001943', (118, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('and FOXA1', 'Gene', (196, 205))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	(', TP53', 'Gene', '7157', (181, 187))	('ARID1A', 'Gene', (189, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('and FOXA1', 'Gene', '3169', (196, 205))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumours', 'Disease', (27, 34))
25820	27925203	It should be noted, however, that we have employed a targeted capture sequencing approach with baits targeting all coding regions of 254 genes recurrently mutated in breast cancer and/or related to DNA repair.	('mutated', 'Var', (155, 162))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('DNA repair', 'biological_process', 'GO:0006281', ('198', '208'))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))
25822	27925203	In conclusion, here we demonstrate that NBCs are a heterogeneous group of tumours that, as a group, differ from common forms of ER+/HER2- breast based on their lack of lack of TP53 mutations, low frequency of PIK3CA mutations (similar to mucinous carcinomas) and enrichment of FOXA1 and TBX3 mutations (similar to lobular carcinomas).	('FOXA1', 'Gene', '3169', (277, 282))	('lobular carcinomas', 'Disease', (314, 332))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (238, 257))	('tumours', 'Disease', (74, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('carcinomas', 'Phenotype', 'HP:0030731', (247, 257))	('FOXA1', 'Gene', (277, 282))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (314, 332))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (314, 331))	('TBX3', 'Gene', '6926', (287, 291))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (238, 256))	('PIK3', 'Gene', (209, 213))	('TBX3', 'Gene', (287, 291))	('PIK3', 'Gene', '5294', (209, 213))	('lack', 'NegReg', (168, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('carcinomas', 'Phenotype', 'HP:0030731', (322, 332))	('TP53', 'Gene', (176, 180))	('mucinous carcinomas', 'Disease', (238, 257))	('lobular carcinomas', 'Disease', 'MESH:D018275', (314, 332))	('mutations', 'Var', (216, 225))
25829	26691964	Of 1,056 patients treated with NT for T3/T4 breast cancer, 107 (10%) had BCS and 949 (90%) had mastectomy.	('patients', 'Species', '9606', (9, 17))	('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))	('BCS', 'Disease', (73, 76))	('T3/T4', 'Var', (38, 43))
25830	26691964	After adjusting with extensive covariables, Hispanic patients (adjusted odds ratio (aOR) = [3.50], 95% confidence interval (CI): 1.38-8.84, P = 0.008) were more likely to have mastectomy than BCS.	('mastectomy', 'Disease', (176, 186))	('aOR', 'molecular_function', 'GO:0033726', ('84', '87'))	('Hispanic', 'Var', (44, 52))	('patients', 'Species', '9606', (53, 61))
26026	15084238	In comparison with IDC, ILC was significantly more likely to occur in older patients, to be larger in size, to be estrogen and progesterone receptor positive, to have lower S-phase fraction, to be diploid, and to be HER-2, p53, and epidermal growth factor receptor negative.	('ILC', 'Disease', (24, 27))	('S-phase fraction', 'MPA', (173, 189))	('estrogen', 'Protein', (114, 122))	('lower', 'NegReg', (167, 172))	('IDC', 'Gene', '4000', (19, 22))	('patients', 'Species', '9606', (76, 84))	('p53', 'Gene', (223, 226))	('IDC', 'Gene', (19, 22))	('p53', 'Gene', '7157', (223, 226))	('epidermal growth factor receptor', 'Gene', '1956', (232, 264))	('diploid', 'Var', (197, 204))	('progesterone receptor', 'Gene', '5241', (127, 148))	('HER-2', 'Gene', '2064', (216, 221))	('S-phase', 'biological_process', 'GO:0051320', ('173', '180'))	('epidermal growth factor receptor', 'Gene', (232, 264))	('HER-2', 'Gene', (216, 221))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('232', '255'))	('progesterone receptor', 'Gene', (127, 148))
26074	15084238	Thus, in comparison with IDC, ILC was more likely to occur in older patients, to be larger in size, to be ER and PgR positive, to have a lower S-phase fraction, to be diploid, and to be negative for HER-2, p53 and EGFR.	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('214', '218'))	('lower', 'NegReg', (137, 142))	('IDC', 'Gene', '4000', (25, 28))	('ILC', 'Disease', (30, 33))	('EGFR', 'Gene', '1956', (214, 218))	('S-phase fraction', 'MPA', (143, 159))	('patients', 'Species', '9606', (68, 76))	('PgR', 'Gene', (113, 116))	('positive', 'Reg', (117, 125))	('PgR', 'Gene', '5241', (113, 116))	('HER-2', 'Gene', (199, 204))	('IDC', 'Gene', (25, 28))	('EGFR', 'Gene', (214, 218))	('HER-2', 'Gene', '2064', (199, 204))	('diploid', 'Var', (167, 174))	('S-phase', 'biological_process', 'GO:0051320', ('143', '150'))
20336	15084238	It has been demonstrated that loss of expression of the cell-cell adhesion molecule E-cadherin in ILC may decrease adhesiveness of cells and facilitate this type of infiltration.	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('facilitate', 'PosReg', (141, 151))	('expression', 'MPA', (38, 48))	('cell-cell adhesion molecule', 'molecular_function', 'GO:0098632', ('56', '83'))	('loss of', 'Var', (30, 37))	('decrease', 'NegReg', (106, 114))	('adhesiveness of cells', 'CPA', (115, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('86', '94'))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('56', '74'))
26124	15084238	Positivity for p53 was found half as often in ILC as in IDC.	('ILC', 'Disease', (46, 49))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (15, 18))	('Positivity', 'Var', (0, 10))	('IDC', 'Gene', '4000', (56, 59))	('IDC', 'Gene', (56, 59))
26148	24621330	The ILC presented with a larger tumor size, more advanced cancer stage, increased rate of hormonal receptor positivity, human epidermal growth factor 2 (HER2) negativity and mastectomy than the IDC.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('126', '149'))	('human', 'Species', '9606', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('increased', 'PosReg', (72, 81))	('IDC', 'Gene', (194, 197))	('HER2', 'Gene', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('HER2', 'Gene', '2064', (153, 157))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('IDC', 'Gene', '4000', (194, 197))	('cancer', 'Disease', (58, 64))	('tumor', 'Disease', (32, 37))	('negativity', 'Var', (159, 169))	('hormonal receptor', 'Protein', (90, 107))
26236	18253121	Lobular carcinomas are characterised by a specific morphology with discohesive small cells usually associated with estradiol receptor (ER), progesterone receptor (PR) positivity and with a low proliferation rate (Sastre-Garau et al, 1996).	('estradiol receptor', 'Gene', (115, 133))	('progesterone receptor', 'Gene', '5241', (140, 161))	('PR', 'Gene', '5241', (163, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('ER', 'Gene', '2099', (135, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (8, 18))	('Lobular carcinomas', 'Disease', (0, 18))	('Lobular carcinomas', 'Disease', 'MESH:D018275', (0, 18))	('estradiol receptor', 'Gene', '2099', (115, 133))	('progesterone receptor', 'Gene', (140, 161))	('Lobular carcinomas', 'Phenotype', 'HP:0030076', (0, 18))	('positivity', 'Var', (167, 177))	('associated', 'Reg', (99, 109))
26318	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))
26361	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))
26362	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))
26380	33001307	This is illustrated in our study by the larger percentage of histological grade 3 invasive cancer among true compared with missed and minimal sign cancers.	('histological', 'Var', (61, 73))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', (147, 154))
26457	22916110	Mutation Discovery in Regions of Segmental Cancer Genome Amplifications with CoNAn-SNV: A Mixture Model for Next Generation Sequencing of Tumors Next generation sequencing has now enabled a cost-effective enumeration of the full mutational complement of a tumor genome:in particular single nucleotide variants (SNVs).	('tumor', 'Disease', (256, 261))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('single nucleotide variants', 'Var', (283, 309))	('Tumors', 'Disease', (138, 144))	('Tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('Tumors', 'Disease', 'MESH:D009369', (138, 144))	('Segmental Cancer', 'Disease', (33, 49))	('Segmental Cancer', 'Disease', 'MESH:C537538', (33, 49))
26460	22916110	We applied CoNAn-SNV to a previously published whole genome shotgun data set obtained from a lobular breast cancer and show that it is able to discover 21 experimentally revalidated somatic non-synonymous mutations in a lobular breast cancer genome that were not detected using copy number insensitive SNV detection algorithms.	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('CoNAn-SNV', 'Chemical', '-', (11, 20))	('lobular breast cancer', 'Disease', (220, 241))	('lobular breast cancer', 'Disease', 'MESH:D013274', (220, 241))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lobular breast cancer', 'Disease', (93, 114))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (220, 241))	('non-synonymous mutations', 'Var', (190, 214))	('lobular breast cancer', 'Disease', 'MESH:D013274', (93, 114))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (93, 114))
26462	22916110	This was also supported by analysis of a recently published lymphoma genome with a relatively quiescent karyotype, where CoNAn-SNV showed similar results to other callers except in regions of copy number gain where increased sensitivity was conferred.	('CoNAn-SNV', 'Chemical', '-', (121, 130))	('lymphoma', 'Disease', 'MESH:D008223', (60, 68))	('lymphoma', 'Phenotype', 'HP:0002665', (60, 68))	('copy number gain', 'Var', (192, 208))	('lymphoma', 'Disease', (60, 68))
26466	22916110	Cancer genomes undergo diverse forms of somatic aberration, including single nucleotide mutations, translocations, gene fusions, deletions, inversions and segmental genome copy number alterations (CNAs).	('deletions', 'Var', (129, 138))	('segmental genome copy number', 'CPA', (155, 183))	('translocations', 'CPA', (99, 113))	('gene fusions', 'Var', (115, 127))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('single nucleotide mutations', 'Var', (70, 97))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('inversions', 'CPA', (140, 150))
26467	22916110	observed recurrent mutations in PIK3CA in breast cancer with allele specific amplifications of the mutant allele in the same tumors and suggested that PIK3CA point mutations with concomitant CNA amplification resulted in synergistic oncogenic effects.	('PIK3CA', 'Gene', '5290', (32, 38))	('point mutations', 'Var', (158, 173))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PIK3CA', 'Gene', (151, 157))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('resulted in', 'Reg', (209, 220))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('PIK3CA', 'Gene', '5290', (151, 157))	('oncogenic effects', 'CPA', (233, 250))	('PIK3CA', 'Gene', (32, 38))
26468	22916110	showed allele specific amplification of EGFR mutant alleles in a lung cancer cell line; examples of amplification co-occurring with somatic mutations in MYC , HRAS , and MET  have also been observed.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('mutant', 'Var', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('HRAS', 'Gene', '3265', (159, 163))	('MYC', 'Gene', '4609', (153, 156))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('EGFR', 'Gene', '1956', (40, 44))	('MYC', 'Gene', (153, 156))	('EGFR', 'Gene', (40, 44))	('HRAS', 'Gene', (159, 163))	('MET', 'Gene', (170, 173))
26472	22916110	These studies have revealed novel somatic point mutations in acute myeloid leukaemia, breast cancer, ovarian cancer, melanoma, lymphoma and lung cancer.	('melanoma, lymphoma', 'Disease', 'MESH:D008545', (117, 135))	('myeloid leukaemia', 'Disease', 'MESH:D007938', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('lung cancer', 'Disease', (140, 151))	('point mutations', 'Var', (42, 57))	('ovarian cancer', 'Disease', (101, 115))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Disease', (86, 99))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (67, 84))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('myeloid leukaemia', 'Disease', (67, 84))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (61, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ovarian cancer', 'Disease', 'MESH:D010051', (101, 115))
26473	22916110	Here we demonstrate how the incorporation of CNA information in SNV discovery in cancer genome sequence data yields additional novel somatic mutations that were undetectable using conventional SNV prediction algorithms designed for normal diploid genomes.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
26475	22916110	We conclude that consideration of copy number results in increased sensitivity to detect both germline and somatic variants in non-diploid regions of cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('variants', 'Var', (115, 123))	('increased', 'PosReg', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
26479	22916110	Therefore to a first approximation, we have defined copy number state, , where LOSS corresponds to a deletion, NEUT is copy number neutral, GAIN approximates to low level duplication, AMP approximates to low-intermediate amplification and HLAMP is a high-level copy number amplification.	('deletion', 'Var', (101, 109))	('LOSS', 'NegReg', (79, 83))	('AMP', 'Chemical', 'MESH:D000249', (184, 187))	('GAIN', 'PosReg', (140, 144))	('AMP', 'Chemical', 'MESH:D000249', (241, 244))
26493	22916110	From the complete list of 2,857 CoNAn-specific predictions, we filtered out any positions that were present in dbSNP v130 and subsequently identified a set of 140 protein coding, non-synonymous substitution SNVs candidates for validation by targeted, ultra deep amplicon sequencing (shown schematically in Figure 4) in the metastatic and primary (from nine years earlier) tumor genome DNA as well as the normal buffy coat genome DNA from the same patient.	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('substitution', 'Var', (194, 206))	('DNA', 'cellular_component', 'GO:0005574', ('385', '388'))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('patient', 'Species', '9606', (447, 454))	('DNA', 'cellular_component', 'GO:0005574', ('429', '432'))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('tumor', 'Disease', (372, 377))
26494	22916110	Note that only one somatic mutation, K187M in ZNF607, a zinc finger protein putatively involved in transcriptional regulation, was also confirmed in the primary tumor.	('K187M', 'Mutation', 'p.K187M', (37, 42))	('K187M', 'Var', (37, 42))	('regulation', 'biological_process', 'GO:0065007', ('115', '125'))	('ZNF607', 'Gene', '84775', (46, 52))	('ZNF607', 'Gene', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('primary tumor', 'Disease', (153, 166))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('primary tumor', 'Disease', 'MESH:D009369', (153, 166))
26498	22916110	Notably, germline variants at positions chr19: 40691038, chr19:42074256, chr19:50869860 and chr19:59415177 within the high level amplicon on chr19 had allelic distributions in the tumour that were skewed significantly away from their normal distribution (Chi Sq test, ).	('chr19:50869860', 'Var', (73, 87))	('chr19:59415177', 'Var', (92, 106))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('chr19', 'Gene', (141, 146))	('chr19:42074256', 'Var', (57, 71))	('tumour', 'Disease', (180, 186))
26499	22916110	These germline SNPs are proximal to the somatic mutations K187M in ZNF607, E24* in PRR19, Q311* in ALDH16A1, E16Q in ZNF480, V328M in LILRA2, and G348E in ZSCAN22.	('V328M', 'Var', (125, 130))	('PRR', 'molecular_function', 'GO:0038187', ('83', '86'))	('E24*', 'SUBSTITUTION', 'None', (75, 79))	('PRR19', 'Gene', '284338', (83, 88))	('ZNF480', 'Gene', '147657', (117, 123))	('ZNF607', 'Gene', '84775', (67, 73))	('ALDH16A1', 'Gene', (99, 107))	('Q311*', 'Var', (90, 95))	('ALDH', 'molecular_function', 'GO:0004030', ('99', '103'))	('LILRA2', 'Gene', '11027', (134, 140))	('E16Q', 'Var', (109, 113))	('ZSCAN22', 'Gene', (155, 162))	('E24*', 'Var', (75, 79))	('ALDH16A1', 'Gene', '126133', (99, 107))	('E16Q', 'Mutation', 'p.E16Q', (109, 113))	('LILRA2', 'Gene', (134, 140))	('G348E', 'Var', (146, 151))	('ZSCAN22', 'Gene', '342945', (155, 162))	('Q311*', 'SUBSTITUTION', 'None', (90, 95))	('G348E', 'Mutation', 'rs1217310466', (146, 151))	('ZNF480', 'Gene', (117, 123))	('V328M', 'Mutation', 'rs768414857', (125, 130))	('K187M', 'Mutation', 'p.K187M', (58, 63))	('K187M', 'Var', (58, 63))	('ZNF607', 'Gene', (67, 73))	('PRR19', 'Gene', (83, 88))
26501	22916110	The enrichment of skewed germline alleles in regions of significant copy number change renders the possible explanation of allelic skewing of somatic variants in the same regions due to tumour-normal admixture extremely unlikely.	('tumour', 'Disease', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('copy number', 'Var', (68, 79))
26503	22916110	Interestingly, the allelic frequency of K187M in ZNF607, the only somatic variant found in the primary tumor (16.67%) was consistent in the metastatic tumor (15.25%), suggesting that the other 19q mutations occurred later in the tumor evolution.	('ZNF607', 'Gene', '84775', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('primary tumor', 'Disease', 'MESH:D009369', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (103, 108))	('K187M', 'Mutation', 'p.K187M', (40, 45))	('K187M', 'Var', (40, 45))	('ZNF607', 'Gene', (49, 55))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('primary tumor', 'Disease', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
26514	22916110	This suggests that the increased sensitivity gained by CoNAn-SNV does not compromise its overall accuracy compared to SNVMix, which was also demonstrated using OncoSNP to assess performance.	('CoNAn-SNV', 'Chemical', '-', (55, 64))	('sensitivity', 'MPA', (33, 44))	('SNVMix', 'Chemical', '-', (118, 124))	('CoNAn-SNV', 'Var', (55, 64))
26516	22916110	CoNAn-SNV is applicable to tumours with quiescent genome architectures as well as those with more disrupted karyotypes; to demonstrate this we evaluated CoNAn-SNV's performance in a lymphoma tumor originally published in Morin et al where 71.9% of the genome was predicted as loss/neutral, 22.1% was gain, 4.30% amplification and 1.67% high-level amplification (see methods).	('CoNAn-SNV', 'Chemical', '-', (153, 162))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('gain', 'PosReg', (300, 304))	('amplification', 'Var', (312, 325))	('high-level amplification', 'MPA', (336, 360))	('lymphoma', 'Phenotype', 'HP:0002665', (182, 190))	('lymphoma tumor', 'Disease', (182, 196))	('CoNAn-SNV', 'Chemical', '-', (0, 9))	('lymphoma tumor', 'Disease', 'MESH:D008223', (182, 196))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumours', 'Disease', (27, 34))	('loss/neutral', 'NegReg', (276, 288))
26522	22916110	CoNAn-SNV produced nearly identical results to the diploid methods in diploid/loss regions of the genome,which suggests strongly that modelling copy number confers a sensitivity advantage without loss of specificity, even in relatively diploid karyotypes and that the CoNAn-SNV model should generalise well to tumours with normal karyotypes.	('tumours', 'Disease', 'MESH:D009369', (310, 317))	('CoNAn-SNV', 'Chemical', '-', (268, 277))	('tumours', 'Disease', (310, 317))	('modelling copy number', 'Var', (134, 155))	('tumour', 'Phenotype', 'HP:0002664', (310, 316))	('CoNAn-SNV', 'Chemical', '-', (0, 9))	('sensitivity', 'MPA', (166, 177))	('tumours', 'Phenotype', 'HP:0002664', (310, 317))
26524	22916110	Unbalanced segmental copy number alterations are very frequent in tumor genomes and the presence of an unbalanced amplification or deletion of DNA would result in altered allelic ratios in randomly sampled sequence.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('DNA', 'Gene', (143, 146))	('tumor', 'Disease', (66, 71))	('altered', 'Reg', (163, 170))	('presence', 'Var', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('allelic ratios', 'MPA', (171, 185))	('deletion', 'Var', (131, 139))
26531	22916110	Overall, CoNAn-SNV is capable of calling more variants in highly amplified CNAs compared with SNVMix and samtools.	('CNAs', 'Gene', (75, 79))	('CoNAn-SNV', 'Chemical', '-', (9, 18))	('highly amplified', 'MPA', (58, 74))	('samtools', 'Chemical', '-', (105, 113))	('SNVMix', 'Chemical', '-', (94, 100))	('variants', 'Var', (46, 54))
26538	22916110	We found that CoNAn-SNV found only an additional 782 variants in the tumor, 22 of which were predicted somatic variants primarily in gain copy number states.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('CoNAn-SNV', 'Chemical', '-', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('variants', 'Var', (53, 61))
26545	22916110	The discovery of 21 new somatic mutations in the lobular breast cancer reveals how incorporation of CNAs into SNV analysis is essential to approaching comprehensive characterization of the somatic mutational landscape tumours by next generation sequencing technology.	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('tumours', 'Phenotype', 'HP:0002664', (218, 225))	('tumours', 'Disease', 'MESH:D009369', (218, 225))	('lobular breast cancer', 'Disease', (49, 70))	('tumours', 'Disease', (218, 225))	('mutations', 'Var', (32, 41))	('lobular breast cancer', 'Disease', 'MESH:D013274', (49, 70))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (49, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
26558	22916110	Tumour and matched normal lymphoma data were cases A03290 and A03291, respectively, selected from.	('Tumour', 'Disease', (0, 6))	('lymphoma', 'Disease', (26, 34))	('A03290', 'Var', (51, 57))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('lymphoma', 'Disease', 'MESH:D008223', (26, 34))	('lymphoma', 'Phenotype', 'HP:0002665', (26, 34))	('A03291', 'Var', (62, 68))	('Tumour', 'Disease', 'MESH:D009369', (0, 6))
26560	22916110	MutationSeq is a feature based classifier used to detect somatic SNVs from tumour-normal paired data and is robust to germline variants as well as strand bias, mapping quality, base quality, homopolymer run and tail-distance to end of the read induced artifacts.	('variants', 'Var', (127, 135))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('tumour', 'Disease', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
26562	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.	('invasive breast carcinomas', 'Disease', 'MESH:D018270', (229, 255))	('breast cancer', 'Phenotype', 'HP:0003002', (371, 384))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (371, 384))	('telomerase activity', 'molecular_function', 'GO:0003720', ('466', '485'))	('breast cancer', 'Disease', (371, 384))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('410', '446'))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('EMT', 'biological_process', 'GO:0001837', ('448', '451'))	('localization', 'biological_process', 'GO:0051179', ('337', '349'))	('formalin', 'Chemical', 'MESH:D005557', (523, 531))	('Breast Cancer', 'Disease', 'MESH:D001943', (111, 124))	('Epithelial to Mesenchymal Transition', 'biological_process', 'GO:0001837', ('46', '82'))	('breast carcinoma', 'Phenotype', 'HP:0003002', (238, 254))	('Telomerase Activity', 'molecular_function', 'GO:0003720', ('88', '107'))	('Breast Cancer', 'Disease', (111, 124))	('Cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('breast carcinomas', 'Phenotype', 'HP:0003002', (238, 255))	('Breast Cancer', 'Phenotype', 'HP:0003002', (111, 124))	('CD44+CD24-low', 'Var', (357, 370))	('invasive breast carcinomas', 'Disease', (229, 255))	('paraffin', 'Chemical', 'MESH:D010232', (539, 547))
26563	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))
26566	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))	('EMT', 'biological_process', 'GO:0001837', ('198', '201'))	('CD44+CD24-low', 'Var', (34, 47))	('promoting', 'PosReg', (263, 272))	('tumor invasiveness', 'Disease', (273, 291))	('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))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))
26585	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))
26589	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.	('transcriptase', 'molecular_function', 'GO:0034062', ('73', '86'))	('human', 'Species', '9606', (117, 122))	('human', 'Species', '9606', (48, 53))	('enzyme complex', 'cellular_component', 'GO:1902494', ('17', '31'))	('telomere', 'cellular_component', 'GO:0005696', ('233', '241'))	('hTERT', 'Gene', '7015', (106, 111))	('telomerase RNA', 'cellular_component', 'GO:0005573', ('123', '137'))	('length', 'MPA', (219, 225))	('telomere', 'cellular_component', 'GO:0000781', ('233', '241'))	('transcriptase', 'molecular_function', 'GO:0003968', ('73', '86'))	('transcriptase', 'molecular_function', 'GO:0003899', ('73', '86'))	('maintain', 'Reg', (206, 214))	('chromosome', 'cellular_component', 'GO:0005694', ('192', '202'))	('TTAGGG repeats', 'Var', (159, 173))	('telomerase RNA', 'molecular_function', 'GO:0000332', ('123', '137'))	('hTERT', 'Gene', (106, 111))
26599	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))	('telomerase activity', 'molecular_function', 'GO:0003720', ('94', '113'))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('parental cancer', 'Disease', (157, 172))
26610	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))
26612	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))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('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))
26613	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.	('exhibited', 'Reg', (94, 103))	('mesenchymal morphology', 'CPA', (106, 128))	('CD44+CD24low', 'Var', (18, 30))	('fibronectin', 'Gene', (184, 195))	('vimentin', 'cellular_component', 'GO:0045099', ('171', '179'))	('vimentin', 'Protein', (171, 179))	('human', 'Species', '9606', (74, 79))	('expressed', 'Reg', (133, 142))	('vimentin', 'cellular_component', 'GO:0045098', ('171', '179'))	('fibronectin', 'Gene', '2335', (184, 195))
26615	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))
26616	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))	('EMT', 'biological_process', 'GO:0001837', ('33', '36'))	('increased', 'PosReg', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cadherin', 'molecular_function', 'GO:0008014', ('112', '120'))	('knock-down', 'Var', (96, 106))	('breast cancer', 'Disease', (58, 71))	('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))
26637	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))	('Mouse', 'Species', '10090', (54, 59))	('Rabbit', 'Species', '9986', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('vimentin', 'cellular_component', 'GO:0045099', ('243', '251'))	('EMT', 'biological_process', 'GO:0001837', ('368', '371'))	('vimentin', 'cellular_component', 'GO:0045098', ('243', '251'))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('tumor', 'Disease', (297, 302))	('cadherin', 'molecular_function', 'GO:0008014', ('279', '287'))
26654	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))
26658	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))
26660	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))
26667	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))
26669	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))
26673	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))
26709	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.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EMT', 'biological_process', 'GO:0001837', ('77', '80'))	('CD44+CD24-low', 'Var', (112, 125))	('EMT', 'biological_process', 'GO:0001837', ('197', '200'))	('EMT', 'biological_process', 'GO:0001837', ('244', '247'))	('invasive tumor', 'Disease', 'MESH:D009369', (47, 61))	('invasive tumor', 'Disease', (47, 61))
26714	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', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutations', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (67, 72))
26720	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))
26721	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))
26725	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))
26728	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))
26735	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))
26741	25624778	who found high percentages of CD44+CD24-low tumor cells in metastatic and recurrent lesion.	('tumor', 'Disease', (44, 49))	('CD44+CD24-low', 'Var', (30, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
26775	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.	('vimentin', 'cellular_component', 'GO:0045098', ('20', '28'))	('breast carcinoma', 'Disease', 'MESH:D001943', (43, 59))	('breast carcinoma', 'Disease', (43, 59))	('CD44+CD24-low', 'Var', (157, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('vimentin', 'cellular_component', 'GO:0045099', ('20', '28'))	('EMT', 'biological_process', 'GO:0001837', ('130', '133'))	('breast carcinoma', 'Phenotype', 'HP:0003002', (43, 59))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('vimentin', 'Protein', (20, 28))
26784	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))
26785	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))
26788	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))
26789	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.	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('predict', 'Reg', (83, 90))	('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))
26794	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))	('telomerase activity', 'molecular_function', 'GO:0003720', ('40', '59'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('breast cancer', 'Disease', (198, 211))
26801	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.	('aggressiveness', 'Disease', 'MESH:D001523', (220, 234))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cadherin', 'molecular_function', 'GO:0008014', ('116', '124'))	('tumor invasiveness', 'Disease', 'MESH:D009369', (197, 215))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('vimentin', 'cellular_component', 'GO:0045099', ('104', '112'))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('DCIS', 'Phenotype', 'HP:0030075', (139, 143))	('tumor invasiveness', 'Disease', (197, 215))	('play', 'Reg', (171, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (289, 302))	('tumor', 'Disease', (69, 74))	('breast cancer', 'Disease', 'MESH:D001943', (289, 302))	('vimentin', 'cellular_component', 'GO:0045098', ('104', '112'))	('aggressiveness', 'Disease', (220, 234))	('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))
26817	28303886	A recent large study of lobular features also categorized several mutations in the PTEN, TBX3, and FOXA1 genes that typify lobular carcinomas.	('mutations', 'Var', (66, 75))	('PTEN', 'Gene', '5728', (83, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('typify lobular carcinomas', 'Disease', (116, 141))	('TBX3', 'Gene', '6926', (89, 93))	('FOXA1', 'Gene', '3169', (99, 104))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (123, 141))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (123, 140))	('typify lobular carcinomas', 'Disease', 'MESH:D018275', (116, 141))	('TBX3', 'Gene', (89, 93))	('FOXA1', 'Gene', (99, 104))	('PTEN', 'Gene', (83, 87))
26838	28303886	The cadherin CDH1 is often used to aid in diagnosis of lobular carcinoma, as lobular breast tumors generally exhibit low expression of this gene related to inactivating mutations, which are found in over half of lobular tumors, though are also present in some ductal tumors.	('CDH1', 'Gene', '999', (13, 17))	('lobular tumors', 'Disease', 'MESH:D018275', (212, 226))	('lobular breast tumors', 'Disease', (77, 98))	('expression', 'MPA', (121, 131))	('ductal tumors', 'Disease', 'MESH:D044584', (260, 273))	('inactivating mutations', 'Var', (156, 178))	('lobular tumors', 'Disease', (212, 226))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('CDH1', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('lobular carcinoma', 'Disease', 'MESH:D018275', (55, 72))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cadherin', 'Gene', '999', (4, 12))	('ductal tumors', 'Disease', (260, 273))	('cadherin', 'Gene', (4, 12))	('lobular carcinoma', 'Disease', (55, 72))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('low', 'NegReg', (117, 120))	('cadherin', 'molecular_function', 'GO:0008014', ('4', '12'))	('breast tumors', 'Phenotype', 'HP:0100013', (85, 98))	('breast tumor', 'Phenotype', 'HP:0100013', (85, 97))	('lobular breast tumors', 'Disease', 'MESH:D018275', (77, 98))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (55, 72))
26893	28303886	Interestingly, agents which act through alkylating at N-7 position of guanine, which includes mustard and platinum compounds, also were predicted in this study to significantly inhibit growth of lobular like cells.	('growth of lobular like cells', 'CPA', (185, 213))	('guanine', 'Chemical', 'MESH:D006147', (70, 77))	('inhibit', 'NegReg', (177, 184))	('alkylating', 'Var', (40, 50))	('platinum', 'Chemical', 'MESH:D010984', (106, 114))
26911	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('VASP', 'Gene', '7408', (48, 52))	('phosphorylation', 'MPA', (22, 37))
26912	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('decreased', 'NegReg', (60, 69))	('phosphorylation', 'MPA', (23, 38))	('HER2', 'Gene', '2064', (111, 115))	('S322', 'Var', (42, 46))	('S322', 'Chemical', '-', (42, 46))	('DCIS', 'Phenotype', 'HP:0030075', (92, 96))
26925	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.	('phosphorylation', 'biological_process', 'GO:0016310', ('144', '159'))	('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))
26926	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))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('localization', 'biological_process', 'GO:0051179', ('60', '72'))	('VASP', 'Gene', '7408', (76, 80))	('membrane', 'cellular_component', 'GO:0016020', ('51', '59'))
26927	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('VASP', 'Gene', (28, 32))	('prostate cancer', 'Disease', (119, 134))	('functions', 'MPA', (280, 289))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('VASP', 'Gene', (293, 297))	('VASP', 'Gene', '7408', (28, 32))	('VASP', 'Gene', '7408', (293, 297))	('S322', 'Var', (259, 263))	('phosphorylation', 'biological_process', 'GO:0016310', ('147', '162'))	('S322', 'Chemical', '-', (259, 263))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))
26930	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.	('tested', 'Reg', (8, 14))	('F-actin accumulation', 'MPA', (154, 174))	('invasive breast cancers', 'Disease', (198, 221))	('Protein Kinase D', 'Gene', '5587', (118, 134))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('increase F-actin accumulation', 'Phenotype', 'HP:0025200', (145, 174))	('PKD', 'Gene', (136, 139))	('VASP', 'Gene', '7408', (37, 41))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('F-actin', 'cellular_component', 'GO:0031941', ('154', '161'))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('Protein Kinase D', 'Gene', (118, 134))	('S322', 'Chemical', '-', (54, 58))	('PKD', 'Gene', '5587', (136, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))	('increase', 'PosReg', (145, 153))	('breast cancers', 'Phenotype', 'HP:0003002', (207, 221))	('VASP', 'Gene', (37, 41))	('S322', 'Var', (54, 58))	('invasive breast cancers', 'Disease', 'MESH:D001943', (198, 221))
26932	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('decrease of PKD2', 'Disease', 'MESH:D016891', (46, 62))
26938	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))
26947	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))	('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))
26951	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))
26958	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.	('cell migration', 'CPA', (160, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('VASP', 'Gene', (83, 87))	('S322', 'Chemical', '-', (71, 75))	('decrease', 'NegReg', (148, 156))	('phosphorylation', 'Var', (43, 58))	('cell migration', 'biological_process', 'GO:0016477', ('160', '174'))	('VASP', 'Gene', '7408', (83, 87))	('HeLa', 'CellLine', 'CVCL:0030', (27, 31))	('S322', 'Var', (71, 75))
26959	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))
26961	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))	('localization', 'biological_process', 'GO:0051179', ('80', '92'))	('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))
26962	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))	('localization', 'biological_process', 'GO:0051179', ('56', '68'))	('phosphorylation', 'biological_process', 'GO:0016310', ('6', '21'))	('membrane', 'cellular_component', 'GO:0016020', ('47', '55'))	('actin reorganization', 'MPA', (104, 124))	('phosphorylation at S322', 'Var', (70, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('70', '85'))	('regulates', 'Reg', (94, 103))	('membrane', 'cellular_component', 'GO:0016020', ('163', '171'))
26964	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))	('PKD1', 'Gene', (31, 35))	('S322', 'Var', (115, 119))	('PKD1', 'Gene', '5310', (31, 35))
26966	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.	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('PKD3', 'Gene', '5312', (69, 73))	('VASP', 'Gene', '7408', (112, 116))	('phosphorylation', 'MPA', (93, 108))	('PKD1', 'Gene', '5310', (60, 64))	('PKD2', 'Gene', '5311', (36, 40))	('S157', 'Var', (120, 124))	('S322', 'Chemical', '-', (129, 133))	('PKD3', 'Gene', (69, 73))	('PKD2', 'Gene', (36, 40))	('S322', 'Var', (129, 133))	('PKD1', 'Gene', (60, 64))	('VASP', 'Gene', (112, 116))
26969	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))	('PKD2', 'Gene', '5311', (104, 108))
26973	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))
26983	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))
26984	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))
26994	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))
26995	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))
27009	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))	('cell motility', 'biological_process', 'GO:0048870', ('93', '106'))	('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))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
27011	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))	('filopodia formation', 'biological_process', 'GO:0046847', ('171', '190'))	('cell migration', 'biological_process', 'GO:0016477', ('195', '209'))	('S322', 'Var', (105, 109))	('S322', 'Chemical', '-', (105, 109))	('VASP', 'Gene', '7408', (31, 35))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('F-actin', 'cellular_component', 'GO:0031941', ('149', '156'))	('F-actin accumulation', 'MPA', (149, 169))	('cell migration', 'CPA', (195, 209))	('VASP', 'Gene', (120, 124))
27015	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
27017	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))	('AMPK', 'molecular_function', 'GO:0004691', ('78', '82'))	('colon cancer', 'Disease', (126, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Phosphorylations', 'MPA', (0, 16))	('at S239', 'Var', (25, 32))	('suppress', 'NegReg', (88, 96))	('PKA', 'cellular_component', 'GO:0005952', ('65', '68'))	('AMPK', 'molecular_function', 'GO:0047322', ('78', '82'))	('PKA', 'molecular_function', 'GO:0004691', ('65', '68'))	('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', 'molecular_function', 'GO:0050405', ('78', '82'))	('AMPK', 'Gene', '5564', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))	('PKG', 'molecular_function', 'GO:0004692', ('70', '73'))
27018	26336132	We did not detect significant changes in phosphorylation of VASP at S239 (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('VASP', 'Gene', (60, 64))	('VASP', 'Gene', '7408', (60, 64))	('S239', 'Var', (68, 72))
27020	26336132	Therefore, we focused on phosphorylation at S322, which can be mediated by PKD enzymes (mainly PKD2 as demonstrated in Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('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))
27040	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('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))
27067	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', '7408', (56, 60))	('VASP', 'Gene', (56, 60))	('ibiTreat', 'Chemical', '-', (99, 107))
27098	23921840	All women diagnosed with an invasive breast cancer with a lobular component, based on ICD-O codes 8520, 8522, and 8524 assigned by CSS, were potentially eligible as ILC cases.	('8522', 'Var', (104, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('invasive breast cancer', 'Disease', (28, 50))	('CSS', 'Chemical', '-', (131, 134))	('women', 'Species', '9606', (4, 9))	('invasive breast cancer', 'Disease', 'MESH:D001943', (28, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
27130	23921840	Current use of non-dihydropyridines for any duration was associated with a 60% increased risk of both IDC and ILC (though the risk estimate for IDC was within the limits of change), but only current use of dihyrdropyridines for 10 years or longer was associated with elevated risks of IDC and ILC (IDC: OR=3.0, 95% CI: 1.0-8.9; ILC: OR=3.4, 95% CI: 1.1-9.9).	('IDC', 'Disease', (285, 288))	('ILC', 'Disease', (293, 296))	('IDC', 'Disease', (102, 105))	('dihydropyridines', 'Chemical', 'MESH:D004095', (19, 35))	('non-dihydropyridines', 'Var', (15, 35))	('dihyrdropyridines', 'Chemical', '-', (206, 223))	('ILC', 'Disease', (110, 113))
27170	22570516	This feature has been associated with the frequent inactivation of the E-cadherin gene (CDH1).	('cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('inactivation', 'Var', (51, 63))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('CDH1', 'Gene', (88, 92))	('CDH1', 'Gene', '999', (88, 92))
27204	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))	('regulation', 'biological_process', 'GO:0065007', ('219', '229'))	('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))	('Ser', 'cellular_component', 'GO:0005790', ('94', '97'))	('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))
27205	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', 'MESH:D001943', (69, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('380', '395'))	('PR', 'Gene', '5241', (40, 42))	('SUMOylation', 'biological_process', 'GO:0016925', ('286', '297'))	('regulation', 'biological_process', 'GO:0065007', ('55', '65'))	('K388', 'Chemical', '-', (299, 303))	('K388', 'Chemical', '-', (338, 342))	('K388R', 'Mutation', 'p.K388R', (338, 343))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('aglepristone', 'Chemical', 'MESH:C419063', (210, 222))	('Ser294', 'MPA', (373, 379))	('Lys388', 'Var', (279, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('Lys388', 'Chemical', '-', (279, 285))	('Ser294', 'Chemical', '-', (373, 379))	('T47D luminal breast cancer', 'Disease', (69, 95))	('Ser', 'cellular_component', 'GO:0005790', ('373', '376'))	('onapristone', 'Chemical', 'MESH:C053238', (194, 205))	('mifepristone', 'Chemical', 'MESH:D015735', (180, 192))	('promegestone', 'Chemical', 'MESH:D011397', (139, 151))	('K388R mutation', 'Var', (338, 352))	('R5020', 'Chemical', 'MESH:D011397', (153, 158))
27207	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))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('Ser294', 'Chemical', '-', (77, 83))	('breast cancer', 'Disease', (137, 150))	('PRs', 'Chemical', '-', (84, 87))	('phospho-Ser294', 'Var', (69, 83))	('implicate', 'Reg', (59, 68))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('89', '112'))	('RUNX2', 'Gene', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
27212	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.	('Ser', 'cellular_component', 'GO:0005790', ('65', '68'))	('EGF', 'Gene', (95, 98))	('EGF', 'molecular_function', 'GO:0005154', ('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))	('formation', 'biological_process', 'GO:0009058', ('21', '30'))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('Ser294', 'Chemical', '-', (65, 71))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('PRs', 'Chemical', '-', (72, 75))
27218	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.	('DNA', 'cellular_component', 'GO:0005574', ('277', '280'))	('copy number variation', 'Var', (254, 275))	('HER2', 'Gene', (75, 79))	('protein', 'MPA', (198, 205))	('HER2', 'Gene', '2064', (75, 79))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('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))	('DNA', 'cellular_component', 'GO:0005574', ('250', '253'))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('DNA methylation', 'biological_process', 'GO:0006306', ('277', '292'))
27219	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))	('MAP3K', 'molecular_function', 'GO:0004709', ('217', '222'))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))
27221	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))	('activation', 'PosReg', (193, 203))	('estrogen receptor', 'Gene', (286, 303))	('mutations', 'Var', (170, 179))	('estrogen receptor', 'Gene', '2099', (286, 303))	('AKT', 'Gene', (207, 210))	('FOXA1', 'Gene', (225, 230))	('increased', 'PosReg', (215, 224))	('activity', 'MPA', (246, 254))	('ER', 'Gene', '2099', (305, 307))	('signaling', 'biological_process', 'GO:0023052', ('309', '318'))	('expression', 'MPA', (231, 241))	('FOXA1', 'Gene', '3169', (225, 230))
27236	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('transcriptional', 'MPA', (48, 63))	('Ser', 'cellular_component', 'GO:0005790', ('22', '25'))	('hyperactivity', 'Disease', (64, 77))	('Phosphorylation', 'Var', (0, 15))	('PR', 'Gene', '5241', (115, 117))	('hyperactivity', 'Phenotype', 'HP:0000752', (64, 77))	('PR', 'Gene', '5241', (19, 21))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))
27239	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))	('Ser', 'cellular_component', 'GO:0005790', ('20', '23'))	('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))
27241	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))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('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))
27243	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))	('transcription', 'biological_process', 'GO:0006351', ('119', '132'))	('gatekeepers', 'Species', '111938', (75, 86))	('PRs', 'Chemical', '-', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('phospho-Ser294 PRs', 'Var', (34, 52))
27245	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))	('T47D', 'CellLine', 'CVCL:0553', (0, 4))	('K388R', 'Mutation', 'p.K388R', (88, 93))	('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))
27248	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))
27266	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))
27281	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))
27291	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))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('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))	('Ser', 'cellular_component', 'GO:0005790', ('252', '255'))	('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))	('Ser', 'cellular_component', 'GO:0005790', ('36', '39'))	('PR', 'Gene', '5241', (33, 35))	('breast tumors', 'Phenotype', 'HP:0100013', (76, 89))	('patient', 'Species', '9606', (169, 176))	('breast tumor', 'Phenotype', 'HP:0100013', (76, 88))
27305	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', '-', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('Ser294', 'Chemical', '-', (74, 80))	('Ser', 'cellular_component', 'GO:0005790', ('150', '153'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('negative', 'NegReg', (35, 43))	('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))	('Ser', 'cellular_component', 'GO:0005790', ('74', '77'))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
27306	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))	('Ser', 'cellular_component', 'GO:0005790', ('295', '298'))	('Ser294', 'Chemical', '-', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('PR', 'Gene', '5241', (37, 39))	('Ser', 'cellular_component', 'GO:0005790', ('30', '33'))	('Ser294', 'Chemical', '-', (303, 309))	('phospho-Ser294', 'Var', (22, 36))
27317	28412963	These tumors also expressed heterogeneous levels of total and phospho-Ser294 PRs.	('Ser', 'cellular_component', 'GO:0005790', ('70', '73'))	('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))
27323	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))	('Ser294', 'Chemical', '-', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('Ser', 'cellular_component', 'GO:0005790', ('31', '34'))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', (96, 109))	('phosphorylation', 'Var', (38, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))
27329	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))	('cell proliferation', 'biological_process', 'GO:0008283', ('158', '176'))	('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))
27332	28412963	We previously demonstrated a proliferative and pro-survival role for MAPK-dependent phosphorylation of PR on Ser294 in breast cancer cells.	('PR', 'Gene', '5241', (103, 105))	('Ser294', 'Chemical', '-', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('proliferative', 'CPA', (29, 42))	('breast cancer', 'Disease', (119, 132))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('phosphorylation', 'Var', (84, 99))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('pro-survival', 'biological_process', 'GO:0043066', ('47', '59'))	('pro-survival', 'CPA', (47, 59))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))
27338	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))	('ERK1', 'molecular_function', 'GO:0004707', ('8', '12'))	('progesterone', 'Chemical', 'MESH:D011374', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('breast tumor', 'Disease', (170, 182))	('ERK 1', 'molecular_function', 'GO:0004707', ('150', '155'))	('blocked', 'NegReg', (110, 117))	('ERKs 1/2', 'Gene', '5595;5594', (81, 89))	('U0126', 'Chemical', 'MESH:C113580', (99, 104))
27344	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))	('PR', 'Gene', '5241', (416, 418))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))	('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))	('RU486', 'Chemical', 'MESH:D015735', (109, 114))	('aglepristone', 'Chemical', 'MESH:C419063', (151, 163))
27358	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.	('gene expression', 'biological_process', 'GO:0010467', ('25', '40'))	('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))
27360	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))
27371	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))
27373	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.	('CDK', 'molecular_function', 'GO:0004693', ('262', '265'))	('proteasome', 'cellular_component', 'GO:0000502', ('77', '87'))	('PR', 'Gene', '5241', (158, 160))	('MAPK', 'Pathway', (254, 258))	('phosphorylation', 'Var', (200, 215))	('CDK2', 'Gene', '1017', (262, 266))	('MAPK', 'molecular_function', 'GO:0004707', ('254', '258'))	('PR', 'Gene', '5241', (219, 221))	('PR', 'Gene', '5241', (21, 23))	('Ser294', 'Chemical', '-', (222, 228))	('ligand', 'molecular_function', 'GO:0005488', ('109', '115'))	('CDK2', 'Gene', (262, 266))	('ligand', 'molecular_function', 'GO:0005488', ('141', '147'))	('Ser', 'cellular_component', 'GO:0005790', ('222', '225'))	('downregulation', 'NegReg', (161, 175))	('proteasome', 'molecular_function', 'GO:0004299', ('77', '87'))	('signaling', 'biological_process', 'GO:0023052', ('267', '276'))	('augmented', 'PosReg', (187, 196))	('phosphorylation', 'biological_process', 'GO:0016310', ('200', '215'))
27374	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))
27376	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))
27392	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))	('Ser', 'cellular_component', 'GO:0005790', ('397', '400'))	('Ser294', 'Chemical', '-', (397, 403))	('AHR', 'Gene', (49, 52))	('PRs', 'Chemical', '-', (578, 581))	('PRs', 'Chemical', '-', (404, 407))	('DNA binding', 'molecular_function', 'GO:0003677', ('531', '542'))	('receptor binding', 'molecular_function', 'GO:0005102', ('453', '469'))	('DNA', 'cellular_component', 'GO:0005574', ('531', '534'))	('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))	('SUMOylation', 'biological_process', 'GO:0016925', ('658', '669'))	('ligand', 'molecular_function', 'GO:0005488', ('643', '649'))	('PR', 'Gene', '5241', (247, 249))	('PR', 'Gene', '5241', (302, 304))
27395	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))	('Ser', 'cellular_component', 'GO:0005790', ('59', '62'))
27404	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))
27409	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))
27410	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))
27416	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))	('MAPK', 'molecular_function', 'GO:0004707', ('304', '308'))	('phosphorylation', 'biological_process', 'GO:0016310', ('309', '324'))	('T47D', 'CellLine', 'CVCL:0553', (136, 140))	('Ser', 'cellular_component', 'GO:0005790', ('330', '333'))	('PR', 'Gene', '5241', (41, 43))
27419	28412963	Surprisingly, both primary and secondary mammosphere formation was greatly attenuated in cells expressing S294A PR relative to controls and cells expressing KR PR.	('S294A', 'Var', (106, 111))	('PR', 'Gene', '5241', (112, 114))	('PR', 'Gene', '5241', (160, 162))	('attenuated', 'NegReg', (75, 85))	('S294A', 'Mutation', 'rs1309400161', (106, 111))	('formation', 'biological_process', 'GO:0009058', ('53', '62'))
27424	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', 'molecular_function', 'GO:0005154', ('162', '165'))	('Ser', 'cellular_component', 'GO:0005790', ('178', '181'))	('EGF', 'Gene', '1950', (162, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('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))	('formation', 'biological_process', 'GO:0009058', ('24', '33'))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('T47D', 'CellLine', 'CVCL:0553', (192, 196))
27425	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))	('EGF', 'molecular_function', 'GO:0005154', ('150', '153'))	('PR', 'Gene', '5241', (46, 48))	('PR', 'Gene', '5241', (113, 115))	('EGF', 'Gene', '1950', (150, 153))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('PR', 'Gene', '5241', (127, 129))	('negative', 'NegReg', (191, 199))	('S294A', 'Mutation', 'rs1309400161', (40, 45))
27426	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))
27427	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))	('greater', 'PosReg', (67, 74))	('PR-B', 'Var', (30, 34))	('larger', 'PosReg', (42, 48))
27428	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))	('RUNX2', 'Gene', (13, 18))	('formation of primary mammospheres', 'CPA', (42, 75))	('K388R', 'Mutation', 'p.K388R', (119, 124))	('K388R', 'Var', (119, 124))	('formation', 'biological_process', 'GO:0009058', ('42', '51'))
27439	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.	('Ser', 'cellular_component', 'GO:0005790', ('216', '219'))	('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))
27455	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', (72, 77))	('tumor', 'Disease', (195, 200))	('breast tumors', 'Phenotype', 'HP:0100013', (65, 78))	('breast tumor', 'Phenotype', 'HP:0100013', (65, 77))	('Ser', 'cellular_component', 'GO:0005790', ('20', '23'))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('PR', 'Gene', '5241', (324, 326))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('tumor', 'Disease', (72, 77))	('breast tumors', 'Disease', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Ser294', 'Chemical', '-', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('breast tumors', 'Disease', 'MESH:D001943', (65, 78))	('PR', 'Gene', '5241', (288, 290))	('PR', 'Gene', '5241', (17, 19))	('gene expression', 'biological_process', 'GO:0010467', ('334', '349'))
27461	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))	('Ser', 'cellular_component', 'GO:0005790', ('95', '98'))	('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))	('regulation', 'biological_process', 'GO:0065007', ('127', '137'))	('PR', 'Gene', '5241', (37, 39))	('Ser294', 'Protein', (95, 101))	('mifepristone', 'Var', (41, 53))	('aglepristone', 'Gene', (58, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('PR', 'Gene', '5241', (261, 263))
27467	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))	('Ser', 'cellular_component', 'GO:0005790', ('204', '207'))
27469	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))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('Ser', 'cellular_component', 'GO:0005790', ('30', '33'))	('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))
27474	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))	('PR', 'Gene', '5241', (64, 66))	('Pax2', 'Gene', (0, 4))	('murine', 'Species', '10090', (17, 23))	('mice', 'Species', '10090', (84, 88))
27487	28412963	AML is primarily caused by gene translocations between strong promoters and the EVI1 and runt-related transcription factor 1 (RUNX1) genes.	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('transcription factor', 'molecular_function', 'GO:0000981', ('102', '122'))	('EV', 'Disease', 'MESH:D004819', (80, 82))	('caused by', 'Reg', (17, 26))	('runt-related transcription factor 1', 'Gene', '861', (89, 124))	('gene translocations', 'Var', (27, 46))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('RUNX1', 'Gene', (126, 131))	('RUNX1', 'Gene', '861', (126, 131))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('runt-related transcription factor 1', 'Gene', (89, 124))	('AML', 'Disease', (0, 3))
27495	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))	('deletion', 'Var', (11, 19))	('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))	('cell proliferation', 'biological_process', 'GO:0008283', ('134', '152'))	('alveolar progenitor cell populations', 'CPA', (42, 78))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('longer', 'PosReg', (180, 186))	('reduced', 'NegReg', (154, 161))	('reduced', 'NegReg', (116, 123))	('Runx2', 'Gene', (0, 5))	('mouse', 'Species', '10090', (209, 214))
27496	28412963	In addition, deletion of RUNX2 in human breast cancer cells resulted in reduced tumorigenic properties, such as invasion and migration.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('reduced', 'NegReg', (72, 79))	('human', 'Species', '9606', (34, 39))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('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))
27498	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))	('K388R', 'Var', (152, 157))	('formation', 'biological_process', 'GO:0009058', ('33', '42'))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('PRs', 'Chemical', '-', (174, 177))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('EGF', 'molecular_function', 'GO:0005154', ('78', '81'))	('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))
27502	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.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Ser294', 'Chemical', '-', (234, 240))	('PR', 'Gene', '5241', (8, 10))	('PR', 'Gene', '5241', (231, 233))	('breast tumor', 'Phenotype', 'HP:0100013', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('Ser', 'cellular_component', 'GO:0005790', ('232', '235'))	('Ser294', 'Var', (234, 240))	('breast tumor', 'Disease', (73, 85))	('gatekeeper', 'Species', '111938', (274, 284))	('breast cancer', 'Phenotype', 'HP:0003002', (288, 301))	('tumor', 'Disease', (80, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('210', '225'))	('breast cancer', 'Disease', 'MESH:D001943', (288, 301))	('tumor', 'Disease', (325, 330))	('breast cancer', 'Disease', (288, 301))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('breast tumor', 'Disease', 'MESH:D001943', (73, 85))
27542	32110411	However, the positivity for both epithelial markers CAM 5.2 and CK AE1/AE3 as well as the breast origin sensitive markers GATA3 and mammaglobin in the tumor cells helped in reaching the correct diagnosis.	('positivity', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('AE3', 'Gene', '6508', (71, 74))	('tumor', 'Disease', (151, 156))	('AE1', 'Gene', '6521', (67, 70))	('AE3', 'Gene', (71, 74))	('helped', 'Reg', (163, 169))	('AE1', 'Gene', (67, 70))	('GATA3', 'Gene', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('GATA3', 'Gene', '2625', (122, 127))
27546	32110411	Gene polymorphisms affecting the activity of this enzyme might explain why some patients have a better response to tamoxifen compared with others.	('response', 'MPA', (103, 111))	('patients', 'Species', '9606', (80, 88))	('activity', 'MPA', (33, 41))	('tamoxifen', 'Chemical', 'MESH:D013629', (115, 124))	('polymorphisms', 'Var', (5, 18))
27610	24266940	In cancer, the loss of E-cadherin function through genetic or epigenetic mechanisms has been implicated in the progression and metastasis of numerous malignancies.	('epigenetic', 'Var', (62, 72))	('implicated', 'Reg', (93, 103))	('metastasis of numerous malignancies', 'Disease', (127, 162))	('metastasis of numerous malignancies', 'Disease', 'MESH:D009362', (127, 162))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('loss', 'NegReg', (15, 19))	('E-cadherin', 'Gene', (23, 33))	('E-cadherin', 'Gene', '999', (23, 33))	('cancer', 'Disease', (3, 9))	('cadherin', 'molecular_function', 'GO:0008014', ('25', '33'))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
27631	24266940	Benign lesions containing genetic and epigenetic alterations are generally accepted to render women possibly more susceptible to neoplastic transformations.	('women', 'Species', '9606', (94, 99))	('neoplastic transformations', 'CPA', (129, 155))	('epigenetic alterations', 'Var', (38, 60))	('genetic', 'Var', (26, 33))
27678	20501751	Specifically, cases with codes 8520 (n=1,550) or 8524 (n=52) were classified as ILC, cases with codes 8500-8503 (n=13,422) or 8523 (n=347) were classified as IDC, and cases with a code of 8522 were classified as IDLC.	('codes 8500-8503', 'Var', (96, 111))	('ILC', 'Disease', (80, 83))	('IDC', 'Gene', '4000', (158, 161))	('IDC', 'Gene', (158, 161))	('codes 8520', 'Var', (25, 35))
27686	20501751	BMI was calculated from self-reported height and weight and was analyzed as a categorical variable according to cut-points for normal weight (less than 25 kg/m2), overweight (25 to 29 kg/m2), and obese status (30 kg/m2 or greater).	('overweight', 'Phenotype', 'HP:0025502', (163, 173))	('less than', 'Var', (142, 151))	('25 to', 'Var', (175, 180))	('obese', 'Disease', 'MESH:D009765', (196, 201))	('obese', 'Disease', (196, 201))
27704	20501751	A clear gradient of increasing risk with increasing breast density was observed for each of the three histologic subtypes: compared to women with a BI-RADS score of 2 (i.e., scattered fibroglandular densities), women with a score of 1 (i.e., almost entirely fat) had a significantly lower risk of IDC, ILC, and IDLC (HRIDC = 0.59, 95% CI: 0.52-0.67; HRILC = 0.48, 95% CI: 0.31-0.74; HRIDLC = 0.41, 95% CI: 0.26-0.66) and women with a score of 4 (i.e., extremely dense) had a significantly higher risk of all three subtypes (HRIDC = 1.62, 95% CI: 1.45-1.81; HRILC = 1.62, 95% CI: 1.15-2.26; HRIDLC = 1.76, 95% CI: 1.27-2.42).	('IDC', 'Gene', '4000', (319, 322))	('ILC', 'Disease', (302, 305))	('score', 'Var', (224, 229))	('women', 'Species', '9606', (135, 140))	('women', 'Species', '9606', (211, 216))	('women', 'Species', '9606', (421, 426))	('IDC', 'Gene', (319, 322))	('IDC', 'Gene', '4000', (526, 529))	('fibroglandular', 'Chemical', '-', (184, 198))	('IDC', 'Gene', (526, 529))	('lower', 'NegReg', (283, 288))	('IDC', 'Gene', '4000', (297, 300))	('IDLC', 'Disease', (311, 315))	('IDC', 'Gene', (297, 300))
27722	20501751	Also consistent with prior studies of breast cancer overall, associations between BMI and risk of IDC were modified by age and HT use, such that BMI was weakly inversely associated with risk in women aged <50 and positively associated with risk among women aged >=50 who were not HT users.	('inversely', 'NegReg', (160, 169))	('IDC', 'Gene', '4000', (98, 101))	('women', 'Species', '9606', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('IDC', 'Gene', (98, 101))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('BMI', 'Var', (145, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('women', 'Species', '9606', (251, 256))
27735	20501751	assessed risk factors for IDLC using a more restrictive case definition such that all IDLC cases were deemed to have invasive ductal and invasive lobular components after centralized review of pathology reports and/or tumor tissue; results from that study indicated a reduced risk of IDLC associated with parity that was similar in magnitude to associations with IDC and ILC, a 2.1-fold (95% CI: 1.0-4.3) increased risk of IDLC in women with a first birth at age 30 or greater versus age 20 or younger that was stronger than for other subtypes, and differences in associations with age at menarche and breastfeeding.	('menarche', 'biological_process', 'GO:0042696', ('589', '597'))	('associations', 'Interaction', (564, 576))	('IDLC', 'Disease', (423, 427))	('women', 'Species', '9606', (431, 436))	('IDC', 'Gene', '4000', (363, 366))	('IDC', 'Gene', (363, 366))	('reduced', 'NegReg', (268, 275))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('parity', 'Var', (305, 311))	('tumor', 'Disease', (218, 223))	('IDLC', 'Disease', (284, 288))
27739	20501751	These associations were largely confined to women aged less than 65 years although, relative to women with a BI-RADS score of 2 (i.e., scattered fibroglandular densities), women with a BI-RADS score of 1 (i.e., almost entirely fat) experienced a significantly reduced breast cancer risk that was similar in magnitude across age strata and across subtypes.	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('fibroglandular', 'Chemical', '-', (145, 159))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('women', 'Species', '9606', (44, 49))	('reduced', 'NegReg', (260, 267))	('BI-RADS score of 1', 'Var', (185, 203))	('breast cancer', 'Disease', (268, 281))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('women', 'Species', '9606', (96, 101))	('women', 'Species', '9606', (172, 177))
27782	30513096	So, we created two data matrices: cancer matrix (1356*1065) and normal matrix (1356*111).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('1356*111', 'Var', (79, 87))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('1356*1065', 'Var', (49, 58))
27841	30513096	The blockade of TGF-beta in colon cancer unleashed a potent and endured cytotoxic T-cell response against cancer cells, inhibited metastases, and rendered metastatic colon cancer more susceptible to anti-PD-1-PD-L1 therapy.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('colon cancer', 'Disease', (166, 178))	('blockade', 'Var', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('metastases', 'Disease', (130, 140))	('cancer', 'Disease', (106, 112))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('rendered', 'Reg', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('colon cancer', 'Phenotype', 'HP:0003003', (166, 178))	('colon cancer', 'Disease', (28, 40))	('inhibited', 'NegReg', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('TGF-beta', 'Gene', '7040', (16, 24))	('cancer', 'Disease', (172, 178))	('colon cancer', 'Disease', 'MESH:D015179', (166, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('more', 'PosReg', (179, 183))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('cancer', 'Disease', (34, 40))	('TGF-beta', 'Gene', (16, 24))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('PD-1', 'Gene', (204, 208))	('PD-1', 'Gene', '5133', (204, 208))
27843	30513096	Furthermore, DcR3 was suggested as a prognostic factor for early tumor detection and a predictor of recurrence after resection in breast cancer, specifically.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('tumor', 'Disease', (65, 70))	('breast cancer', 'Gene', '672', (130, 143))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('DcR3', 'Var', (13, 17))	('breast cancer', 'Gene', (130, 143))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
27847	30513096	Due to the higher immune system-tumor interactions involved, TNBC and HER2 were thought to be more immunogenic than Luminal A.	('HER2', 'Gene', (70, 74))	('TNBC', 'Var', (61, 65))	('system-tumor', 'Disease', (25, 37))	('HER2', 'Gene', '2064', (70, 74))	('interactions', 'Interaction', (38, 50))	('system-tumor', 'Disease', 'MESH:D009369', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('higher', 'PosReg', (11, 17))
27851	30513096	The response rate of blockading PD-1/PD-L1 in breast cancer patients has been tested in several hormone receptor subtypes.	('breast cancer', 'Gene', '672', (46, 59))	('patients', 'Species', '9606', (60, 68))	('breast cancer', 'Gene', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PD-1', 'Gene', (32, 36))	('blockading', 'Var', (21, 31))	('PD-1', 'Gene', '5133', (32, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
27860	24252758	We analyzed the ultrasound features of the tumors according to the ACR BI-RADS -US classification system stratified by hormone receptor status, HER2 status, histology grade, tumor type (ductal versus lobular), triple-negativity, breast density, tumor size, lymph node involvement and patient's age.	('tumor', 'Disease', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('hormone receptor', 'Gene', (119, 135))	('triple-negativity', 'Var', (210, 227))	('hormone receptor', 'Gene', '3164', (119, 135))	('HER2', 'Gene', '2064', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('HER2', 'Gene', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (245, 250))	('tumors', 'Disease', (43, 49))	('tumor', 'Disease', (43, 48))	('patient', 'Species', '9606', (284, 291))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
27911	24252758	HER2 positivity was defined as strong complete membrane staining of >= 10%of the tumor cells (i.e.	('positivity', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('membrane', 'cellular_component', 'GO:0016020', ('47', '55'))	('HER2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('HER2', 'Gene', '2064', (0, 4))	('tumor', 'Disease', (81, 86))
27936	24252758	As described elsewhere, triple negativity of breast cancer has a relevant effect on the sonomorphology.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('sonomorphology', 'MPA', (88, 102))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('triple negativity', 'Var', (24, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))
27964	24252758	Focusing on the HER2 status, architectural distortions were observed significantly more often in HER2 positive tumors than in HER2 negative tumors (91% versus 78%).	('HER2', 'Gene', (97, 101))	('positive', 'Var', (102, 110))	('architectural distortions', 'CPA', (29, 54))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('HER2', 'Gene', '2064', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HER2', 'Gene', (16, 20))	('observed', 'Reg', (60, 68))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('HER2', 'Gene', '2064', (16, 20))	('HER2', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HER2', 'Gene', '2064', (126, 130))
27990	24252758	Usually, round or oval shape is associated with benign lesions, but may also occur in certain types of breast cancer.	('occur', 'Reg', (77, 82))	('benign lesions', 'Disease', (48, 62))	('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))	('round', 'Var', (9, 14))
28124	19362281	Given the unique histologic appearance of single file tumor infiltration seen in ILC compared to the broader invasive front seen with invasive ductal carcinoma, patchy response to chemotherapy may be more likely to compromise accurate margin assessment in ILC patients.	('compromise', 'NegReg', (215, 225))	('patchy', 'Var', (161, 167))	('ILC', 'Disease', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (143, 159))	('ILC', 'Disease', (256, 259))	('patients', 'Species', '9606', (260, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('accurate margin assessment', 'MPA', (226, 252))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (134, 159))	('tumor', 'Disease', (54, 59))	('invasive ductal carcinoma', 'Disease', (134, 159))
28207	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))
28247	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))	('uptake', 'biological_process', 'GO:0098657', ('77', '83'))	('c-erbB-2', 'Gene', (18, 26))	('c-erbB-2', 'Gene', '2064', (18, 26))	('uptake', 'biological_process', 'GO:0098739', ('77', '83'))	('higher', 'PosReg', (56, 62))	('>= 10%', 'Var', (28, 34))
28254	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))
28256	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.	('uptake', 'biological_process', 'GO:0098657', ('302', '308'))	('uptake', 'biological_process', 'GO:0098739', ('302', '308'))	('breast disorders', 'Disease', (93, 109))	('breast cancer', 'Disease', 'MESH:D001943', (204, 217))	('breast disorders', 'Disease', 'MESH:D001941', (93, 109))	('uptake', 'biological_process', 'GO:0098657', ('76', '82'))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('uptake', 'biological_process', 'GO:0098739', ('76', '82'))	('breast cancer', 'Disease', (204, 217))	('diffuse', 'Var', (52, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (204, 217))	('99mTc-Sestamibi', 'Chemical', 'MESH:D017256', (60, 75))
28264	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))	('uptake', 'biological_process', 'GO:0098657', ('35', '41'))	('99mTc-(V)DMSA', 'Var', (157, 170))	('uptake', 'biological_process', 'GO:0098739', ('35', '41'))
28373	28764784	ER, PR, HER2, and Ki67 have all been shown to be important prognostic indicators for breast cancer.	('ER', 'Gene', '2099', (0, 2))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('HER2', 'Gene', (8, 12))	('breast cancer', 'Disease', (85, 98))	('HER2', 'Gene', '2064', (8, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('Ki67', 'Var', (18, 22))	('ER', 'Gene', '2099', (9, 11))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
28390	28764784	A genomic analysis found that HER2 gene mutations were frequently present in relapsed invasive lobular breast cancers with a classic E-cad gene mutation.	('invasive lobular breast cancers', 'Disease', (86, 117))	('breast cancers', 'Phenotype', 'HP:0003002', (103, 117))	('present', 'Reg', (66, 73))	('E-cad', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (95, 116))	('mutations', 'Var', (40, 49))	('HER2', 'Gene', (30, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('HER2', 'Gene', '2064', (30, 34))	('invasive lobular breast cancers', 'Disease', 'MESH:D013274', (86, 117))	('E-cad', 'Gene', '999', (133, 138))
28493	33544698	Overall, HER-2 gene amplification occurs at a significantly lower rate in ILC, but also has been linked to adverse outcomes.	('HER-2', 'Gene', '2064', (9, 14))	('HER-2', 'Gene', (9, 14))	('ILC', 'Disease', (74, 77))	('linked', 'Reg', (97, 103))	('gene amplification', 'Var', (15, 33))	('lower', 'NegReg', (60, 65))
28494	33544698	Most cases of ILCs with HER-2 overexpression and or amplification generally have the pleomorphic variant.	('overexpression', 'PosReg', (30, 44))	('pleomorphic', 'Disease', (85, 96))	('HER-2', 'Gene', '2064', (24, 29))	('ILCs', 'Disease', (14, 18))	('amplification', 'Var', (52, 65))	('HER-2', 'Gene', (24, 29))
28505	33544698	Most cases of ILCs with HER-2 overexpression and/or amplification generally represent the pleomorphic variant.	('overexpression', 'PosReg', (30, 44))	('HER-2', 'Gene', '2064', (24, 29))	('ILCs', 'Disease', (14, 18))	('amplification', 'Var', (52, 65))	('HER-2', 'Gene', (24, 29))
28592	33544698	HER-2 positivity is linked exclusively to a pleomorphic variant of ILC and is not encountered in classic ILC according to other published data.	('ILC', 'Disease', (67, 70))	('positivity', 'Var', (6, 16))	('HER-2', 'Gene', '2064', (0, 5))	('HER-2', 'Gene', (0, 5))	('linked', 'Reg', (20, 26))
28597	33544698	In the past, many studies have shown the association between HER-2 amplification or overexpression and reduced or absent PR expression.	('overexpression', 'PosReg', (84, 98))	('PR', 'Gene', '5241', (121, 123))	('reduced', 'NegReg', (103, 110))	('amplification', 'Var', (67, 80))	('HER-2', 'Gene', '2064', (61, 66))	('absent', 'NegReg', (114, 120))	('HER-2', 'Gene', (61, 66))
28601	33544698	In a recent study, 1 in 5 hereditary breast and ovarian cancers patients in the Arab world have BRCA mutations, although its association with HER-2-positive ILC remains unknown due to its rarity, and may need further studies.	('BRCA', 'Gene', '672', (96, 100))	('mutations', 'Var', (101, 110))	('patients', 'Species', '9606', (64, 72))	('BRCA', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (26, 63))	('ovarian cancers', 'Phenotype', 'HP:0100615', (48, 63))	('HER-2', 'Gene', '2064', (142, 147))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('HER-2', 'Gene', (142, 147))
28609	33544698	Overall, HER-2 positivity is an independent prognostic factor which is associated with undesired survival outcomes in patients diagnosed with ILC.	('HER-2', 'Gene', '2064', (9, 14))	('ILC', 'Disease', (142, 145))	('HER-2', 'Gene', (9, 14))	('positivity', 'Var', (15, 25))	('patients', 'Species', '9606', (118, 126))
28638	31899528	Patients with single hormone receptor-positive tumors have an intermediate prognosis between double hormone receptor-positive (best survival) and double hormone receptor-negative (worst survival) tumors, whereas there is no survival difference between patients who have ER-positive/PR-negative tumors and patients who have ER-negative/PR-positive tumors.	('hormone receptor', 'Gene', '3164', (21, 37))	('hormone receptor', 'Gene', '3164', (100, 116))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('ER', 'Gene', '2099', (270, 272))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('hormone receptor', 'Gene', (153, 169))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumors', 'Disease', (294, 300))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('tumors', 'Disease', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('patients', 'Species', '9606', (252, 260))	('tumors', 'Disease', (347, 353))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumors', 'Disease', 'MESH:D009369', (294, 300))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('PR', 'Gene', '5241', (282, 284))	('hormone receptor', 'Gene', (21, 37))	('hormone receptor', 'Gene', (100, 116))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('double', 'Var', (146, 152))	('ER', 'Gene', '2099', (323, 325))	('patients', 'Species', '9606', (305, 313))	('hormone receptor', 'Gene', '3164', (153, 169))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('PR', 'Gene', '5241', (335, 337))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))
28708	31899528	Compared with positive ERBB2 status, negative ERBB2 status was statistically significantly associated with better BCSS in the ER-positive/PR-positive subtype and with worse BCSS in the ER-negative/PR-positive and ER-negative/PR-negative subtypes.	('ERBB2', 'Gene', (23, 28))	('BC', 'Disease', 'MESH:D001943', (114, 116))	('ERBB2', 'Gene', '2064', (23, 28))	('ER', 'Gene', '2099', (185, 187))	('BC', 'Phenotype', 'HP:0003002', (173, 175))	('BC', 'Disease', 'MESH:D001943', (173, 175))	('PR', 'Gene', '5241', (138, 140))	('better', 'PosReg', (107, 113))	('PR', 'Gene', '5241', (197, 199))	('BC', 'Phenotype', 'HP:0003002', (114, 116))	('negative', 'Var', (37, 45))	('PR', 'Gene', '5241', (225, 227))	('ERBB2', 'Gene', '2064', (46, 51))	('ER', 'Gene', '2099', (46, 48))	('ER', 'Gene', '2099', (23, 25))	('ERBB2', 'Gene', (46, 51))	('ER', 'Gene', '2099', (126, 128))	('ER', 'Gene', '2099', (213, 215))
28823	31456094	In this study, the rate of margin positivity among ILC patients was 16.2%, and did not differ in the pre- and post-guideline eras.	('margin positivity', 'Var', (27, 44))	('pre', 'molecular_function', 'GO:0003904', ('101', '104'))	('eras', 'Gene', '3266', (125, 129))	('patients', 'Species', '9606', (55, 63))	('eras', 'Gene', (125, 129))	('ILC', 'Disease', (51, 54))
28993	29794798	CESM is more acceptable and feasible than MRI, as it reduces patient's stress.	('patient', 'Species', '9606', (61, 68))	('CESM', 'Var', (0, 4))	('reduces', 'NegReg', (53, 60))
29036	27980389	MammaPrint High Risk status was associated with worse clinical outcome in invasive lobular breast cancer.	('High Risk status', 'Var', (11, 27))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('invasive lobular breast cancer', 'Disease', (74, 104))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (74, 104))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (83, 104))
29040	27980389	In the patient group without LN involvement (n = 144), MammaPrint was validated for OS, DMFI, and DMFS in univariate (Table 2) and multivariate (Table 3) survival analyses.	('DMFS', 'Chemical', '-', (98, 102))	('patient', 'Species', '9606', (7, 14))	('DMFI', 'Disease', (88, 92))	('DMFI', 'Chemical', '-', (88, 92))	('OS', 'Chemical', '-', (84, 86))	('DMFS', 'Var', (98, 102))
29064	24366306	Germline CDH1 mutations in bilateral lobular carcinoma in situ Invasive lobular breast cancer (ILC) and lobular carcinoma in situ (LCIS) are characterised by loss of E-cadherin expression.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (45, 62))	('E-cadherin', 'Gene', (166, 176))	('E-cadherin', 'Gene', '999', (166, 176))	('lobular carcinoma', 'Disease', 'MESH:D018275', (104, 121))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (37, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (37, 62))	('lobular breast cancer', 'Disease', 'MESH:D013274', (72, 93))	('expression', 'MPA', (177, 187))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (72, 93))	('lobular carcinoma in situ', 'Disease', (37, 62))	('LCIS', 'Phenotype', 'HP:0030076', (131, 135))	('lobular carcinoma', 'Disease', 'MESH:D018275', (37, 54))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (104, 129))	('mutations', 'Var', (14, 23))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (104, 129))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CDH1', 'Gene', '999', (9, 13))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (112, 129))	('situ Invasive lobular breast cancer', 'Phenotype', 'HP:0006625', (58, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('lobular carcinoma in situ', 'Disease', (104, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('168', '176'))	('CDH1', 'Gene', (9, 13))	('lobular breast cancer', 'Disease', (72, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
29065	24366306	However germline CDH1 mutations are rare in cases of ILC with no family history of hereditary diffuse gastric cancer (HDGC) and have not been described in women with LCIS.	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (83, 116))	('women', 'Species', '9606', (155, 160))	('CDH1', 'Gene', '999', (17, 21))	('hereditary diffuse gastric cancer', 'Disease', (83, 116))	('ILC', 'Disease', (53, 56))	('HDGC', 'Disease', 'MESH:D013274', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('LCIS', 'Phenotype', 'HP:0030076', (166, 170))	('mutations', 'Var', (22, 31))	('CDH1', 'Gene', (17, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('HDGC', 'Disease', (118, 122))
29067	24366306	Sanger sequencing revealed four pathogenic germline mutations, including a novel splicing mutation (c.48+1G>A).	('pathogenic', 'Reg', (32, 42))	('c.48+1G>A', 'Mutation', 'rs1440280370', (100, 109))	('c.48+1G>A', 'Var', (100, 109))	('splicing', 'biological_process', 'GO:0045292', ('81', '89'))
29068	24366306	The remaining three (c.1465insC, c.1942G>T, c.2398delC) have been previously described.	('c.2398delC', 'Var', (44, 54))	('c.2398delC', 'Mutation', 'rs587783048', (44, 54))	('c.1465insC', 'Var', (21, 31))	('c.1465insC', 'Mutation', 'c.1465insC', (21, 31))	('c.1942G>T', 'Var', (33, 42))	('c.1942G>T', 'Mutation', 'rs138101372', (33, 42))
29071	24366306	We have shown that germline CDH1 mutations are associated with early onset of bilateral LCIS with or without ILC in women without a family history of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('CDH1', 'Gene', (28, 32))	('associated with', 'Reg', (47, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('women', 'Species', '9606', (116, 121))	('mutations', 'Var', (33, 42))	('gastric cancer', 'Disease', (150, 164))	('ILC', 'Disease', (109, 112))	('CDH1', 'Gene', '999', (28, 32))	('LCIS', 'Phenotype', 'HP:0030076', (88, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('bilateral LCIS', 'Disease', (78, 92))
29072	24366306	CDH1 mutation screening should be considered in women with early onset of bilateral LCIS/ILC with no family history of HDGC.	('HDGC', 'Disease', (119, 123))	('CDH1', 'Gene', '999', (0, 4))	('women', 'Species', '9606', (48, 53))	('HDGC', 'Disease', 'MESH:D013274', (119, 123))	('LCIS', 'Phenotype', 'HP:0030076', (84, 88))	('bilateral LCIS/ILC', 'Disease', (74, 92))	('mutation', 'Var', (5, 13))	('CDH1', 'Gene', (0, 4))
29075	24366306	ILC and LCIS are characterised by loss of expression of E-cadherin, which is due to a combination of somatic mutations, loss of heterozygosity and hypermethylation.	('loss of heterozygosity', 'Var', (120, 142))	('hypermethylation', 'Var', (147, 163))	('cadherin', 'molecular_function', 'GO:0008014', ('58', '66'))	('expression', 'MPA', (42, 52))	('LCIS', 'Disease', (8, 12))	('ILC', 'Disease', (0, 3))	('LCIS', 'Phenotype', 'HP:0030076', (8, 12))	('loss', 'NegReg', (34, 38))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))
29077	24366306	Women who have had LCIS are 2.4 times more likely to develop invasive breast cancer compared with the general population.	('LCIS', 'Var', (19, 23))	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('develop', 'PosReg', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('LCIS', 'Phenotype', 'HP:0030076', (19, 23))
29082	24366306	Germline CDH1 mutations were initially reported in patients with hereditary diffuse gastric cancer (HDGC).	('HDGC', 'Disease', 'MESH:D013274', (100, 104))	('hereditary diffuse gastric cancer', 'Disease', (65, 98))	('HDGC', 'Disease', (100, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('CDH1', 'Gene', (9, 13))	('patients', 'Species', '9606', (51, 59))	('reported', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('CDH1', 'Gene', '999', (9, 13))	('mutations', 'Var', (14, 23))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (65, 98))
29084	24366306	However, germline CDH1 mutations in women with ILC that are present without a family history of HDGC appear to be rare.	('HDGC', 'Disease', 'MESH:D013274', (96, 100))	('CDH1', 'Gene', (18, 22))	('HDGC', 'Disease', (96, 100))	('CDH1', 'Gene', '999', (18, 22))	('women', 'Species', '9606', (36, 41))	('mutations', 'Var', (23, 32))	('ILC', 'Disease', (47, 50))
29085	24366306	Of the 408 cases of LCIS/ILC with no family history of HDGC screened for CDH1 mutations and reported in the literature, only three germline mutations have been described, all in cases of ILC (Table 1).	('ILC', 'Disease', (187, 190))	('CDH1', 'Gene', (73, 77))	('HDGC', 'Disease', 'MESH:D013274', (55, 59))	('LCIS', 'Phenotype', 'HP:0030076', (20, 24))	('CDH1', 'Gene', '999', (73, 77))	('HDGC', 'Disease', (55, 59))	('mutations', 'Var', (78, 87))
29086	24366306	In the current study, we aimed to assess the frequency of germline mutations in CDH1 in bilateral LCIS or ILC testing the hypothesis that cases of bilateral LCIS/ILC are more likely to have an inherited component to their disease.	('component to their disease', 'Disease', (203, 229))	('LCIS', 'Phenotype', 'HP:0030076', (157, 161))	('LCIS', 'Phenotype', 'HP:0030076', (98, 102))	('bilateral LCIS/ILC', 'Disease', (147, 165))	('component to their disease', 'Disease', 'MESH:C562869', (203, 229))	('CDH1', 'Gene', (80, 84))	('bilateral LCIS', 'Disease', (88, 102))	('germline mutations', 'Var', (58, 76))	('ILC', 'Disease', (106, 109))	('CDH1', 'Gene', '999', (80, 84))
29087	24366306	This hypothesis is supported by a recent retrospective study from France of all 165 index cases who had undergone CDH1 mutation screening in their region from 2006 to 2012.	('CDH1', 'Gene', (114, 118))	('mutation', 'Var', (119, 127))	('CDH1', 'Gene', '999', (114, 118))
29088	24366306	They identified 18 individuals with CDH1 mutations, three of which had bilateral ILC before the age of 50 prior to developing gastric cancer.	('mutations', 'Var', (41, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('gastric cancer', 'Disease', (126, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('CDH1', 'Gene', (36, 40))	('CDH1', 'Gene', '999', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
29099	24366306	Four germline mutations were identified in four individuals: one donor splice-site mutation (c.48+1G>A), two frame-shift mutations (c.1465insC, c.2398delC) and a nonsense substitution (c.1942G>T), (Table 2, Figure 1).	('c.1942G>T', 'Var', (185, 194))	('donor', 'Species', '9606', (65, 70))	('c.2398delC', 'Var', (144, 154))	('c.1465insC', 'Mutation', 'c.1465insC', (132, 142))	('c.2398delC', 'Mutation', 'rs587783048', (144, 154))	('c.1942G>T', 'Mutation', 'rs138101372', (185, 194))	('c.48+1G>A', 'Mutation', 'rs1440280370', (93, 102))	('c.48+1G>A', 'Var', (93, 102))	('c.1465insC', 'Var', (132, 142))
29100	24366306	The c.48+1G>A mutation is novel, affecting the donor splice site of intron 1 and occurred in an individual with bilateral LCIS and ILC at the age of 51 with a family history of breast cancer.	('breast cancer', 'Disease', (177, 190))	('donor splice site of intron 1', 'MPA', (47, 76))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('donor', 'Species', '9606', (47, 52))	('LCIS', 'Phenotype', 'HP:0030076', (122, 126))	('c.48+1G>A', 'Mutation', 'rs1440280370', (4, 13))	('occurred', 'Reg', (81, 89))	('c.48+1G>A', 'Var', (4, 13))	('affecting', 'Reg', (33, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
29101	24366306	These three mutations have been previously described as follows: c.1942G>T, a somatic mutation in colon cancer; c.1465insC, a germline mutation in diffuse gastric cancer; and c.2398delC, a founder mutation in four Newfoundland families with diffuse gastric and ILC.	('c.2398delC', 'Var', (175, 185))	('c.1465insC', 'Var', (112, 122))	('c.2398delC', 'Mutation', 'rs587783048', (175, 185))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (155, 169))	('c.1942G>T', 'Var', (65, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('c.1465insC', 'Mutation', 'c.1465insC', (112, 122))	('colon cancer', 'Disease', (98, 110))	('c.1942G>T', 'Mutation', 'rs138101372', (65, 74))	('gastric cancer', 'Disease', (155, 169))	('gastric cancer', 'Disease', 'MESH:D013274', (155, 169))
29102	24366306	The c.1465insC mutation occurred in an individual with bilateral pure LCIS at the age of 46 whose mother had breast cancer at the age of 43.	('pure', 'molecular_function', 'GO:0034023', ('65', '69'))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('c.1465insC', 'Var', (4, 14))	('occurred', 'Reg', (24, 32))	('LCIS', 'Phenotype', 'HP:0030076', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('c.1465insC', 'Mutation', 'c.1465insC', (4, 14))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
29105	24366306	Using a control dataset (no personal history of breast cancer) from the King's College London exome sequencing database, we have found no truncating or splice-site mutations in CDH1 of 190 ethnicity matched individuals with no personal history of breast cancer (P=0.002, Fisher's exact test).	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('splice-site mutations', 'Var', (152, 173))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Disease', (247, 260))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('breast cancer', 'Disease', (48, 61))	('CDH1', 'Gene', (177, 181))	('CDH1', 'Gene', '999', (177, 181))	('truncating', 'MPA', (138, 148))
29106	24366306	Four (8%) of the bilateral cases in our cohort of LCIS/ILC were found to have a germline mutation in CDH1.	('CDH1', 'Gene', '999', (101, 105))	('LCIS', 'Phenotype', 'HP:0030076', (50, 54))	('CDH1', 'Gene', (101, 105))	('germline', 'Var', (80, 88))
29107	24366306	The frequency of CDH1 mutations is much higher than previous studies of LCIS/ILC without a personal or family history of gastric cancer where only 0.7% of the sporadic or familial cases of LCIS/ILC without HDGC carry CDH1 mutations (P=0.003, Fisher's exact test), (Table 1).	('HDGC', 'Disease', 'MESH:D013274', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('CDH1', 'Gene', '999', (17, 21))	('CDH1', 'Gene', (217, 221))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('CDH1', 'Gene', '999', (217, 221))	('LCIS', 'Phenotype', 'HP:0030076', (189, 193))	('HDGC', 'Disease', (206, 210))	('LCIS', 'Phenotype', 'HP:0030076', (72, 76))	('mutations', 'Var', (222, 231))	('mutations', 'Var', (22, 31))	('CDH1', 'Gene', (17, 21))	('gastric cancer', 'Disease', (121, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
29111	24366306	We have shown for the first time that CDH1 mutations predispose to LCIS, with 12.5% (1 out of 8) of bilateral pure LCIS and 11.5% (3 out of 26) of bilateral LCIS with ILC having CDH1 mutations in this study.	('CDH1', 'Gene', (38, 42))	('LCIS', 'Phenotype', 'HP:0030076', (157, 161))	('CDH1', 'Gene', (178, 182))	('pure', 'molecular_function', 'GO:0034023', ('110', '114'))	('CDH1', 'Gene', '999', (38, 42))	('CDH1', 'Gene', '999', (178, 182))	('predispose', 'Reg', (53, 63))	('mutations', 'Var', (43, 52))	('LCIS', 'Phenotype', 'HP:0030076', (115, 119))	('LCIS', 'Phenotype', 'HP:0030076', (67, 71))	('LCIS', 'Disease', (67, 71))
29112	24366306	Interestingly, none of the cases with bilateral LCIS and non-lobular invasive disease (11 cases) had CDH1 mutations, suggesting that the presence of a germline CDH1 mutation in bilateral LCIS predisposes to the development of ILC rather than IDC.	('non-lobular invasive disease', 'Disease', (57, 85))	('CDH1', 'Gene', (101, 105))	('CDH1', 'Gene', (160, 164))	('mutation', 'Var', (165, 173))	('IDC', 'Disease', (242, 245))	('CDH1', 'Gene', '999', (101, 105))	('non-lobular invasive disease', 'Disease', 'MESH:D018275', (57, 85))	('LCIS', 'Phenotype', 'HP:0030076', (48, 52))	('LCIS', 'Phenotype', 'HP:0030076', (187, 191))	('ILC', 'Disease', (226, 229))	('CDH1', 'Gene', '999', (160, 164))	('predisposes to', 'Reg', (192, 206))
29115	24366306	Although they gave no family history of gastric cancer it is possible that they may develop diffuse gastric cancer (DGC) in the future, as showed that the estimated cumulative risk of gastric cancer is higher (83%) than that for breast cancer (39%) in women with CDH1 mutations.	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('gastric cancer', 'Disease', (40, 54))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('breast cancer', 'Disease', (229, 242))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('gastric cancer', 'Disease', (100, 114))	('mutations', 'Var', (268, 277))	('women', 'Species', '9606', (252, 257))	('develop', 'PosReg', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))	('gastric cancer', 'Disease', (184, 198))	('CDH1', 'Gene', '999', (263, 267))	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('DGC', 'cellular_component', 'GO:0016010', ('116', '119'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CDH1', 'Gene', (263, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))
29118	24366306	Using an age threshold of less than 50 years would miss some CDH1 mutation carriers.	('CDH1', 'Gene', '999', (61, 65))	('mutation', 'Var', (66, 74))	('CDH1', 'Gene', (61, 65))
29119	24366306	Lowering the age threshold further to less than 45 years for mutation screening would result in 28% of eligible patients having a CDH1 mutation in this study, Table 3.	('CDH1', 'Gene', '999', (130, 134))	('mutation', 'Var', (135, 143))	('CDH1', 'Gene', (130, 134))	('patients', 'Species', '9606', (112, 120))
29120	24366306	The current consensus guidelines recommend annual mammography and breast MRI starting at the age of 35 for CDH1 mutation carriers.	('carriers', 'Reg', (121, 129))	('CDH1', 'Gene', '999', (107, 111))	('mutation', 'Var', (112, 120))	('CDH1', 'Gene', (107, 111))
29122	24366306	As MRI has been shown to have the lowest false negative rate in detecting ILC compared with mammography and ultrasound, and is routinely used for pre-operative work-up of ILC, it would seem prudent to continue MRI surveillance in CDH1 carriers rather than switch to mammography alone at the age of 50.	('CDH1', 'Gene', (230, 234))	('CDH1', 'Gene', '999', (230, 234))	('ILC', 'Disease', (74, 77))	('false', 'biological_process', 'GO:0071878', ('41', '46'))	('pre', 'molecular_function', 'GO:0003904', ('146', '149'))	('carriers', 'Var', (235, 243))	('false', 'biological_process', 'GO:0071877', ('41', '46'))
29123	24366306	CDH1 carriers may also benefit from chemoprevention as the NSABP Breast Cancer Prevention Trial (P-1) study showed that women with a history of LCIS who took tamoxifen had almost half the risk (relative risk=0.54) of developing an invasive cancer rather than women with a history of LCIS randomised to placebo.	('Breast Cancer', 'Phenotype', 'HP:0003002', (65, 78))	('women', 'Species', '9606', (259, 264))	('LCIS', 'Phenotype', 'HP:0030076', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('CDH1', 'Gene', '999', (0, 4))	('P-1', 'Gene', (97, 100))	('tamoxifen', 'Chemical', 'MESH:D013629', (158, 167))	('invasive cancer', 'Disease', (231, 246))	('invasive cancer', 'Disease', 'MESH:D009362', (231, 246))	('carriers', 'Var', (5, 13))	('Breast Cancer', 'Disease', (65, 78))	('women', 'Species', '9606', (120, 125))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('P-1', 'Gene', '1423', (97, 100))	('Breast Cancer', 'Disease', 'MESH:D001943', (65, 78))	('LCIS', 'Phenotype', 'HP:0030076', (283, 287))	('CDH1', 'Gene', (0, 4))
29124	24366306	As the penetrance of gastric cancer in CDH1 carriers with bilateral LCIS/ILC and no family history of DGC is not known, it is difficult to recommend prophylactic gastrectomy in these cases.	('gastric cancer', 'Phenotype', 'HP:0012126', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('carriers', 'Var', (44, 52))	('gastric cancer', 'Disease', (21, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (21, 35))	('CDH1', 'Gene', (39, 43))	('LCIS', 'Phenotype', 'HP:0030076', (68, 72))	('CDH1', 'Gene', '999', (39, 43))	('DGC', 'cellular_component', 'GO:0016010', ('102', '105'))
29125	24366306	In conclusion, two studies including our own, have shown that CDH1 mutations in bilateral LCIS or ILC are more common than previously thought.	('CDH1', 'Gene', '999', (62, 66))	('LCIS', 'Phenotype', 'HP:0030076', (90, 94))	('CDH1', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))
29126	24366306	If further studies confirm these findings then, CDH1 testing could be offered to individuals with bilateral LCIS/ILC under the age of 50, enabling us to identify patients with CDH1 mutations who may benefit from regular breast MRI screening and endoscopic surveillance for diffuse gastric cancer.	('patients', 'Species', '9606', (162, 170))	('CDH1', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('LCIS', 'Phenotype', 'HP:0030076', (108, 112))	('CDH1', 'Gene', (176, 180))	('gastric cancer', 'Disease', (281, 295))	('CDH1', 'Gene', '999', (176, 180))	('CDH1', 'Gene', '999', (48, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (281, 295))	('mutations', 'Var', (181, 190))	('gastric cancer', 'Phenotype', 'HP:0012126', (281, 295))
29127	23714731	A Neu View of Invasive Lobular Breast Cancer Genome sequencing of relapsed, invasive lobular breast cancer identified actionable mutations in 86% of cases.	('Lobular Breast Cancer', 'Phenotype', 'HP:0006625', (23, 44))	('Invasive Lobular Breast Cancer', 'Disease', 'MESH:D013274', (14, 44))	('invasive lobular breast cancer', 'Disease', (76, 106))	('Invasive Lobular Breast Cancer', 'Disease', (14, 44))	('Breast Cancer', 'Phenotype', 'HP:0003002', (31, 44))	('Neu', 'Gene', '2064', (2, 5))	('mutations', 'Var', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('invasive lobular breast cancer', 'Disease', 'MESH:D013274', (76, 106))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (85, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('relapsed', 'Disease', (66, 74))	('Neu', 'Gene', (2, 5))
29128	23714731	HER2 alterations occur in 27% of cases, including four cases with activating HER2 mutations and one with a novel HER2-GRB7 gene fusion.	('HER2', 'Gene', (77, 81))	('HER2', 'Gene', (113, 117))	('activating', 'PosReg', (66, 76))	('GRB7', 'Gene', '2886', (118, 122))	('HER2', 'Gene', '2064', (113, 117))	('mutations', 'Var', (82, 91))	('alterations', 'Var', (5, 16))	('HER2', 'Gene', (0, 4))	('GRB7', 'Gene', (118, 122))	('HER2', 'Gene', '2064', (77, 81))	('HER2', 'Gene', '2064', (0, 4))
29131	23714731	They identified HER2 activating mutations and a HER2 gene fusion in a high percentage of these patients.	('HER2', 'Gene', '2064', (48, 52))	('activating', 'PosReg', (21, 31))	('patients', 'Species', '9606', (95, 103))	('HER2', 'Gene', (16, 20))	('HER2', 'Gene', '2064', (16, 20))	('gene fusion', 'Var', (53, 64))	('HER2', 'Gene', (48, 52))
29139	23714731	Prior cancer genome sequencing studies on lobular breast cancers include a Canadian study, which identified 4 cases with HER2 mutations, and The Cancer Genome Atlas (TCGA) Breast Cancer Project, which performed next-generation DNA sequencing on 36 newly diagnosed, lobular breast cancer cases and identified HER2 mutations in 9% of these cases.	('HER2', 'Gene', '2064', (121, 125))	('Cancer Genome Atlas (TCGA) Breast Cancer', 'Disease', 'MESH:D001943', (145, 185))	('cancer', 'Disease', (280, 286))	('cancer', 'Disease', (57, 63))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (42, 63))	('Breast Cancer', 'Phenotype', 'HP:0003002', (172, 185))	('DNA', 'cellular_component', 'GO:0005574', ('227', '230'))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('HER2', 'Gene', '2064', (308, 312))	('mutations', 'Var', (126, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('lobular breast cancer', 'Disease', 'MESH:D013274', (42, 63))	('HER2', 'Gene', (121, 125))	('lobular breast cancers', 'Disease', 'MESH:D013274', (42, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (50, 64))	('lobular breast cancer', 'Disease', (265, 286))	('cancer', 'Disease', (6, 12))	('mutations', 'Var', (313, 322))	('lobular breast cancers', 'Disease', (42, 64))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('HER2', 'Gene', (308, 312))	('lobular breast cancer', 'Disease', 'MESH:D013274', (265, 286))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (265, 286))
29140	23714731	The clinical and therapeutic importance of HER2 gene amplification in breast cancer has been known for more than 20 years, but the presence of HER2 mutations in breast cancer, independent of HER2 gene amplification has only been recently identified.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('HER2', 'Gene', (191, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (161, 174))	('HER2', 'Gene', (43, 47))	('amplification', 'Var', (53, 66))	('HER2', 'Gene', '2064', (191, 195))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('HER2', 'Gene', '2064', (43, 47))	('HER2', 'Gene', (143, 147))	('breast cancer', 'Disease', (70, 83))	('HER2', 'Gene', '2064', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))
29141	23714731	We and others have functionally tested these HER2 mutations and determined that the majority of breast cancer-associated HER2 mutations are activating mutations that increase cellular transformation and tumor formation.	('HER2', 'Gene', '2064', (121, 125))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('increase', 'PosReg', (166, 174))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('breast cancer', 'Disease', (96, 109))	('HER2', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('mutations', 'Var', (126, 135))	('cellular transformation', 'CPA', (175, 198))	('HER2', 'Gene', '2064', (45, 49))	('formation', 'biological_process', 'GO:0009058', ('209', '218'))	('HER2', 'Gene', (121, 125))
29143	23714731	Interestingly, the HER2 mutation L755S produces de novo resistance to the reversible tyrosine kinase inhibitor, lapatinib, and is found in lapatinib-naive patients, but this mutation can be inhibited in vitro and in cells with low nanomolar doses of neratinib.	('HER2', 'Gene', (19, 23))	('neratinib', 'Chemical', 'MESH:C487932', (250, 259))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('94', '110'))	('HER2', 'Gene', '2064', (19, 23))	('lapatinib', 'Chemical', 'MESH:D000077341', (139, 148))	('L755S', 'Var', (33, 38))	('L755S', 'Mutation', 'rs121913470', (33, 38))	('patients', 'Species', '9606', (155, 163))	('lapatinib', 'Chemical', 'MESH:D000077341', (112, 121))	('tyrosine', 'Chemical', 'MESH:D014443', (85, 93))
29144	23714731	A multi-institutional, phase II clinical trial to screen for HER2 mutations in metastatic breast cancer and to treat mutation positive patients with neratinib is currently enrolling patients.1 In this study, Ross and colleagues identified actionable alterations in 86% of patients, including HER2 alterations in 27%.	('patients', 'Species', '9606', (135, 143))	('alterations', 'Reg', (297, 308))	('HER2', 'Gene', '2064', (61, 65))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('alterations', 'Var', (250, 261))	('breast cancer', 'Disease', (90, 103))	('HER2', 'Gene', (61, 65))	('neratinib', 'Chemical', 'MESH:C487932', (149, 158))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (272, 280))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('HER2', 'Gene', (292, 296))	('HER2', 'Gene', '2064', (292, 296))
29145	23714731	These HER2 alterations included tyrosine kinase domain mutations (L755S, A775_G776insYVMA, P780_Y781insGSP, and V842I), an extracellular domain mutation at a known hotspot (S310F), a novel HER2-GRB7 fusion gene, and 1 case with HER2 amplification.	('HER2', 'Gene', (228, 232))	('L755S', 'Mutation', 'rs121913470', (66, 71))	('S310F', 'Var', (173, 178))	('extracellular', 'cellular_component', 'GO:0005576', ('123', '136'))	('GRB7', 'Gene', (194, 198))	('G776insYVMA', 'Mutation', 'c.776insG,YVMA', (78, 89))	('HER2', 'Gene', '2064', (6, 10))	('HER2', 'Gene', '2064', (189, 193))	('V842I', 'Mutation', 'rs1057519738', (112, 117))	('S310F', 'Mutation', 'rs1057519816', (173, 178))	('Y781insGSP', 'Mutation', 'c.781insY,GSP', (96, 106))	('V842I', 'Var', (112, 117))	('HER2', 'Gene', '2064', (228, 232))	('GRB7', 'Gene', '2886', (194, 198))	('A775_G776insYVMA', 'Var', (73, 89))	('L755S', 'Var', (66, 71))	('tyrosine', 'Chemical', 'MESH:D014443', (32, 40))	('P780_Y781insGSP', 'Var', (91, 106))	('HER2', 'Gene', (6, 10))	('HER2', 'Gene', (189, 193))	('tyrosine kinase domain', 'MPA', (32, 54))
29146	23714731	Actionable alterations in other genes include AKT1 E17K mutation (9% of cases), PIK3CA mutations (36% of cases), and FGFR1 amplification (14% of cases).	('E17K', 'Mutation', 'rs121434592', (51, 55))	('AKT1', 'Gene', '207', (46, 50))	('FGFR1', 'Gene', (117, 122))	('PIK3CA', 'Gene', (80, 86))	('FGFR1', 'Gene', '2260', (117, 122))	('AKT1', 'Gene', (46, 50))	('FGFR', 'molecular_function', 'GO:0005007', ('117', '121'))	('amplification', 'Var', (123, 136))	('PIK3CA', 'Gene', '5290', (80, 86))	('E17K mutation', 'Var', (51, 64))	('mutations', 'Var', (87, 96))
29147	23714731	The frequency of HER2 alterations in this study is higher than in prior sequencing studies of lobular breast cancer, and this may be due to the focus on relapsed cases or due to the requirement for E-cadherin (CDH1) mutations as an eligibility criteria.	('CDH1', 'Gene', (210, 214))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cadherin', 'molecular_function', 'GO:0008014', ('200', '208'))	('E-cadherin', 'Gene', (198, 208))	('E-cadherin', 'Gene', '999', (198, 208))	('CDH1', 'Gene', '999', (210, 214))	('HER2', 'Gene', (17, 21))	('alterations', 'Var', (22, 33))	('HER2', 'Gene', '2064', (17, 21))	('mutations', 'Var', (216, 225))	('lobular breast cancer', 'Disease', 'MESH:D013274', (94, 115))	('lobular breast cancer', 'Disease', (94, 115))
29148	23714731	The Cancer Genome Atlas study focused on newly diagnosed patients and reported a 9% frequency of HER2 mutations in lobular breast cancer.	('HER2', 'Gene', (97, 101))	('HER2', 'Gene', '2064', (97, 101))	('patients', 'Species', '9606', (57, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lobular breast cancer', 'Disease', 'MESH:D013274', (115, 136))	('lobular breast cancer', 'Disease', (115, 136))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (115, 136))
29149	23714731	If this difference in HER2 mutation frequencies between newly diagnosed and relapsed cases is reproduced by additional studies, then it would suggest that HER2 mutations increase the rate of breast cancer recurrence.	('HER2', 'Gene', '2064', (155, 159))	('mutations', 'Var', (160, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))	('increase', 'PosReg', (170, 178))	('HER2', 'Gene', (22, 26))	('HER2', 'Gene', '2064', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('HER2', 'Gene', (155, 159))
29151	23714731	It is pertinent to note that while HER2 mutations/gene fusions are enriched in lobular breast cancer in this study (23% in CDH1 mutated, lobular cases compared to 2% in ductal breast cancer cases), they are not exclusive to lobular breast cancer.	('HER2', 'Gene', '2064', (35, 39))	('mutations/gene fusions', 'Var', (40, 62))	('lobular breast cancer', 'Disease', 'MESH:D013274', (79, 100))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (79, 100))	('CDH1', 'Gene', '999', (123, 127))	('ductal breast cancer', 'Disease', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('CDH1', 'Gene', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('HER2', 'Gene', (35, 39))	('lobular breast cancer', 'Disease', (224, 245))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('ductal breast cancer', 'Disease', 'MESH:D001943', (169, 189))	('mutated', 'Var', (128, 135))	('lobular breast cancer', 'Disease', 'MESH:D013274', (224, 245))	('lobular breast cancer', 'Disease', (79, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (224, 245))
29152	23714731	The authors note that of the 10 breast cancer associated HER2 mutations that they identified in their sequencing studies, half are seen in CDH1 mutant, lobular breast cancer cases and the other half occur in ductal breast cancers.	('lobular breast cancer', 'Phenotype', 'HP:0006625', (152, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('HER2', 'Gene', '2064', (57, 61))	('breast cancers', 'Phenotype', 'HP:0003002', (215, 229))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('mutant', 'Var', (144, 150))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('breast cancer', 'Disease', (32, 45))	('ductal breast cancers', 'Disease', (208, 229))	('seen', 'Reg', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('CDH1', 'Gene', '999', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mutations', 'Var', (62, 71))	('HER2', 'Gene', (57, 61))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('CDH1', 'Gene', (139, 143))	('ductal breast cancers', 'Disease', 'MESH:D001943', (208, 229))	('lobular breast cancer', 'Disease', (152, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('lobular breast cancer', 'Disease', 'MESH:D013274', (152, 173))
29154	23714731	While functional studies on many of the actionable mutations have been previously published, the effects of the HER2-GRB7 gene fusion have not been tested.	('mutations', 'Var', (51, 60))	('GRB7', 'Gene', '2886', (117, 121))	('GRB7', 'Gene', (117, 121))	('HER2', 'Gene', (112, 116))	('HER2', 'Gene', '2064', (112, 116))
29157	23714731	The fusion of the GRB7 SH2 domain would then covalently link a downstream signaling protein to HER2.	('GRB7', 'Gene', '2886', (18, 22))	('GRB7', 'Gene', (18, 22))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('fusion', 'Var', (4, 10))	('HER2', 'Gene', (95, 99))	('HER2', 'Gene', '2064', (95, 99))	('link', 'Interaction', (56, 60))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))
29160	23714731	Targeting HER2 mutations with irreversible tyrosine kinase inhibitors is an attractive strategy and a phase II clinical trial using this approach is enrolling patients.1 Sequencing relapsed, lobular breast cancer patients for HER2 mutations, which will be missed by routine HER2 testing (immunohistochemistry or fluorescence in situ hybridization, FISH) will be important.	('lobular breast cancer', 'Disease', (191, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lobular breast cancer', 'Disease', 'MESH:D013274', (191, 212))	('mutations', 'Var', (231, 240))	('HER2', 'Gene', (274, 278))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (191, 212))	('HER2', 'Gene', (226, 230))	('HER2', 'Gene', '2064', (274, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))	('HER2', 'Gene', '2064', (226, 230))	('tyrosine', 'Chemical', 'MESH:D014443', (43, 51))	('patients', 'Species', '9606', (213, 221))	('HER2', 'Gene', (10, 14))	('patients', 'Species', '9606', (159, 167))	('HER2', 'Gene', '2064', (10, 14))
29161	23714731	Next-generation sequencing has the additional advantage of identifying other actionable targets, such as AKT1 or PIK3CA mutations and FGFR1 amplification.	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('PIK3CA', 'Gene', (113, 119))	('FGFR1', 'Gene', (134, 139))	('PIK3CA', 'Gene', '5290', (113, 119))	('FGFR1', 'Gene', '2260', (134, 139))	('amplification', 'Var', (140, 153))	('AKT1', 'Gene', '207', (105, 109))	('mutations', 'Var', (120, 129))	('AKT1', 'Gene', (105, 109))
29224	31061694	MMTV was found to be an RNA virus that can cause insertional mutations and activation of many proto-oncogenes in human organs.	('cause', 'Reg', (43, 48))	('insertional mutations', 'Var', (49, 70))	('activation', 'PosReg', (75, 85))	('proto-oncogenes', 'Gene', (94, 109))	('RNA', 'cellular_component', 'GO:0005562', ('24', '27'))	('MMTV', 'Species', '11757', (0, 4))	('human', 'Species', '9606', (113, 118))
29226	31061694	On the other hand, in vitro studies in animal models have shown that MMTV not only causes mammary tumors in inbred strains of mice, but it also induces lymphomas in these animals.	('MMTV', 'Species', '11757', (69, 73))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mice', 'Species', '10090', (126, 130))	('lymphomas', 'Disease', (152, 161))	('lymphomas', 'Disease', 'MESH:D008223', (152, 161))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('lymphomas', 'Phenotype', 'HP:0002665', (152, 161))	('MMTV', 'Var', (69, 73))	('induces', 'Reg', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('causes', 'Reg', (83, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (152, 160))
29227	31061694	One of the other hypothesis regarding multiple primary malignant neoplasm, as in our case, is that during fetal life the cells with somatic mutations migrate to different sites and organs of the body and later on, during adulthood, these cells become malignant, possibly secondary to environmental exposure.	('malignant neoplasm', 'Disease', 'MESH:D009369', (55, 73))	('malignant neoplasm', 'Disease', (55, 73))	('neoplasm', 'Phenotype', 'HP:0002664', (65, 73))	('mutations', 'Var', (140, 149))
29255	28894989	For immunofluorescence staining, non-specific epitopes were masked with 5% normal goat serum (NGS) and 0.05% Tween-20 in 1x Tris-buffered saline (TBS), followed by incubation with primary antibody (beta-catenin, 1:100; vimentin, 1:400; pan-cytokeratin, 1:200; CD44, 1:300) for 18 h at 4  C, washed with TBS and incubated with secondary Alexa Fluor-conjugated antibodies (1:400) and DAPI (1 mug/ml) (1 h, RT).	('vimentin', 'Gene', (219, 227))	('antibody', 'cellular_component', 'GO:0042571', ('188', '196'))	('mug', 'molecular_function', 'GO:0043739', ('390', '393'))	('antibody', 'cellular_component', 'GO:0019815', ('188', '196'))	('goat', 'Species', '9925', (82, 86))	('TBS', 'Disease', (146, 149))	('TBS', 'Disease', (303, 306))	('DAPI', 'Chemical', 'MESH:C007293', (382, 386))	('beta-catenin', 'Gene', (198, 210))	('TBS', 'Disease', 'None', (303, 306))	('antibody', 'cellular_component', 'GO:0019814', ('188', '196'))	('vimentin', 'cellular_component', 'GO:0045098', ('219', '227'))	('TBS', 'Disease', 'None', (146, 149))	('antibody', 'molecular_function', 'GO:0003823', ('188', '196'))	('vimentin', 'cellular_component', 'GO:0045099', ('219', '227'))	('1:400', 'Var', (371, 376))	('beta-catenin', 'Gene', '1499', (198, 210))	('vimentin', 'Gene', '7431', (219, 227))
29283	28894989	To verify epithelial collective invasion irrespective of E-cadherin expression, we scored the presence of E-cadherin or, when E-cadherin was not detected, CD44 along cell-cell interactions within multicellular nests and strands in the peri-tumor fibrous or adipose tissue.	('tumor', 'Disease', (240, 245))	('CD44', 'Var', (155, 159))	('epithelia', 'Disease', 'None', (10, 19))	('epithelia', 'Disease', (10, 19))	('cadherin', 'molecular_function', 'GO:0008014', ('59', '67'))	('cadherin', 'molecular_function', 'GO:0008014', ('108', '116'))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('cadherin', 'molecular_function', 'GO:0008014', ('128', '136'))
29307	28894989	Consistently, distant metastasis-free survival was significantly reduced in patients with high CI scores (Fig.	('high', 'Var', (90, 94))	('patients', 'Species', '9606', (76, 84))	('reduced', 'NegReg', (65, 72))	('distant metastasis-free survival', 'CPA', (14, 46))
29315	28894989	The pattern of CD44-positive cell-cell interactions in ILC is consistent with an experimental ILC mouse model after somatic inactivation of the E-cadherin gene, where invading cells retain multicellular organization instead of disseminating individually.	('inactivation', 'Var', (124, 136))	('cadherin', 'molecular_function', 'GO:0008014', ('146', '154'))	('ILC', 'Disease', (55, 58))	('mouse', 'Species', '10090', (98, 103))
29474	27994939	For AL13-3 ER(+) IDC [Figure 6a], we observe no interactions involving phenotype 7 (ER low, HER2 medium, and PR high) or phenotype 8 (ER medium, HER2 medium, PR high), denoting a lack of ER(-)/PR(+) cells for this patient.	('HER2', 'Gene', (145, 149))	('patient', 'Species', '9606', (214, 221))	('HER2', 'Gene', '2064', (145, 149))	('AL13-3', 'Var', (4, 10))	('ER', 'Gene', '2099', (11, 13))	('HER2', 'Gene', '2064', (92, 96))	('interactions', 'Interaction', (48, 60))	('HER2', 'Gene', (92, 96))	('ER', 'Gene', '2099', (84, 86))	('PR', 'Gene', '5241', (193, 195))	('ER', 'Gene', '2099', (93, 95))	('ER', 'Gene', '2099', (146, 148))	('ER', 'Gene', '2099', (187, 189))	('PR', 'Gene', '5241', (109, 111))	('ER', 'Gene', '2099', (134, 136))	('PR', 'Gene', '5241', (158, 160))
29594	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))	('pure', 'molecular_function', 'GO:0034023', ('61', '65'))	('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))
29600	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))	('fibrocystic breasts', 'Disease', (76, 95))	('papillary breast carcinomas', 'Disease', 'MESH:D002291', (148, 175))	('ILC', 'Disease', (115, 118))	('fibrocystic breasts', 'Disease', 'MESH:D005348', (76, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('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))	('IDC', 'Gene', (108, 111))	('DCIS', 'Disease', (99, 103))
29649	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))
29663	15743508	Removal of CLDN4 disrupts fibril organization and increases junction permeability.	('fibril', 'cellular_component', 'GO:0099512', ('26', '32'))	('disrupts', 'NegReg', (17, 25))	('CLDN4', 'Gene', '1364', (11, 16))	('fibril organization', 'biological_process', 'GO:0097435', ('26', '45'))	('Removal', 'Var', (0, 7))	('fibril organization', 'MPA', (26, 45))	('increases', 'PosReg', (50, 59))	('junction permeability', 'MPA', (60, 81))	('CLDN4', 'Gene', (11, 16))
29671	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))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('83', '101'))	('CLDN4', 'Gene', '1364', (49, 54))	('tumour', 'Disease', (106, 112))	('CLDN1', 'Gene', (39, 44))	('CLDN4', 'Gene', (49, 54))
29782	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))
29833	21436945	Biologically ILC is more often PR+, ER+, diploid and HER-2, p53, and epidermal growth factor receptor (EPGFR) negative compared to IDC.	('IDC', 'Gene', (131, 134))	('HER-2', 'Gene', '2064', (53, 58))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('69', '92'))	('epidermal growth factor receptor', 'Gene', (69, 101))	('HER-2', 'Gene', (53, 58))	('p53', 'Gene', (60, 63))	('PR+', 'Var', (31, 34))	('ER+', 'Var', (36, 39))	('negative', 'NegReg', (110, 118))	('EPGFR', 'Gene', (103, 108))	('ILC', 'Disease', (13, 16))	('EPGFR', 'Gene', '1956', (103, 108))	('p53', 'Gene', '7157', (60, 63))	('epidermal growth factor receptor', 'Gene', '1956', (69, 101))	('IDC', 'Gene', '4000', (131, 134))	('diploid', 'Var', (41, 48))
29839	21436945	Based on this study, the presence of coarsely granular chromatin, nuclear size >44 microm2 and cell size > 82 microm2 are the only features diagnostic of ductal versus lobular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('cell size', 'CPA', (95, 104))	('coarsely granular chromatin', 'Protein', (37, 64))	('chromatin', 'cellular_component', 'GO:0000785', ('55', '64'))	('ductal versus lobular carcinoma', 'Disease', (154, 185))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (168, 185))	('nuclear size', 'CPA', (66, 78))	('ductal versus lobular carcinoma', 'Disease', 'MESH:D018299', (154, 185))	('> 82 microm2', 'Var', (105, 117))	('>44 microm2', 'Var', (79, 90))
29853	12402149	Oestrogen and progesterone receptors, tumour proliferative activity, the expression of cyclin A, p16ink4A, p27kip1, p21waf1, p53, bcl-2, and levels of vascular endothelial growth factor and hypoxia-inducible factor-1alpha (HIF-1alpha) were evaluated in 190 in ductal and 67 lobular carcinomas.	('cyclin', 'molecular_function', 'GO:0016538', ('87', '93'))	('bcl-2', 'Gene', '596', (130, 135))	('p16ink4A', 'Gene', (97, 105))	('vascular endothelial growth factor', 'Gene', '7422', (151, 185))	('lobular carcinomas', 'Disease', (274, 292))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('151', '185'))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (274, 292))	('vascular endothelial growth factor', 'Gene', (151, 185))	('HIF-1alpha', 'Gene', '3091', (223, 233))	('hypoxia-inducible factor-1alpha', 'Gene', (190, 221))	('p16ink4A', 'Gene', '1029', (97, 105))	('p21waf1', 'Var', (116, 123))	('ductal', 'Disease', (260, 266))	('p53', 'Gene', '7157', (125, 128))	('cyclin A', 'Gene', '890', (87, 95))	('progesterone receptor', 'Gene', (14, 35))	('bcl-2', 'Gene', (130, 135))	('HIF-1alpha', 'Gene', (223, 233))	('lobular carcinomas', 'Disease', 'MESH:D018275', (274, 292))	('progesterone receptor', 'Gene', '5241', (14, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('bcl-2', 'molecular_function', 'GO:0015283', ('130', '135'))	('carcinomas', 'Phenotype', 'HP:0030731', (282, 292))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('p53', 'Gene', (125, 128))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (190, 221))	('p27kip1', 'Gene', '1027', (107, 114))	('cyclin A', 'Gene', (87, 95))	('tumour', 'Disease', (38, 44))	('p27kip1', 'Gene', (107, 114))
29866	12402149	In an effort to obtain a more integrated understanding of the different breast cancer phenotypes, and to investigate whether bio-molecular profiles can distinguish between the two most common histotypes, we explored the inter-relations among several biologic variables (consolidated or of a more recent acquisition) related to hormone dependence (ER and PgR), proliferative activity potential (thymidine labelling index (TLI), cyclin A), cell-cycle and apoptosis control (p16ink4A, p27kip1, p21waf1, p53 and bcl-2) and angiogenesis (VEGF and hypoxia-inducible factor-1alpha (HIF-1alpha)) in IDC and ILC.	('PgR', 'Gene', '5241', (354, 357))	('p21waf1', 'Var', (491, 498))	('p53', 'Gene', '7157', (500, 503))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('bcl-2', 'Gene', (508, 513))	('apoptosis control', 'CPA', (453, 470))	('breast cancer', 'Disease', (72, 85))	('apoptosis', 'biological_process', 'GO:0097194', ('453', '462'))	('hypoxia-inducible factor-1alpha', 'Gene', (542, 573))	('apoptosis', 'biological_process', 'GO:0006915', ('453', '462'))	('HIF-1alpha', 'Gene', (575, 585))	('p53', 'Gene', (500, 503))	('VEGF', 'Gene', '7422', (533, 537))	('angiogenesis', 'biological_process', 'GO:0001525', ('519', '531'))	('p27kip1', 'Gene', '1027', (482, 489))	('bcl-2', 'Gene', '596', (508, 513))	('PgR', 'Gene', (354, 357))	('VEGF', 'Gene', (533, 537))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('IDC', 'Disease', (591, 594))	('p27kip1', 'Gene', (482, 489))	('p16ink4A', 'Gene', (472, 480))	('cell-cycle', 'biological_process', 'GO:0007049', ('438', '448'))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (542, 573))	('cell-cycle', 'CPA', (438, 448))	('thymidine', 'Chemical', 'MESH:D013936', (394, 403))	('cyclin A', 'Gene', '890', (427, 435))	('ILC', 'Disease', (599, 602))	('bcl-2', 'molecular_function', 'GO:0015283', ('508', '513'))	('cyclin', 'molecular_function', 'GO:0016538', ('427', '433'))	('p16ink4A', 'Gene', '1029', (472, 480))	('HIF-1alpha', 'Gene', '3091', (575, 585))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cyclin A', 'Gene', (427, 435))	('angiogenesis', 'CPA', (519, 531))
29870	12402149	The tumour specimen was in part incubated with 3H-thymidine, fixed in neutral 10% buffered formaldehyde and then processed for conventional histological procedures for proliferative activity determination according to Silvestrini et al (1994) and for the in situ evaluation of the expression of p53, bcl-2, p16ink4A, p21waf1, p27kip1 and cyclin A, in part frozen in liquid nitrogen and stored at -80 C for ER and PgR detection by ligand-binding assay, as previously described (Ronchi et al, 1986), and for the determination of VEGF and HIF-1alpha levels (Table 1).	('ligand', 'molecular_function', 'GO:0005488', ('430', '436'))	('PgR', 'Gene', (413, 416))	('p21waf1', 'Var', (317, 324))	('cyclin A', 'Gene', (338, 346))	('p53', 'Gene', '7157', (295, 298))	('p27kip1', 'Gene', '1027', (326, 333))	('VEGF', 'Gene', '7422', (527, 531))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('HIF-1alpha', 'Gene', (536, 546))	('bcl-2', 'Gene', (300, 305))	('p27kip1', 'Gene', (326, 333))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('3H-thymidine', 'Chemical', '-', (47, 59))	('tumour', 'Disease', (4, 10))	('VEGF', 'Gene', (527, 531))	('p53', 'Gene', (295, 298))	('PgR', 'Gene', '5241', (413, 416))	('bcl-2', 'molecular_function', 'GO:0015283', ('300', '305'))	('p16ink4A', 'Gene', (307, 315))	('binding', 'molecular_function', 'GO:0005488', ('437', '444'))	('bcl-2', 'Gene', '596', (300, 305))	('cyclin', 'molecular_function', 'GO:0016538', ('338', '344'))	('p16ink4A', 'Gene', '1029', (307, 315))	('HIF-1alpha', 'Gene', '3091', (536, 546))	('cyclin A', 'Gene', '890', (338, 346))
29874	12402149	Expression of the other cell cycle-related proteins was immunohistochemically detected using monoclonal antibodies against p16ink4A (Santa Cruz Biotechnology, Santa Cruz, CA, USA), p21waf1 (Calbiochem, La Jolla, CA, USA), p27kip1 (BD Transduction Laboratories, San Diego, CA, USA), and cyclin A (Novocastra Laboratories Ltd, Newcastle upon Tyne, UK) with dilutions, incubation times and procedures described in Table 1.	('p27kip1', 'Gene', '1027', (222, 229))	('p16ink4A', 'Gene', (123, 131))	('p16ink4A', 'Gene', '1029', (123, 131))	('p21waf1', 'Var', (181, 188))	('gain', 'Disease', 'MESH:D015430', (116, 120))	('p27kip1', 'Gene', (222, 229))	('cell cycle', 'biological_process', 'GO:0007049', ('24', '34'))	('gain', 'Disease', (116, 120))	('cyclin', 'molecular_function', 'GO:0016538', ('286', '292'))	('cyclin A', 'Gene', (286, 294))	('Transduction', 'biological_process', 'GO:0009293', ('234', '246'))	('cyclin A', 'Gene', '890', (286, 294))
29883	12402149	For p16ink4A, p21waf1, p27kip1 and cyclin A, we used cut-off values that in preliminary analyses provided relevant prognostic information (Daidone et al, 2000b).	('p16ink4A', 'Gene', '1029', (4, 12))	('p21waf1', 'Var', (14, 21))	('p16ink4A', 'Gene', (4, 12))	('cyclin', 'molecular_function', 'GO:0016538', ('35', '41'))	('p27kip1', 'Gene', (23, 30))	('cyclin A', 'Gene', (35, 43))	('p27kip1', 'Gene', '1027', (23, 30))	('cyclin A', 'Gene', '890', (35, 43))
29888	12402149	Conversely, no difference was found between ILC and IDC considering the frequency distribution of PgR, p16ink4A, p27kip1, p21waf1, bcl-2 and HIF-1alpha protein expression.	('HIF-1alpha', 'Gene', (141, 151))	('p16ink4A', 'Gene', (103, 111))	('p27kip1', 'Gene', (113, 120))	('p16ink4A', 'Gene', '1029', (103, 111))	('PgR', 'Gene', '5241', (98, 101))	('bcl-2', 'molecular_function', 'GO:0015283', ('131', '136'))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('bcl-2', 'Gene', '596', (131, 136))	('bcl-2', 'Gene', (131, 136))	('PgR', 'Gene', (98, 101))	('p27kip1', 'Gene', '1027', (113, 120))	('HIF-1alpha', 'Gene', '3091', (141, 151))	('p21waf1', 'Var', (122, 129))
29891	12402149	p21waf1 was directly related to TLI (P=0.002) and cyclin A expression (P=0.02).	('p21waf1', 'Var', (0, 7))	('cyclin A', 'Gene', (50, 58))	('cyclin A', 'Gene', '890', (50, 58))	('TLI', 'Disease', (32, 35))	('cyclin', 'molecular_function', 'GO:0016538', ('50', '56'))
29897	12402149	Conversely, a direct correlation between p21waf1 and cyclin A (P=0.03), between p16ink4A and tumour size (P=0.03), between VEGF and HIF-1alpha (P=0.05) and between p27kip1 and ER (P=0.05) was present only in ILC.	('cyclin A', 'Gene', (53, 61))	('p27kip1', 'Gene', '1027', (164, 171))	('tumour', 'Disease', (93, 99))	('p21waf1', 'Var', (41, 48))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('cyclin A', 'Gene', '890', (53, 61))	('VEGF', 'Gene', '7422', (123, 127))	('HIF-1alpha', 'Gene', (132, 142))	('VEGF', 'Gene', (123, 127))	('p27kip1', 'Gene', (164, 171))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('p16ink4A', 'Gene', (80, 88))	('p16ink4A', 'Gene', '1029', (80, 88))	('cyclin', 'molecular_function', 'GO:0016538', ('53', '59'))	('HIF-1alpha', 'Gene', '3091', (132, 142))
29922	12402149	Mutation of the p53 gene and the generation of a nonfunctional protein that accumulates in the cell both inhibit the formation of the complex and result in the constitutive availability of the transcription factor and the subsequent transactivation of the VEGF gene (Ravi et al, 2000).	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('formation of the complex', 'MPA', (117, 141))	('constitutive availability', 'MPA', (160, 185))	('VEGF', 'Gene', '7422', (256, 260))	('transactivation', 'biological_process', 'GO:2000144', ('233', '248'))	('inhibit', 'NegReg', (105, 112))	('transcription factor', 'molecular_function', 'GO:0000981', ('193', '213'))	('p53', 'Gene', (16, 19))	('Mutation', 'Var', (0, 8))	('transactivation', 'PosReg', (233, 248))	('p53', 'Gene', '7157', (16, 19))	('VEGF', 'Gene', (256, 260))	('transcription', 'biological_process', 'GO:0006351', ('193', '206'))	('formation', 'biological_process', 'GO:0009058', ('117', '126'))
29927	31028995	A full multidisciplinary team is crucial for the management of patients with CDH1 mutation.	('mutation', 'Var', (82, 90))	('CDH1', 'Gene', (77, 81))	('CDH1', 'Gene', '999', (77, 81))	('patients', 'Species', '9606', (63, 71))
29928	31028995	Germline CDH1 mutations, classically associated with hereditary diffuse gastric cancer (HDGC), also imply an increased lifetime risk of developing lobular breast cancer (LBC) in a highly penetrant autosomal dominant manner.	('HDGC', 'Disease', (88, 92))	('LBC', 'Disease', (170, 173))	('lobular breast cancer', 'Disease', (147, 168))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (53, 86))	('lobular breast cancer', 'Disease', 'MESH:D013274', (147, 168))	('HDGC', 'Disease', 'MESH:D013274', (88, 92))	('hereditary diffuse gastric cancer', 'Disease', (53, 86))	('CDH1', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('LBC', 'Disease', 'MESH:D013274', (170, 173))	('associated', 'Reg', (37, 47))	('CDH1', 'Gene', '999', (9, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (147, 168))	('mutations', 'Var', (14, 23))	('LBC', 'Phenotype', 'HP:0006625', (170, 173))
29929	31028995	We report a 44-year-old woman CDH1 mutation carrier with a strong family history of cancer, who previously had prophylactic total gastrectomy.	('CDH1', 'Gene', '999', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('carrier', 'molecular_function', 'GO:0005215', ('44', '51'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('woman', 'Species', '9606', (24, 29))	('mutation', 'Var', (35, 43))	('CDH1', 'Gene', (30, 34))
29932	31028995	The current consensus guidelines for women with pathogenic CDH1 mutations recommend annual mammography, ultrasound, breast MRI scans and clinical breast examination starting at the age of 35.	('women', 'Species', '9606', (37, 42))	('CDH1', 'Gene', '999', (59, 63))	('mutations', 'Var', (64, 73))	('pathogenic', 'Reg', (48, 58))	('CDH1', 'Gene', (59, 63))
29934	31028995	Conflicting evidences and lacking data about the benefits in terms of overall survival, disease-free survival and the long-term outcomes related to prophylactic bilateral mastectomy for CDH1 mutation carriers restrict the instruction for this type of procedure to selected cases, which should always be managed by a multidisciplinary team.	('CDH1', 'Gene', (186, 190))	('CDH1', 'Gene', '999', (186, 190))	('mutation carriers', 'Var', (191, 208))	('carriers', 'Var', (200, 208))
29936	31028995	An important role is played by genetic factors, up to 25% of hereditary cases is due to mutations of highly penetrant genes, such as BRCA1, BRCA2, CDH1, PTEN, TP53 and STK11, each one regulating a specific clinical syndrome.	('CDH1', 'Gene', '999', (147, 151))	('due', 'Reg', (81, 84))	('mutations', 'Var', (88, 97))	('PTEN', 'Gene', (153, 157))	('STK11', 'Gene', (168, 173))	('TP53', 'Gene', '7157', (159, 163))	('BRCA2', 'Gene', (140, 145))	('TP53', 'Gene', (159, 163))	('PTEN', 'Gene', '5728', (153, 157))	('BRCA1', 'Gene', '672', (133, 138))	('STK11', 'molecular_function', 'GO:0033868', ('168', '173'))	('STK11', 'Gene', '6794', (168, 173))	('BRCA1', 'Gene', (133, 138))	('CDH1', 'Gene', (147, 151))	('BRCA2', 'Gene', '675', (140, 145))
29937	31028995	In particular, the lifetime risk of developing hereditary diffuse gastric cancer (HDGC) and lobular breast cancer (LBC) in CDH1 mutation carriers has been estimated to be 80% and 60% respectively.	('LBC', 'Disease', (115, 118))	('CDH1', 'Gene', '999', (123, 127))	('lobular breast cancer', 'Disease', 'MESH:D013274', (92, 113))	('lobular breast cancer', 'Disease', (92, 113))	('HDGC', 'Disease', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (92, 113))	('LBC', 'Disease', 'MESH:D013274', (115, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (47, 80))	('HDGC', 'Disease', 'MESH:D013274', (82, 86))	('mutation', 'Var', (128, 136))	('CDH1', 'Gene', (123, 127))	('LBC', 'Phenotype', 'HP:0006625', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('hereditary diffuse gastric cancer', 'Disease', (47, 80))
29939	31028995	CDH1 mutation is involved in the loss of E-Cadherin expression, which leads to disruption of cell-binding complexes.	('Cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('CDH1', 'Gene', '999', (0, 4))	('loss', 'NegReg', (33, 37))	('disruption of', 'MPA', (79, 92))	('expression', 'MPA', (52, 62))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('E-Cadherin', 'Gene', (41, 51))	('cell-binding', 'Interaction', (93, 105))	('E-Cadherin', 'Gene', '999', (41, 51))	('mutation', 'Var', (5, 13))	('CDH1', 'Gene', (0, 4))
29941	31028995	In this report we describe our experience in CDH1 mutation carriers management, not well-established in literature yet.	('CDH1', 'Gene', '999', (45, 49))	('mutation', 'Var', (50, 58))	('CDH1', 'Gene', (45, 49))
29942	31028995	Our study outlines how pathogenic CDH1 mutation correlates closely with LBC and that enables an invasive procedure such as bilateral prophylactic mastectomy.	('mutation', 'Var', (39, 47))	('CDH1', 'Gene', '999', (34, 38))	('LBC', 'Disease', 'MESH:D013274', (72, 75))	('LBC', 'Phenotype', 'HP:0006625', (72, 75))	('enables', 'Reg', (85, 92))	('LBC', 'Disease', (72, 75))	('CDH1', 'Gene', (34, 38))
29943	31028995	A 44-year-old woman with an inherited pathogenic CDH1 mutation visited our department asking for a bilateral prophylactic mastectomy.	('mutation', 'Var', (54, 62))	('CDH1', 'Gene', (49, 53))	('CDH1', 'Gene', '999', (49, 53))	('woman', 'Species', '9606', (14, 19))	('pathogenic', 'Reg', (38, 48))
29949	31028995	She had also been tested for BRCA mutations with negative results.	('mutations', 'Var', (34, 43))	('BRCA', 'Gene', (29, 33))	('BRCA', 'Gene', '672', (29, 33))
29959	31028995	The aggressive behavior of invasive lobular carcinoma combined with the high penetrance of CDH1 mutations justifies breast Risk-Reducing options.	('CDH1', 'Gene', '999', (91, 95))	('invasive lobular carcinoma', 'Disease', (27, 53))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (27, 53))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (36, 53))	('aggressive behavior', 'biological_process', 'GO:0002118', ('4', '23'))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('CDH1', 'Gene', (91, 95))	('aggressive behavior', 'Phenotype', 'HP:0000718', (4, 23))	('mutations', 'Var', (96, 105))
29960	31028995	The current consensus guidelines for CDH1 mutation carriers recommend annual mammography, ultrasound and breast MRI scans, combined with clinical breast exam starting at the age of 35.3,20, Benign lesion (ALH and LCIS) are usually estrogen-receptor-positive and/or progesterone-receptor-positive and human epidermal growth factor receptor 2-negative.	('Benign lesion', 'Disease', 'MESH:D051437', (190, 203))	('LCIS', 'Phenotype', 'HP:0030076', (213, 217))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('306', '329'))	('Benign lesion', 'Disease', (190, 203))	('human', 'Species', '9606', (300, 305))	('mutation', 'Var', (42, 50))	('CDH1', 'Gene', (37, 41))	('CDH1', 'Gene', '999', (37, 41))
29965	31028995	The lack of data about the risk of developing breast cancer in CDH1 mutation carriers brings risk-reducing surgery currently under discussion.	('CDH1', 'Gene', (63, 67))	('mutation', 'Var', (68, 76))	('CDH1', 'Gene', '999', (63, 67))	('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))
29967	31028995	Moreover, the young onset of malignant breast neoplasia associated with a genetic susceptibility led the American Society of Breast Surgeons (ASCO), the Society of Surgical Oncology (SSO) and the NCCN breast cancer risk-reduction Guidelines to regard bilateral risk-reducing mastectomy as a reasonable option for women with deleterious mutations in BRCA1, BRCA2, CDH1, TP53, PALB2, STK11 or PTEN.	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('CDH1', 'Gene', (363, 367))	('STK11', 'molecular_function', 'GO:0033868', ('382', '387'))	('STK11', 'Gene', (382, 387))	('TP53', 'Gene', (369, 373))	('BRCA2', 'Gene', (356, 361))	('PTEN', 'Gene', (391, 395))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('Oncology', 'Phenotype', 'HP:0002664', (173, 181))	('breast neoplasia', 'Phenotype', 'HP:0100013', (39, 55))	('neoplasia', 'Phenotype', 'HP:0002664', (46, 55))	('malignant breast neoplasia', 'Disease', 'MESH:D001943', (29, 55))	('women', 'Species', '9606', (313, 318))	('PTEN', 'Gene', '5728', (391, 395))	('BRCA1', 'Gene', '672', (349, 354))	('STK11', 'Gene', '6794', (382, 387))	('NCCN breast cancer', 'Disease', 'MESH:D001943', (196, 214))	('BRCA2', 'Gene', '675', (356, 361))	('NCCN breast cancer', 'Disease', (196, 214))	('PALB2', 'Gene', (375, 380))	('BRCA1', 'Gene', (349, 354))	('malignant breast neoplasia', 'Disease', (29, 55))	('TP53', 'Gene', '7157', (369, 373))	('mutations', 'Var', (336, 345))	('PALB2', 'Gene', '79728', (375, 380))	('CDH1', 'Gene', '999', (363, 367))
29968	31028995	The prophylactic surgery procedure has been demostrated to confer survival benefits in CDH1 mutation carriers even if it doesn't completely eliminate breast cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('mutation', 'Var', (92, 100))	('CDH1', 'Gene', (87, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('CDH1', 'Gene', '999', (87, 91))	('benefits', 'PosReg', (75, 83))	('survival', 'CPA', (66, 74))
29972	31028995	Pathogenic mutation carriers prefer these complications rather than the fear of developing breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('mutation', 'Var', (11, 19))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
29981	31028995	To this day there is no uniformly accepted indication to perform prophylactic mastectomy in CDH1 mutation carriers: current consensus guidelines often recommended breast surveillance.	('breast surveillance', 'Disease', (163, 182))	('CDH1', 'Gene', (92, 96))	('mutation', 'Var', (97, 105))	('carriers', 'Reg', (106, 114))	('CDH1', 'Gene', '999', (92, 96))
30020	30100081	In some cases, 11C-methionine even outperformed 18F-FDG.	('11C-methionine', 'Chemical', '-', (15, 29))	('18F-FDG', 'Chemical', 'MESH:D019788', (48, 55))	('11C-methionine', 'Var', (15, 29))	('outperformed', 'NegReg', (35, 47))
30022	30100081	Physiologic sites of uptake of 11C-methionine include the liver and bone marrow, which could limit evaluation of breast cancer metastases.	('breast cancer metastases', 'Disease', 'MESH:D009362', (113, 137))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('uptake', 'biological_process', 'GO:0098739', ('21', '27'))	('uptake', 'biological_process', 'GO:0098657', ('21', '27'))	('11C-methionine', 'Var', (31, 45))	('11C-methionine', 'Chemical', '-', (31, 45))	('breast cancer metastases', 'Disease', (113, 137))
30050	30100081	A direct comparison of 18F-fluciclovine and FDG for metastatic ILC could provide evidence of where 18F-fluciclovine may improve staging in ILC.	('18F-fluciclovine', 'Var', (99, 115))	('18F-fluciclovine', 'Chemical', 'MESH:C117460', (99, 115))	('18F-fluciclovine', 'Chemical', 'MESH:C117460', (23, 39))	('improve', 'PosReg', (120, 127))	('ILC', 'Disease', (139, 142))	('staging', 'MPA', (128, 135))
30060	30100081	Multiple radiolabeled tyrosine analogs have been developed for tumor imaging, including L-[1-11C]tyrosine.	('tumor', 'Disease', (63, 68))	('tyrosine', 'Chemical', 'MESH:D014443', (97, 105))	('tyrosine', 'Chemical', 'MESH:D014443', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('L-[1-11C]tyrosine', 'Var', (88, 105))	('L-[1-11C]tyrosine', 'Chemical', '-', (88, 105))
30061	30100081	L-[1-11C]tyrosine successfully demonstrated uptake in breast malignancies and had lower uptake than 18F-FDG in a limited number of benign lesions.	('uptake', 'biological_process', 'GO:0098739', ('88', '94'))	('L-[1-11C]tyrosine', 'Var', (0, 17))	('uptake', 'MPA', (88, 94))	('L-[1-11C]tyrosine', 'Chemical', '-', (0, 17))	('breast malignancies', 'Disease', (54, 73))	('uptake', 'biological_process', 'GO:0098657', ('44', '50'))	('uptake', 'biological_process', 'GO:0098739', ('44', '50'))	('uptake', 'MPA', (44, 50))	('18F-FDG', 'Chemical', 'MESH:D019788', (100, 107))	('breast malignancies', 'Disease', 'MESH:D001943', (54, 73))	('uptake', 'biological_process', 'GO:0098657', ('88', '94'))
30115	30151336	The 1D5 monoclonal antibody against the estrogen receptors M7047 (diluted at 1 : 100, Dako, Glostrup, Denmark) and the NCL monoclonal antibody against the progesterone receptors M3569 (diluted at 1 : 100, Novocastra, Newcastle, England) were used in the IHC determination of the ERs and PRs.	('antibody', 'cellular_component', 'GO:0019814', ('134', '142'))	('antibody', 'cellular_component', 'GO:0019815', ('134', '142'))	('NCL', 'Gene', '4691', (119, 122))	('NCL', 'Gene', (119, 122))	('antibody', 'cellular_component', 'GO:0019815', ('19', '27'))	('antibody', 'molecular_function', 'GO:0003823', ('134', '142'))	('antibody', 'cellular_component', 'GO:0019814', ('19', '27'))	('antibody', 'molecular_function', 'GO:0003823', ('19', '27'))	('antibody', 'cellular_component', 'GO:0042571', ('134', '142'))	('M7047', 'Var', (59, 64))	('antibody', 'cellular_component', 'GO:0042571', ('19', '27'))
30131	30151336	The whole sections of the tumor tissue were examined by two independent examiners (Ivana Mise and Majda Vucic) at the magnification of x40 and x100, and then most of the preparation or at least 2000 cells at the magnification of x400.	('x40', 'Var', (135, 138))	('Mise', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('x100', 'Var', (143, 147))	('Mise', 'Gene', '58493', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
30203	30151336	Moreover, the frequent and strong Sdc1 expression in the nodal metastasis (found in almost 90% of cases) assumes a very high probability of further disintegration of the malignant cells, and it presents a significant source of the new metastases.	('metastases', 'Disease', (235, 245))	('Sdc1', 'Gene', (34, 38))	('metastases', 'Disease', 'MESH:D009362', (235, 245))	('expression', 'Var', (39, 49))
30293	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.	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('105', '123'))	('binding', 'molecular_function', 'GO:0005488', ('128', '135'))	('E-cadherin', 'Gene', (20, 30))	('alpha', 'Protein', (139, 144))	('E-cadherin', 'Gene', '999', (20, 30))	('adherens junction', 'cellular_component', 'GO:0005912', ('63', '80'))	('binding', 'Interaction', (128, 135))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('LCIS', 'Phenotype', 'HP:0030076', (188, 192))	('Inactivation', 'Var', (0, 12))	('cadherin', 'molecular_function', 'GO:0008014', ('22', '30'))
30315	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))	('growth pattern', 'biological_process', 'GO:0040007', ('125', '139'))	('growth pattern', 'biological_process', 'GO:0007150', ('125', '139'))	('MMP9', 'molecular_function', 'GO:0004229', ('61', '65'))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (152, 169))	("'Indian file' growth pattern", 'MPA', (111, 139))	('MMP9', 'Gene', (61, 65))	('invasive lobular carcinoma', 'Disease', (143, 169))
30381	23849133	Synchronous appendiceal and intramucosal gastric signet ring cell carcinomas in an individual with CDH1-associated hereditary diffuse gastric carcinoma: a case report of a novel association and review of the literature Hereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome associated with mutations of the E-cadherin gene (CDH1).	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('CDH1', 'Gene', '999', (347, 351))	('E-cadherin', 'Gene', (330, 340))	('intramucosal gastric signet ring cell carcinomas', 'Disease', (28, 76))	('gastric carcinoma', 'Disease', 'MESH:D013274', (238, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('gastric carcinoma', 'Disease', 'MESH:D013274', (134, 151))	('E-cadherin', 'Gene', '999', (330, 340))	('autosomal dominant cancer syndrome', 'Disease', 'MESH:D009386', (262, 296))	('gastric carcinoma', 'Disease', (238, 255))	('CDH1', 'Gene', (347, 351))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('gastric carcinoma', 'Disease', (134, 151))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (238, 255))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (134, 151))	('CDH1', 'Gene', '999', (99, 103))	('autosomal dominant cancer syndrome', 'Disease', (262, 296))	('associated', 'Reg', (297, 307))	('CDH1', 'Gene', (99, 103))	('mutations', 'Var', (313, 322))	('intramucosal gastric signet ring cell carcinomas', 'Disease', 'MESH:D018279', (28, 76))	('cadherin', 'molecular_function', 'GO:0008014', ('332', '340'))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
30384	23849133	A 51- year old woman, with known CDH1 mutation carrier status and a prior history of lobular breast carcinoma underwent prophylactic total gastrectomy which revealed multifocal intramucosal signet ring cell carcinoma.	('woman', 'Species', '9606', (15, 20))	('carrier', 'molecular_function', 'GO:0005215', ('47', '54'))	('multifocal intramucosal signet ring cell carcinoma', 'Disease', (166, 216))	('breast carcinoma', 'Phenotype', 'HP:0003002', (93, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('CDH1', 'Gene', (33, 37))	('lobular breast carcinoma', 'Disease', (85, 109))	('mutation', 'Var', (38, 46))	('multifocal intramucosal signet ring cell carcinoma', 'Disease', 'MESH:D018279', (166, 216))	('CDH1', 'Gene', '999', (33, 37))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (85, 109))
30387	23849133	Hereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome accounting for approximately 1 to 3% of all gastric carcinoma, associated with mutations of the E-cadherin (Cadherin-1; CDH1) gene.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('Cadherin', 'molecular_function', 'GO:0008014', ('186', '194'))	('CDH1', 'Gene', (198, 202))	('Cadherin-1', 'Gene', '999', (186, 196))	('autosomal dominant cancer syndrome', 'Disease', (43, 77))	('mutations', 'Var', (157, 166))	('associated', 'Reg', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Cadherin-1', 'Gene', (186, 196))	('cadherin', 'molecular_function', 'GO:0008014', ('176', '184'))	('gastric carcinoma', 'Disease', 'MESH:D013274', (19, 36))	('gastric carcinoma', 'Disease', 'MESH:D013274', (122, 139))	('gastric carcinoma', 'Disease', (19, 36))	('gastric carcinoma', 'Disease', (122, 139))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (19, 36))	('E-cadherin', 'Gene', (174, 184))	('autosomal dominant cancer syndrome', 'Disease', 'MESH:D009386', (43, 77))	('E-cadherin', 'Gene', '999', (174, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (122, 139))	('CDH1', 'Gene', '999', (198, 202))
30392	23849133	Additional clinical indications for genetic testing for CDH1 mutations include: HDGC in two relatives with histologic confirmation of tumor in only one individual, diffuse gastric carcinoma in an individual < 40 years regardless of family history, or individuals and families with both signet ring cell gastric carcinoma (including one case before 50 years of age) and lobular breast carcinoma.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (303, 320))	('ring cell gastric carcinoma', 'Disease', 'MESH:D013274', (293, 320))	('CDH1', 'Gene', (56, 60))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (369, 393))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('breast carcinoma', 'Phenotype', 'HP:0003002', (377, 393))	('lobular breast carcinoma', 'Disease', (369, 393))	('ring cell gastric carcinoma', 'Disease', (293, 320))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('gastric carcinoma', 'Disease', 'MESH:D013274', (172, 189))	('mutations', 'Var', (61, 70))	('gastric carcinoma', 'Disease', (172, 189))	('HDGC', 'Disease', (80, 84))	('tumor', 'Disease', (134, 139))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (172, 189))	('CDH1', 'Gene', '999', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('gastric carcinoma', 'Disease', 'MESH:D013274', (303, 320))	('carcinoma', 'Phenotype', 'HP:0030731', (384, 393))
30395	23849133	Unfortunately, the insidious and multifocal nature of early signet ring cell carcinoma diminishes the sensitivity of endoscopic detection with current techniques, and prophylactic gastrectomy should be considered for any individual with a CDH1 mutation, regardless of the results of endoscopic surveillance.	('sensitivity', 'MPA', (102, 113))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('diminishes', 'NegReg', (87, 97))	('mutation', 'Var', (244, 252))	('CDH1', 'Gene', (239, 243))	('CDH1', 'Gene', '999', (239, 243))	('carcinoma', 'Disease', (77, 86))
30398	23849133	Female carriers of the CDH1 mutation also have a predisposition for lobular breast carcinoma.	('breast carcinoma', 'Phenotype', 'HP:0003002', (76, 92))	('mutation', 'Var', (28, 36))	('CDH1', 'Gene', (23, 27))	('lobular breast carcinoma', 'Disease', (68, 92))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('CDH1', 'Gene', '999', (23, 27))
30405	23849133	With respect to the molecular pathogenesis of HDGC, it is not surprising that the CDH1 mutation predisposes to malignancies with a dyshesive signet ring cell morphology such as diffuse gastric carcinoma and lobular breast carcinoma.	('lobular breast carcinoma', 'Disease', (207, 231))	('gastric carcinoma', 'Disease', 'MESH:D013274', (185, 202))	('breast carcinoma', 'Phenotype', 'HP:0003002', (215, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (207, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('gastric carcinoma', 'Disease', (185, 202))	('CDH1', 'Gene', '999', (82, 86))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (185, 202))	('pathogenesis', 'biological_process', 'GO:0009405', ('30', '42'))	('mutation', 'Var', (87, 95))	('CDH1', 'Gene', (82, 86))	('predisposes', 'Reg', (96, 107))	('malignancies', 'Disease', (111, 123))
30406	23849133	Approximately 25-50% of families with HDGC syndrome have an inactivating germline mutation of the tumor suppressor gene Cadherin-1 (CDH1) that encodes E-cadherin.	('Cadherin-1', 'Gene', '999', (120, 130))	('tumor', 'Disease', (98, 103))	('CDH1', 'Gene', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('inactivating', 'Var', (60, 72))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CDH1', 'Gene', '999', (132, 136))	('Cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('HDGC syndrome', 'Disease', (38, 51))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('E-cadherin', 'Gene', (151, 161))	('Cadherin-1', 'Gene', (120, 130))	('HDGC syndrome', 'Disease', 'MESH:D013274', (38, 51))	('cadherin', 'molecular_function', 'GO:0008014', ('153', '161'))	('E-cadherin', 'Gene', '999', (151, 161))
30409	23849133	When CDH1 is mutated, there is loss of normal cell adhesion and cell polarity; disaggregation of cells also promotes local invasion and metastases of neoplastic cells, and loss of CDH1 is a common molecular event in advanced sporadic malignancies.	('cell polarity', 'biological_process', 'GO:0007163', ('64', '77'))	('CDH1', 'Gene', '999', (5, 9))	('malignancies', 'Disease', 'MESH:D009369', (234, 246))	('loss', 'Var', (172, 176))	('local invasion', 'CPA', (117, 131))	('CDH1', 'Gene', (180, 184))	('CDH1', 'Gene', (5, 9))	('malignancies', 'Disease', (234, 246))	('metastases', 'Disease', (136, 146))	('promotes', 'PosReg', (108, 116))	('CDH1', 'Gene', '999', (180, 184))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('mutated', 'Var', (13, 20))	('cell adhesion', 'biological_process', 'GO:0007155', ('46', '59'))
30410	23849133	Somatic inactivation of the second allele is thought to result from promoter hypermethylation, mutations of CDH1, or loss of heterozygosity.	('CDH1', 'Gene', (108, 112))	('loss of heterozygosity', 'Var', (117, 139))	('CDH1', 'Gene', '999', (108, 112))	('mutations', 'Var', (95, 104))	('promoter', 'MPA', (68, 76))
30412	23849133	Interestingly, one genetic study of HDGC kindreds found one family with an intact second CDH-1 allele and detectable E-cadherin protein in neoplastic cells, and postulated that a 50% reduction in CDH-1 function may be enough to promote tumorigenesis; other explanations include: a dominant-negative effect of the germline mutation or a missense mutation of the wild-type allele.	('CDH-1', 'Gene', (89, 94))	('reduction', 'NegReg', (183, 192))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('function', 'MPA', (202, 210))	('CDH-1', 'Gene', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('E-cadherin', 'Gene', '999', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('CDH-1', 'Gene', '999', (89, 94))	('cadherin', 'molecular_function', 'GO:0008014', ('119', '127'))	('CDH-1', 'Gene', '999', (196, 201))	('germline mutation', 'Var', (313, 330))	('E-cadherin', 'Gene', (117, 127))	('tumor', 'Disease', (236, 241))	('missense mutation', 'Var', (336, 353))	('promote', 'PosReg', (228, 235))
30413	23849133	Furthermore, 50% of sporadic cases of diffuse gastric carcinoma and lobular breast carcinoma are also associated with inactivation of CDH1 and loss of E-cadherin expression, most frequently through promoter methylation; this event appears to be critical for the development of tumors with this unique morphologic phenotype.	('CDH1', 'Gene', '999', (134, 138))	('promoter methylation', 'Var', (198, 218))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('gastric carcinoma', 'Disease', 'MESH:D013274', (46, 63))	('lobular breast carcinoma', 'Disease', (68, 92))	('gastric carcinoma', 'Disease', (46, 63))	('CDH1', 'Gene', (134, 138))	('tumors', 'Disease', (277, 283))	('breast carcinoma', 'Phenotype', 'HP:0003002', (76, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (46, 63))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('loss', 'NegReg', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('methylation', 'biological_process', 'GO:0032259', ('207', '218'))	('inactivation', 'Var', (118, 130))	('expression', 'MPA', (162, 172))	('E-cadherin', 'Gene', (151, 161))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (68, 92))	('cadherin', 'molecular_function', 'GO:0008014', ('153', '161'))	('E-cadherin', 'Gene', '999', (151, 161))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
30417	23849133	Several studies have documented mutations of CDH1 in cell lines and tissue samples from colorectal carcinoma, albeit rarely.	('CDH1', 'Gene', '999', (45, 49))	('colorectal carcinoma', 'Disease', (88, 108))	('mutations', 'Var', (32, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (88, 108))	('CDH1', 'Gene', (45, 49))
30418	23849133	Only three of these studies correlated the expression of E-cadherin with the morphology of the carcinoma from which the cell line/tissue sample was derived; as expected, loss of expression of E-cadherin typically correlated with a poorly differentiated/signet ring cell growth pattern.	('carcinoma', 'Disease', (95, 104))	('growth pattern', 'biological_process', 'GO:0040007', ('270', '284'))	('loss of', 'Var', (170, 177))	('expression', 'MPA', (178, 188))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '999', (57, 67))	('carcinoma', 'Disease', 'MESH:D002277', (95, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cadherin', 'molecular_function', 'GO:0008014', ('59', '67'))	('E-cadherin', 'Gene', (192, 202))	('E-cadherin', 'Gene', '999', (192, 202))	('cell growth', 'biological_process', 'GO:0016049', ('265', '276'))	('correlated', 'Reg', (213, 223))	('growth pattern', 'biological_process', 'GO:0007150', ('270', '284'))	('cadherin', 'molecular_function', 'GO:0008014', ('194', '202'))
30419	23849133	Alteration of the association between E-cadherin and beta-catenin may represent an alternative tumorigenesis pathway to inactivation of the APC gene in the HDGC cohort.	('inactivation', 'Var', (120, 132))	('Alteration', 'Var', (0, 10))	('APC', 'Gene', (140, 143))	('APC', 'Gene', '324', (140, 143))	('association', 'Interaction', (18, 29))	('beta-catenin', 'Gene', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('E-cadherin', 'Gene', (38, 48))	('APC', 'cellular_component', 'GO:0005680', ('140', '143'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))	('E-cadherin', 'Gene', '999', (38, 48))	('beta-catenin', 'Gene', '1499', (53, 65))	('HDGC', 'Disease', (156, 160))	('tumor', 'Disease', (95, 100))
30420	23849133	In the English literature, there are at least twenty-six reported cases of colorectal carcinoma occurring in CDH1-associated HDGC kindreds; an additional eight cases of colorectal carcinoma exist in families with a history of diffuse gastric carcinoma that have tested negative for CDH1 mutations and did not meet the criteria for hereditary nonpolyposis colon cancer (HNPCC).	('hereditary nonpolyposis colon cancer', 'Disease', 'MESH:D003123', (331, 367))	('mutations', 'Var', (287, 296))	('CDH1', 'Gene', (109, 113))	('diffuse', 'Disease', (226, 233))	('colorectal carcinoma', 'Disease', (75, 95))	('hereditary nonpolyposis colon cancer', 'Phenotype', 'HP:0006716', (331, 367))	('CDH1', 'Gene', '999', (282, 286))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (75, 95))	('HNPCC', 'Gene', (369, 374))	('colorectal carcinoma', 'Disease', (169, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('gastric carcinoma', 'Disease', 'MESH:D013274', (234, 251))	('HNPCC', 'Gene', '4436', (369, 374))	('CDH1', 'Gene', (282, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('HNPCC', 'Phenotype', 'HP:0006716', (369, 374))	('gastric carcinoma', 'Disease', (234, 251))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (169, 189))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (234, 251))	('colon cancer', 'Phenotype', 'HP:0003003', (355, 367))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('hereditary nonpolyposis colon cancer', 'Disease', (331, 367))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('CDH1', 'Gene', '999', (109, 113))
30424	23849133	Of reported cases, only one has been diagnosed as a signet ring cell carcinoma; there is at least one additional case of a colonic signet ring cell carcinoma occurring in a family with familial gastric carcinoma that tested negative for the CDH1 mutation (and negative for HNPCC).	('carcinoma', 'Disease', (202, 211))	('colonic signet ring cell carcinoma', 'Disease', 'MESH:D018279', (123, 157))	('colonic signet ring cell carcinoma', 'Disease', (123, 157))	('carcinoma', 'Disease', 'MESH:D002277', (202, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('HNPCC', 'Gene', (273, 278))	('carcinoma', 'Disease', (69, 78))	('negative', 'NegReg', (224, 232))	('carcinoma', 'Disease', (148, 157))	('familial gastric carcinoma', 'Disease', (185, 211))	('HNPCC', 'Gene', '4436', (273, 278))	('CDH1', 'Gene', '999', (241, 245))	('HNPCC', 'Phenotype', 'HP:0006716', (273, 278))	('familial gastric carcinoma', 'Disease', 'MESH:D013274', (185, 211))	('mutation', 'Var', (246, 254))	('CDH1', 'Gene', (241, 245))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (194, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('carcinoma', 'Disease', 'MESH:D002277', (69, 78))	('carcinoma', 'Disease', 'MESH:D002277', (148, 157))
30431	23849133	Genetic screening, performed one year after her mastectomy, confirmed that she was also a CDH1 gene mutation carrier.	('CDH1', 'Gene', '999', (90, 94))	('mutation', 'Var', (100, 108))	('carrier', 'molecular_function', 'GO:0005215', ('109', '116'))	('CDH1', 'Gene', (90, 94))
30503	17389037	Inactivating mutations of E-cadherin gene are very frequent in ILC.	('E-cadherin gene', 'Gene', (26, 41))	('Inactivating mutations', 'Var', (0, 22))	('ILC', 'Gene', '10850', (63, 66))	('ILC', 'Gene', (63, 66))	('frequent', 'Reg', (51, 59))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))
30628	17389037	Mutations of this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer.	('breast', 'Disease', (52, 58))	('Mutations', 'Var', (0, 9))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('colorectal, thyroid and ovarian cancer', 'Disease', 'MESH:D015179', (60, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('correlated', 'Reg', (27, 37))	('gastric', 'Disease', 'MESH:D013274', (43, 50))	('gastric', 'Disease', (43, 50))
30629	17389037	During tumor progression, E-cadherin can be functionally inactivated or silenced by different mechanisms such as post-translational control, somatic mutations, downregulation of gene expression through promoter hypermethylation, histone deacetylation, and transcriptional repression.	('downregulation', 'NegReg', (160, 174))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))	('silenced', 'NegReg', (72, 80))	('histone deacetylation', 'biological_process', 'GO:0016575', ('229', '250'))	('tumor', 'Disease', (7, 12))	('gene expression', 'MPA', (178, 193))	('E-cadherin', 'Protein', (26, 36))	('transcriptional repression', 'Var', (256, 282))	('promoter hypermethylation', 'Var', (202, 227))	('histone', 'MPA', (229, 236))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('inactivated', 'NegReg', (57, 68))	('gene expression', 'biological_process', 'GO:0010467', ('178', '193'))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
30648	17389037	Aberrant expression of CTHRC1 has recently been reported in human solid tumors, including cancers of the gastrointestinal tract, lung, breast, thyroid, ovarian, cervix, liver, and the pancreas.	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers of the gastrointestinal tract', 'Disease', (90, 127))	('cancers of the gastrointestinal tract', 'Disease', 'MESH:D004067', (90, 127))	('thyroid', 'Disease', (143, 150))	('cervix', 'Disease', (161, 167))	('Aberrant expression', 'Var', (0, 19))	('reported', 'Reg', (48, 56))	('ovarian', 'Disease', (152, 159))	('solid tumors', 'Disease', (66, 78))	('CTHRC1', 'Gene', '115908', (23, 29))	('liver', 'Disease', (169, 174))	('pancreas', 'Disease', (184, 192))	('breast', 'Disease', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('cancers of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (90, 127))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('CTHRC1', 'Gene', (23, 29))	('lung', 'Disease', (129, 133))	('human', 'Species', '9606', (60, 65))
30651	17389037	The loss of SFRP1 is known to be associated with breast cancer progression and poor prognosis in early stages, and a similar expression profile is seen in our study.	('SFRP1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('SFRP1', 'Gene', '6422', (12, 17))	('associated', 'Reg', (33, 43))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('loss', 'Var', (4, 8))
30655	17389037	TGFbeta signaling inhibitors have been shown to prevent EMT, to inhibit mammary tumor viability and to block metastasis in various murine models.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('murine', 'Species', '10090', (131, 137))	('EMT', 'CPA', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TGFbeta', 'Gene', (0, 7))	('block metastasis', 'Disease', (103, 119))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('tumor', 'Disease', (80, 85))	('signaling', 'biological_process', 'GO:0023052', ('8', '17'))	('inhibit', 'NegReg', (64, 71))	('block metastasis', 'Disease', 'MESH:D009362', (103, 119))	('prevent', 'NegReg', (48, 55))	('inhibitors', 'Var', (18, 28))
30656	17389037	According to these results, we propose that deregulated TGFbeta signaling is likely to be more important in lobular carcinogenesis.	('lobular carcinogenesis', 'Disease', 'MESH:D063646', (108, 130))	('lobular carcinogenesis', 'Disease', (108, 130))	('deregulated', 'Var', (44, 55))	('TGFbeta', 'Protein', (56, 63))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))
30777	30094484	A tumor was considered ER negative if gene score <6.5, ER positive >=6.5, PR negative <5.5, and PR positive >=5.5.	('negative', 'NegReg', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('PR', 'Gene', '5241', (96, 98))	('ER', 'Gene', '2099', (55, 57))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('PR', 'Gene', '5241', (74, 76))	('tumor', 'Disease', (2, 7))	('gene score <6.5', 'Var', (38, 53))	('ER', 'Gene', '2099', (23, 25))
30779	30094484	Descriptive statistics were calculated for the RS result based on originally reported cutoffs (Low <18, Intermediate 18-30, High >=31), as well as the cutoff points used for the TAILORx (Low <11, Intermediate 11-25, and High  25) and RxPONDER (Low <=25 and High  25) clinical trials.	('Low <=25', 'Var', (244, 252))	('Low <18', 'Var', (95, 102))	('Low <11', 'Var', (187, 194))	('ER', 'Gene', '2099', (240, 242))
30801	30094484	Patients with tubular carcinoma remained the least likely subtype to have a high RS (3.2%), and patients with ILC variants (18.5%) and IDC (18.3%) were the most likely to have a high RS.	('high RS', 'MPA', (76, 83))	('IDC', 'Disease', (135, 138))	('tubular carcinoma', 'Disease', 'MESH:D000230', (14, 31))	('tubular carcinoma', 'Disease', (14, 31))	('variants', 'Var', (114, 122))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('patients', 'Species', '9606', (96, 104))	('ILC', 'Disease', (110, 113))
30823	30094484	Patients with other variants of lobular carcinoma have been described in the literature as having a greater degree of cellular atypia and pleomorphism, which is often associated with a poor clinical outcome compared to classic-type ILC and IDC.	('lobular carcinoma', 'Phenotype', 'HP:0030076', (32, 49))	('lobular carcinoma', 'Disease', (32, 49))	('cellular atypia', 'CPA', (118, 133))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('pleomorphism', 'Var', (138, 150))	('lobular carcinoma', 'Disease', 'MESH:D018275', (32, 49))
30830	30094484	Only 1 of 36 patients with ILC and non-pleomorphic variants was found to have a high RS result.	('non-pleomorphic variants', 'Var', (35, 59))	('ILC', 'Disease', (27, 30))	('patients', 'Species', '9606', (13, 21))
30832	30094484	In addition, a higher proportion of patients with variants of ILC had a high-risk RS result compared to patients with classic ILC (8.4% vs. 2.5%).	('ILC', 'Gene', (62, 65))	('patients', 'Species', '9606', (104, 112))	('variants', 'Var', (50, 58))	('patients', 'Species', '9606', (36, 44))
30833	30094484	Patients with variants of ILC and IDC had a similar mean RS result and distribution of recurrence scores, while patients with ILC of classic type had a lower mean RS and a lower percentage of patients with a high recurrence score compared to patients with IDC.	('variants', 'Var', (14, 22))	('ILC', 'Disease', (26, 29))	('patients', 'Species', '9606', (192, 200))	('patients', 'Species', '9606', (112, 120))	('Patients', 'Species', '9606', (0, 8))	('IDC', 'Disease', (34, 37))	('patients', 'Species', '9606', (242, 250))
30839	30094484	It is possible that patients with tumors of special histologic subtype felt to be at higher risk for recurrence based on standard clinic-pathologic features were selected for Oncotype DX testing, and that our results overestimate the proportion of high RS results in this group, although the likelihood of this is minimized by the large number of samples studied.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (20, 28))	('high', 'Var', (248, 252))	('overestimate', 'NegReg', (217, 229))
30872	26788154	Levels of tumor markers were within normal limits, as follows: Carcinoembryonic antigen (CEA), 1.7 ng/ml (normal, <5.0 ng/ml); carbohydrate antigen (CA) 19-9, 6.2 ng/ml (normal, <37.0 ng/ml); CA125, 10.7 U/ml (normal, <35.0 U/ml); and CA15-3, 12.6 U/ml (normal, <28.0 U/ml).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Carcinoembryonic antigen', 'Gene', (63, 87))	('Carcinoembryonic antigen', 'Gene', '1084', (63, 87))	('carbohydrate antigen', 'Chemical', '-', (127, 147))	('tumor', 'Disease', (10, 15))	('CA125', 'Var', (192, 197))	('CEA', 'Gene', (89, 92))	('CA15-3', 'Var', (235, 241))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('CEA', 'Gene', '1084', (89, 92))
30874	26788154	IHC also indicated positivity for cytokeratin (CK) 7 and negativity for CK20 in both tumors.	('positivity', 'Var', (19, 29))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('CK20', 'Gene', (72, 76))	('CK20', 'Gene', '54474', (72, 76))	('cytokeratin', 'Protein', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
30944	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))	('Chroma', 'Disease', (144, 150))	('time-delay line', 'MPA', (56, 71))
30954	21833355	Unwanted residual signals were blocked using a band-pass filter (BPF) (hq660/40m-2p, Chroma, VT).	('VT', 'Disease', 'MESH:D017180', (93, 95))	('Chroma', 'Disease', 'None', (85, 91))	('a band', 'cellular_component', 'GO:0031672', ('45', '51'))	('Chroma', 'Disease', (85, 91))	('hq660/40m-2p', 'Var', (71, 83))
30966	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))
31025	18974135	ERRgamma-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity.	('ERRgamma', 'Gene', (0, 8))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('activator protein 1', 'Gene', (83, 102))	('TAM', 'Chemical', 'MESH:D013629', (132, 135))	('AP1', 'cellular_component', 'GO:0005907', ('104', '107'))	('AP1', 'Gene', '3725', (104, 107))	('enhance', 'PosReg', (124, 131))	('ERRgamma', 'Gene', '2104', (0, 8))	('AP1', 'Gene', (104, 107))	('transcription', 'biological_process', 'GO:0006351', ('16', '29'))	('activator protein 1', 'Gene', '3725', (83, 102))	('inhibition', 'Var', (69, 79))	('increased', 'PosReg', (38, 47))	('TAM sensitivity', 'MPA', (132, 147))
31026	18974135	These data support a role for ERRgamma/AP1 signaling in the development of TAM resistance, and suggest that expression of ERRgamma may be a marker of poor Tamoxifen response.	('ERRgamma/AP1', 'Gene', '2104;3725', (30, 42))	('ERRgamma', 'Gene', (122, 130))	('ERRgamma', 'Gene', '2104', (30, 38))	('ERRgamma', 'Gene', '2104', (122, 130))	('TAM', 'Chemical', 'MESH:D013629', (75, 78))	('AP1', 'cellular_component', 'GO:0005907', ('39', '42'))	('ERRgamma/AP1', 'Gene', (30, 42))	('ERRgamma', 'Gene', (30, 38))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('Tamoxifen', 'Chemical', 'MESH:D013629', (155, 164))	('expression', 'Var', (108, 118))
31050	18974135	Our mechanistic studies demonstrate that knockdown of ERRgamma in the resistant cell line, and overexpression of ERRgamma in endocrine-responsive lobular breast cancer cells, modulates TAM sensitivity.	('ERRgamma', 'Gene', '2104', (54, 62))	('ERRgamma', 'Gene', '2104', (113, 121))	('modulates', 'Reg', (175, 184))	('endocrine-responsive lobular breast cancer', 'Disease', (125, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('endocrine-responsive lobular breast cancer', 'Disease', 'MESH:D013274', (125, 167))	('ERRgamma', 'Gene', (54, 62))	('overexpression', 'PosReg', (95, 109))	('ERRgamma', 'Gene', (113, 121))	('TAM sensitivity', 'MPA', (185, 200))	('TAM', 'Chemical', 'MESH:D013629', (185, 188))	('knockdown', 'Var', (41, 50))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (146, 167))
31051	18974135	Finally, we show that ERRgamma-driven transcription is increased in the resistant SUM44/LCCTam cell line, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity in this model system.	('TAM sensitivity', 'MPA', (173, 188))	('ERRgamma', 'Gene', '2104', (22, 30))	('activator protein 1', 'Gene', (124, 143))	('TAM', 'Chemical', 'MESH:D013629', (173, 176))	('AP1', 'Gene', '3725', (145, 148))	('transcription', 'biological_process', 'GO:0006351', ('38', '51'))	('enhance', 'PosReg', (165, 172))	('increased', 'PosReg', (55, 64))	('AP1', 'Gene', (145, 148))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('ERRgamma', 'Gene', (22, 30))	('AP1', 'cellular_component', 'GO:0005907', ('145', '148'))	('activator protein 1', 'Gene', '3725', (124, 143))	('inhibition', 'Var', (110, 120))
31077	18974135	qPCR reactions for each cDNA sample and a standard curve were performed using TaqMan Universal PCR Master Mix and the following TaqMan Gene Expression Assay primers (Applied Biosystems): ESR1 = Hs00174860_m1; ESRRG = Hs00155006_m1; and the housekeeping gene RPLP0 = Hs99999902_m1) as in.	('Hs00174860_m1', 'Var', (194, 207))	('Gene Expression', 'biological_process', 'GO:0010467', ('135', '150'))	('ESR1', 'Gene', '2099', (187, 191))	('RPLP0', 'Gene', (258, 263))	('ESRRG', 'Gene', '2104', (209, 214))	('ESR1', 'Gene', (187, 191))	('RPLP0', 'Gene', '6175', (258, 263))	('Mix', 'Gene', (106, 109))	('ESRRG', 'Gene', (209, 214))	('Mix', 'Gene', '83881', (106, 109))
31103	18974135	SUM44 cells treated with 1 muM 4HT show a significantly greater fraction of cells arrested in the G1 phase as compared to EtOH-treated controls (p<=0.001, data not shown), while 4HT no longer induces an accumulation of LCCTam cells in G1 (p=0.722, data not shown).	('G1 phase', 'biological_process', 'GO:0051318', ('98', '106'))	('muM', 'Gene', '56925', (27, 30))	('4HT', 'Chemical', '-', (178, 181))	('muM', 'Gene', (27, 30))	('4HT', 'Var', (178, 181))	('4HT', 'Chemical', '-', (31, 34))	('EtOH', 'Chemical', '-', (122, 126))	('cells arrested', 'CPA', (76, 90))
31104	18974135	Together, these findings show that SUM44 cell growth and cell cycle progression are efficiently inhibited by 4HT, but that LCCTam cells have acquired resistance to the inhibitory effects of this antiestrogen.	('4HT', 'Chemical', '-', (109, 112))	('4HT', 'Var', (109, 112))	('inhibited', 'NegReg', (96, 105))	('cell cycle progression', 'CPA', (57, 79))	('cell cycle', 'biological_process', 'GO:0007049', ('57', '67'))	('SUM44 cell growth', 'CPA', (35, 52))	('cell growth', 'biological_process', 'GO:0016049', ('41', '52'))
31114	18974135	We hypothesized that if increased expression of ERRgamma in LCCTam cells performs a functional role in the acquired TAM resistance phenotype, knockdown of receptor expression should restore TAM sensitivity.	('ERRgamma', 'Gene', (48, 56))	('TAM sensitivity', 'MPA', (190, 205))	('expression', 'MPA', (34, 44))	('restore', 'PosReg', (182, 189))	('TAM', 'Chemical', 'MESH:D013629', (190, 193))	('ERRgamma', 'Gene', '2104', (48, 56))	('TAM', 'Chemical', 'MESH:D013629', (116, 119))	('knockdown', 'Var', (142, 151))	('increased', 'PosReg', (24, 33))	('acquired TAM resistance phenotype', 'MPA', (107, 140))
31117	18974135	Importantly, ERRgamma knockdown also partially restores sensitivity to 4HT in the LCCTam cells (Figure 3B, p=0.03 vs. siERRgamma EtOH and p<0.001 vs. siC in 1000 nM 4HT) with no effect on the expression of ERalpha (Figure 3A, inset, bottom panel).	('4HT', 'Chemical', '-', (71, 74))	('ERalpha', 'Gene', (206, 213))	('ERRgamma', 'Gene', '2104', (13, 21))	('restores', 'PosReg', (47, 55))	('ERRgamma', 'Gene', '2104', (120, 128))	('ERalpha', 'Gene', '2099', (206, 213))	('EtOH', 'Chemical', '-', (129, 133))	('knockdown', 'Var', (22, 31))	('4HT', 'Chemical', '-', (165, 168))	('sensitivity', 'MPA', (56, 67))	('ERRgamma', 'Gene', (13, 21))	('ERRgamma', 'Gene', (120, 128))
31122	18974135	In agreement with our results in Figure 1C, 4HT significantly reduces BrdU incorporation in SUM44 cells transfected with the empty vector pSG5 (Figure 4A, panel ii vs. iv, 48.9% vs. 16.9% BrdU incorporation, p<0.001).	('BrdU', 'Chemical', 'MESH:D001973', (188, 192))	('reduces', 'NegReg', (62, 69))	('4HT', 'Chemical', '-', (44, 47))	('pSG5', 'Gene', '5673', (138, 142))	('4HT', 'Var', (44, 47))	('BrdU incorporation', 'MPA', (70, 88))	('pSG5', 'Gene', (138, 142))	('pSG', 'cellular_component', 'GO:0034515', ('138', '141'))	('BrdU', 'Chemical', 'MESH:D001973', (70, 74))	('BrdU incorporation', 'MPA', (188, 206))
31156	18974135	One is loss or mutation of ERalpha, while others include alterations in the profile of hormone receptor co-activators and co-repressors expressed by the tumor, differential metabolism of antiestrogens, and changes in the expression of additional genes that control cell proliferation and/or apoptosis.	('mutation', 'Var', (15, 23))	('loss', 'NegReg', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('profile of', 'MPA', (76, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('291', '300'))	('metabolism', 'biological_process', 'GO:0008152', ('173', '183'))	('metabolism', 'MPA', (173, 183))	('apoptosis', 'biological_process', 'GO:0006915', ('291', '300'))	('alterations', 'Reg', (57, 68))	('hormone receptor', 'Gene', (87, 103))	('ERalpha', 'Gene', (27, 34))	('hormone receptor', 'Gene', '3164', (87, 103))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('changes', 'Reg', (206, 213))	('tumor', 'Disease', (153, 158))	('ERalpha', 'Gene', '2099', (27, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('265', '283'))	('expression', 'MPA', (221, 231))
31438	32257203	The pathology report described the lesion as a G2, ER+ and PR+ (90 and 80% expression, respectively), Ki67 50% and HER2+ (immunohistochemical score 3+) ILC.	('PR', 'Gene', '5241', (59, 61))	('HER2', 'Gene', (115, 119))	('Ki67', 'Var', (102, 106))	('HER2', 'Gene', '2064', (115, 119))	('ER', 'Gene', '2099', (51, 53))	('ER', 'Gene', '2099', (116, 118))
31441	32257203	At that point, a right radical mastectomy was performed, and analyses of the resected breast tissue revealed a G2, ER+ and PR+ (40 and 50% expression, respectively), Ki67 30% and HER2- ILC.	('ER', 'Gene', '2099', (180, 182))	('ER', 'Gene', '2099', (115, 117))	('HER2', 'Gene', (179, 183))	('Ki67', 'Var', (166, 170))	('HER2', 'Gene', '2064', (179, 183))	('PR', 'Gene', '5241', (123, 125))
31452	32257203	The patient underwent left breast quadrantectomy and ipsilateral axillary lymphadenectomy for a pT1c pN0 IDC, G2, ER+ and PR+ (90% expression for both), Ki67 15% and HER2-.	('HER2', 'Gene', (166, 170))	('HER2', 'Gene', '2064', (166, 170))	('patient', 'Species', '9606', (4, 11))	('ER', 'Gene', '2099', (114, 116))	('PR', 'Gene', '5241', (122, 124))	('ER', 'Gene', '2099', (167, 169))	('Ki67', 'Var', (153, 157))
31462	32257203	Biopsy of the breast mass revealed an ER+ and PR+ (90 and 80% expression, respectively), G2, Ki67 30% and HER2- IDC.	('breast mass', 'Phenotype', 'HP:0032408', (14, 25))	('ER', 'Gene', '2099', (107, 109))	('HER2', 'Gene', (106, 110))	('PR', 'Gene', '5241', (46, 48))	('HER2', 'Gene', '2064', (106, 110))	('Ki67', 'Var', (93, 97))	('ER', 'Gene', '2099', (38, 40))
31474	32257203	The patient underwent left mastectomy and ipsilateral axillary lymphadenectomy for a pT2 pN3 ER+ and PR+ (90 and 20% expression, respectively) G2, Ki67 12%, HER2- ILC.	('ER', 'Gene', '2099', (158, 160))	('PR', 'Gene', '5241', (101, 103))	('Ki67', 'Var', (147, 151))	('patient', 'Species', '9606', (4, 11))	('HER2', 'Gene', (157, 161))	('ER', 'Gene', '2099', (93, 95))	('HER2', 'Gene', '2064', (157, 161))
31510	30246500	Primary tumours frequently co-expressed oestrogen receptor cofactors (GATA3, FOXA1) and harboured amplifications at 8p12, 8q24, and 11q13.	('oestrogen receptor', 'Protein', (40, 58))	('GATA3', 'Gene', '2625', (70, 75))	('Primary tumours', 'Disease', 'MESH:D009369', (0, 15))	('FOXA1', 'Gene', '3169', (77, 82))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('co-expressed', 'Reg', (27, 39))	('8q24', 'Var', (122, 126))	('Primary tumours', 'Disease', (0, 15))	('FOXA1', 'Gene', (77, 82))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('GATA3', 'Gene', (70, 75))
31512	30246500	ESR1 and novel AR mutations were identified.	('AR', 'Gene', '367', (15, 17))	('ESR1', 'Gene', (0, 4))	('ESR1', 'Gene', '2099', (0, 4))	('mutations', 'Var', (18, 27))
31542	30246500	The Comprehensive Capture Panel v2 (Peter MacCallum Cancer Centre, Melbourne, Australia) screens for mutations in the coding regions and splice sites of 386 cancer-related genes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('screens', 'Reg', (89, 96))	('Peter MacCallum Cancer', 'Disease', (36, 58))	('cancer', 'Disease', (157, 163))	('Peter MacCallum Cancer', 'Disease', 'MESH:C537884', (36, 58))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))
31544	30246500	Variants were called with GATK HaplotypeCaller for normal DNA, or MuTect, GATK Indellocator, and VarScanSomatic for tumour.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('Variants', 'Var', (0, 8))	('tumour', 'Disease', (116, 122))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
31546	30246500	A custom filter was applied to capture variants meeting the following criteria: present in tumour and not matched normal; present in <10% of samples tested with this panel; present in <0.4% of individuals in the Exome Server Project; present in <0.4% of individuals in the 1000 Genomes study; not intronic (excluding splicing regions); not synonymous; not in an untranslated region; and not in an intergenic region.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Disease', (91, 97))	('splicing', 'biological_process', 'GO:0045292', ('317', '325'))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('variants', 'Var', (39, 47))
31547	30246500	Copy-number alterations were validated in the primary tumour and multiple metastases from two cases (GM63 and GM78) using the nanoString nCounter v2 Cancer CN Assay, following the manufacturer's instructions (MAN-C0024-02, nanoString, Bio-strategy, VIC, Australia).	('MAN', 'Species', '9606', (209, 212))	('alterations', 'Var', (12, 23))	('primary tumour', 'Disease', (46, 60))	('GM63', 'Chemical', '-', (101, 105))	('GM78', 'Chemical', '-', (110, 114))	('primary tumour', 'Disease', 'MESH:D009369', (46, 60))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('metastases', 'Disease', (74, 84))	('metastases', 'Disease', 'MESH:D009362', (74, 84))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Disease', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
31570	30246500	The primary tumours (n = 9) displayed copy-number alterations (CNAs) consistent with ER positive primary tumours 29, 30, with gains (1q, 7q, 8q, 11q, 16p, and 17q) and losses (8p, 16q, 22q, and Xq) identified in over 50% of the samples (supplementary material, Figure S6).	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('primary tumours', 'Disease', 'MESH:D009369', (4, 19))	('gains', 'PosReg', (126, 131))	('primary tumours', 'Disease', (4, 19))	('primary tumours', 'Disease', 'MESH:D009369', (97, 112))	('8p', 'Var', (176, 178))	('losses', 'NegReg', (168, 174))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('primary tumours', 'Disease', (97, 112))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('copy-number alterations', 'MPA', (38, 61))
31571	30246500	The most common alterations in ovarian metastases (n = 17, CNAs identified in over 50% of samples) included gain at 1p/q, 3p, 6p, 7p/q, 8q, 12q, 15q, and 17q, 19p/q; and loss at 8p, 13p/q, 16q, 22q and Xq (supplementary material, Figure S6).	('ovarian metastases', 'Disease', 'MESH:D009362', (31, 49))	('gain', 'PosReg', (108, 112))	('loss', 'NegReg', (170, 174))	('ovarian metastases', 'Disease', (31, 49))	('7p/q', 'Var', (130, 134))
31575	30246500	FGFR1 was amplified in the primary tumour alone in cases GM78 and GM74.	('GM78', 'Chemical', '-', (57, 61))	('GM74', 'Chemical', '-', (66, 70))	('GM78', 'Var', (57, 61))	('primary tumour', 'Disease', 'MESH:D009369', (27, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('primary tumour', 'Disease', (27, 41))	('GM74', 'Var', (66, 70))
31576	30246500	Co-amplification of 8p12 and 11q13 has been associated with resistance to endocrine therapy 31 and was present in 2 of 9 (22%) of the primary tumours and 3 of 17 (17.6%) of the ovarian metastases (supplementary material, Figure S12).	('associated', 'Reg', (44, 54))	('primary tumours', 'Disease', (134, 149))	('S12', 'Gene', '6268', (228, 231))	('primary tumours', 'Disease', 'MESH:D009369', (134, 149))	('S12', 'Gene', (228, 231))	('ovarian metastases', 'Disease', 'MESH:D009362', (177, 195))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('ovarian metastases', 'Disease', (177, 195))	('Co-amplification', 'Var', (0, 16))	('resistance to endocrine therapy 31', 'MPA', (60, 94))
31577	30246500	Among the matched cases, FGFR1 and CCND1 were co-amplified in the primary tumour only in GM78, and the metastases only in GM59.	('GM', 'Chemical', '-', (122, 124))	('GM', 'Chemical', '-', (89, 91))	('primary tumour', 'Disease', 'MESH:D009369', (66, 80))	('GM78', 'Var', (89, 93))	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('FGFR1', 'Gene', '2260', (25, 30))	('GM78', 'Chemical', '-', (89, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('CCND1', 'Gene', '595', (35, 40))	('FGFR1', 'Gene', (25, 30))	('metastases', 'Disease', (103, 113))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('primary tumour', 'Disease', (66, 80))	('CCND1', 'Gene', (35, 40))
31581	30246500	CDH1 was mutated in five of seven (71.4%) primary tumours, all five of which were of lobular histological type.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('primary tumours', 'Disease', (42, 57))	('CDH1', 'Gene', '999', (0, 4))	('mutated', 'Var', (9, 16))	('primary tumours', 'Disease', 'MESH:D009369', (42, 57))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('CDH1', 'Gene', (0, 4))
31582	30246500	Metastases from these cases harboured the same CDH1 mutation as the primary tumours.	('CDH1', 'Gene', '999', (47, 51))	('primary tumours', 'Disease', 'MESH:D009369', (68, 83))	('primary tumours', 'Disease', (68, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('Metastases', 'Disease', (0, 10))	('mutation', 'Var', (52, 60))	('CDH1', 'Gene', (47, 51))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
31583	30246500	PIK3CA was mutated in four of seven primary tumours; GM74 had two PIK3CA mutations in the primary tumour, yet only one (c.3140A>G) was shared with the ovarian metastasis (supplementary material, Figure S10).	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('ovarian metastasis', 'Disease', (151, 169))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('S10', 'Gene', (202, 205))	('PIK3CA', 'Gene', (66, 72))	('primary tumour', 'Disease', 'MESH:D009369', (36, 50))	('ovarian metastasis', 'Disease', 'MESH:D009362', (151, 169))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('primary tumour', 'Disease', 'MESH:D009369', (90, 104))	('GM74', 'Chemical', '-', (53, 57))	('primary tumours', 'Disease', 'MESH:D009369', (36, 51))	('primary tumour', 'Disease', (90, 104))	('primary tumours', 'Disease', (36, 51))	('PIK3CA', 'Gene', (0, 6))	('c.3140A>G', 'Var', (120, 129))	('S10', 'Gene', '6204', (202, 205))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutations', 'Var', (73, 82))	('c.3140A>G', 'Mutation', 'rs121913279', (120, 129))
31584	30246500	An ESR1 mutation (c.1387T>C, S463P) was identified in two of six metastases sampled from case GM63 (Figure 4, supplementary material, Table S11), and AR was mutated in two cases.	('S11', 'Gene', (140, 143))	('c.1387T>C, S463P', 'Var', (18, 34))	('metastases', 'Disease', 'MESH:D009362', (65, 75))	('ESR1', 'Gene', (3, 7))	('c.1387T>C', 'Mutation', 'rs1057519714', (18, 27))	('GM63', 'Chemical', '-', (94, 98))	('AR', 'Gene', '367', (150, 152))	('S463P', 'Mutation', 'rs1057519714', (29, 34))	('S11', 'Gene', '6267', (140, 143))	('ESR1', 'Gene', '2099', (3, 7))	('metastases', 'Disease', (65, 75))
31585	30246500	In case GM63 a novel nonsense mutation (c.2011C>T, Gln671*; Figure 4D) was identified in all the distant metastases, but not the primary tumour or lymph node metastasis.	('Gln671*', 'Var', (51, 58))	('metastases', 'Disease', (105, 115))	('c.2011C>T', 'Mutation', 'c.2011C>T', (40, 49))	('GM63', 'Chemical', '-', (8, 12))	('primary tumour', 'Disease', (129, 143))	('Gln671', 'Chemical', '-', (51, 57))	('primary tumour', 'Disease', 'MESH:D009369', (129, 143))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('c.2011C>T', 'Var', (40, 49))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
31587	30246500	Missense mutations at this codon (Q671L and Q671R) have been reported for oesophageal and prostate cancer respectively (COSMIC 32).	('Q671R', 'Mutation', 'p.Q671R', (44, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('oesophageal and prostate cancer', 'Disease', 'MESH:D011471', (74, 105))	('Q671L', 'Mutation', 'p.Q671L', (34, 39))	('Q671L', 'Var', (34, 39))	('Q671R', 'Var', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
31588	30246500	All tumours in GM78 harboured a novel AR mutation (c.869G>T; C290F), and all were positive for AR by IHC (Figure 3B).	('c.869G>T', 'Mutation', 'rs754986642', (51, 59))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('AR', 'Gene', '367', (95, 97))	('AR', 'Gene', '367', (38, 40))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('C290F', 'Var', (61, 66))	('GM78', 'Chemical', '-', (15, 19))	('C290F', 'SUBSTITUTION', 'None', (61, 66))	('tumours', 'Disease', (4, 11))
31589	30246500	Again, this point mutation has not been previously reported (COSMIC 32, however a c.867G>A mutation resulting in the same amino acid change has been reported in one primary breast cancer 33.	('primary breast cancer', 'Disease', 'MESH:D001943', (165, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('primary breast cancer', 'Disease', (165, 186))	('c.867G>A', 'Var', (82, 90))	('c.867G>A', 'Mutation', 'rs747680662', (82, 90))
31590	30246500	All cases shared at least one mutation between the primary tumour and metastases (supplementary material, Figures S7-S11, individual case reports), along with unique mutations present in either the primary tumour alone (e.g.	('primary tumour', 'Disease', 'MESH:D009369', (51, 65))	('S11', 'Gene', (117, 120))	('S11', 'Gene', '6267', (117, 120))	('metastases', 'Disease', 'MESH:D009362', (70, 80))	('mutation', 'Var', (30, 38))	('primary tumour', 'Disease', (198, 212))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('primary tumour', 'Disease', 'MESH:D009369', (198, 212))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('metastases', 'Disease', (70, 80))	('primary tumour', 'Disease', (51, 65))
31591	30246500	TBX3 in GM06BR), or metastases alone (e.g.	('TBX3', 'Gene', '6926', (0, 4))	('GM06BR', 'Var', (8, 14))	('metastases', 'Disease', (20, 30))	('TBX3', 'Gene', (0, 4))	('GM', 'Chemical', '-', (8, 10))	('metastases', 'Disease', 'MESH:D009362', (20, 30))
31592	30246500	RB1, TP53 in GM74LO).	('RB1', 'Gene', '5925', (0, 3))	('TP53', 'Gene', '7157', (5, 9))	('GM74', 'Chemical', '-', (13, 17))	('TP53', 'Gene', (5, 9))	('RB1', 'Gene', (0, 3))	('GM74LO', 'Var', (13, 19))
31598	30246500	HER2, basal markers, p53), and expressed Ki67 at relatively low frequency.	('Ki67', 'Var', (41, 45))	('p53', 'Gene', '7157', (21, 24))	('basal markers', 'CPA', (6, 19))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('p53', 'Gene', (21, 24))
31616	30246500	To illustrate, case GM78 had high expression of ER and AR in all samples, yet PR expression decreased from 80% in the primary tumour to 10% in three of four metastases; expression of GATA3 went from 100% positive to negative in all metastases; and FOXA1 expression went from ~40% positive to 100% positive in all metastases.	('expression', 'MPA', (34, 44))	('primary tumour', 'Disease', 'MESH:D009369', (118, 132))	('metastases', 'Disease', 'MESH:D009362', (313, 323))	('GATA3', 'Gene', '2625', (183, 188))	('metastases', 'Disease', 'MESH:D009362', (232, 242))	('metastases', 'Disease', (313, 323))	('primary tumour', 'Disease', (118, 132))	('GATA3', 'Gene', (183, 188))	('metastases', 'Disease', (232, 242))	('GM78', 'Chemical', '-', (20, 24))	('FOXA1', 'Gene', '3169', (248, 253))	('decreased', 'NegReg', (92, 101))	('AR', 'Gene', '367', (55, 57))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('GM78', 'Var', (20, 24))	('FOXA1', 'Gene', (248, 253))	('metastases', 'Disease', (157, 167))	('PR expression', 'MPA', (78, 91))
31619	30246500	Genomic alterations may also contribute to the aggressive behaviour of these tumours.	('aggressive behaviour', 'CPA', (47, 67))	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('contribute', 'Reg', (29, 39))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('tumours', 'Disease', (77, 84))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (47, 67))	('behaviour', 'biological_process', 'GO:0007610', ('58', '67'))	('Genomic alterations', 'Var', (0, 19))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
31621	30246500	In a group of mostly older women treated with letrozole in the neoadjuvant setting, Giltnane et al 31, 50 identified the pro-survival effects of amplified FGFR1 and/or CCND1 in oestrogen-deprived ER+/HER2- breast cancer, and that the combination of ER antagonists with FGFR1 or CDK4/6 inhibitors could increase cancer cell death.	('increase', 'PosReg', (302, 310))	('HER2', 'Gene', '2064', (200, 204))	('pro-survival', 'biological_process', 'GO:0043066', ('121', '133'))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('FGFR1', 'Gene', '2260', (155, 160))	('CCND1', 'Gene', '595', (168, 173))	('amplified', 'Var', (145, 154))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('CDK4/6', 'Gene', '1019;1021', (278, 284))	('breast cancer', 'Disease', (206, 219))	('CDK', 'molecular_function', 'GO:0004693', ('278', '281'))	('CCND1', 'Gene', (168, 173))	('cancer cell death', 'Disease', 'MESH:D003643', (311, 328))	('FGFR1', 'Gene', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('HER2', 'Gene', (200, 204))	('FGFR', 'molecular_function', 'GO:0005007', ('155', '159'))	('letrozole', 'Chemical', 'MESH:D000077289', (46, 55))	('FGFR1', 'Gene', (155, 160))	('FGFR', 'molecular_function', 'GO:0005007', ('269', '273'))	('cell death', 'biological_process', 'GO:0008219', ('318', '328'))	('cancer cell death', 'Disease', (311, 328))	('CDK4/6', 'Gene', (278, 284))	('women', 'Species', '9606', (27, 32))	('FGFR1', 'Gene', '2260', (269, 274))
31623	30246500	Mutations in ESR1 are particularly important in endocrine therapy resistance, producing protein products that function independently of ligand binding 51, 52, 53.	('ESR1', 'Gene', (13, 17))	('ligand', 'molecular_function', 'GO:0005488', ('136', '142'))	('important', 'Reg', (35, 44))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('binding', 'molecular_function', 'GO:0005488', ('143', '150'))	('Mutations', 'Var', (0, 9))	('ESR1', 'Gene', '2099', (13, 17))
31624	30246500	Detecting mutant ESR1 in circulating DNA may therefore prove to be an important biomarker of relapse 54, 55, though heterogeneity between metastases in the same patient may be confounding.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('metastases', 'Disease', (138, 148))	('mutant', 'Var', (10, 16))	('patient', 'Species', '9606', (161, 168))	('metastases', 'Disease', 'MESH:D009362', (138, 148))	('relapse 54', 'Disease', (93, 103))	('ESR1', 'Gene', '2099', (17, 21))	('ESR1', 'Gene', (17, 21))
31625	30246500	Indeed, we identified a previously reported ESR1 mutation (S463P 56) in just two of six metastases from one case.	('metastases', 'Disease', (88, 98))	('S463P', 'Mutation', 'rs1057519714', (59, 64))	('S463P 56', 'Var', (59, 67))	('ESR1', 'Gene', '2099', (44, 48))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('ESR1', 'Gene', (44, 48))
31626	30246500	Mutation of AR is a mechanism of treatment resistance in castrate-resistant prostate cancer 57, with most variants occurring in the ligand binding domain (analogous to ESR1 mutations).	('variants', 'Var', (106, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('ligand', 'molecular_function', 'GO:0005488', ('132', '138'))	('AR', 'Gene', '367', (12, 14))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('Mutation', 'Var', (0, 8))	('ESR1', 'Gene', (168, 172))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('ESR1', 'Gene', '2099', (168, 172))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mechanism', 'Reg', (20, 29))	('occurring', 'Reg', (115, 124))
31629	30246500	In one case, all tumours harboured the variant, and in the other only the distant metastases harboured the variant, correlating with loss of protein expression.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('protein expression', 'MPA', (141, 159))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('variant', 'Var', (39, 46))	('loss', 'NegReg', (133, 137))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('harboured', 'Reg', (25, 34))	('tumours', 'Disease', (17, 24))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (82, 92))
31630	30246500	These novel mutations reside in exon 1, which encodes the N-terminal Activator Function-1 (AF-1) domain (C290F), and in exon 4 at the beginning of the ligand binding domain (LBD, G671*) 57.	('G671*', 'SUBSTITUTION', 'None', (179, 184))	('binding', 'molecular_function', 'GO:0005488', ('158', '165'))	('AF-1', 'Disease', (91, 95))	('C290F', 'Var', (105, 110))	('ligand', 'molecular_function', 'GO:0005488', ('151', '157'))	('AF-1', 'Disease', 'MESH:C538261', (91, 95))	('C290F', 'SUBSTITUTION', 'None', (105, 110))	('G671*', 'Var', (179, 184))
31631	30246500	The functional roles of these alterations in breast cancer are yet to be elucidated, though we hypothesise they will impair functional AR owing to: (1) the importance of exon 1 for wild-type AR activity and (2) loss of the LBD 58, 59.	('LBD', 'Var', (223, 226))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('AR', 'Gene', '367', (135, 137))	('loss', 'NegReg', (211, 215))	('impair', 'NegReg', (117, 123))	('AR', 'Gene', '367', (191, 193))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('alterations', 'Var', (30, 41))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))
31632	30246500	These changes are worthy of further investigation given the analogous mechanisms of ESR1 mutations in endocrine resistance, and the lack of understanding of the role of AR in ER-positive metastatic breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('AR', 'Gene', '367', (169, 171))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('ESR1', 'Gene', '2099', (84, 88))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('ESR1', 'Gene', (84, 88))	('endocrine resistance', 'MPA', (102, 122))	('breast cancer', 'Disease', (198, 211))
31637	30246500	Where possible, sampling and analysis of metastatic deposits may be beneficial for treatment planning, for example changing endocrine therapy if metastatic deposits harbour unique ESR1/AR mutations or other hormone signalling-associated changes, or consideration of CDK4/6 or FGFR inhibitors for cases harbouring amplification of CCND1 and/or FGFR1.	('CCND1', 'Gene', (330, 335))	('changing', 'Reg', (115, 123))	('ESR1', 'Gene', '2099', (180, 184))	('FGFR1', 'Gene', (343, 348))	('signalling', 'biological_process', 'GO:0023052', ('215', '225'))	('CDK4/6', 'Gene', (266, 272))	('FGFR', 'molecular_function', 'GO:0005007', ('276', '280'))	('CCND1', 'Gene', '595', (330, 335))	('FGFR1', 'Gene', '2260', (343, 348))	('changes', 'Reg', (237, 244))	('ESR1', 'Gene', (180, 184))	('CDK4/6', 'Gene', '1019;1021', (266, 272))	('CDK', 'molecular_function', 'GO:0004693', ('266', '269'))	('mutations', 'Var', (188, 197))	('amplification', 'Var', (313, 326))	('FGFR', 'molecular_function', 'GO:0005007', ('343', '347'))	('AR', 'Gene', '367', (185, 187))
31654	24000989	These changes affect blood flow and micro-vascular permeability leading to impaired delivery of nutrients and oxygen, as well as impaired fluid drainage and increased interstitial fluid pressure.	('micro-vascular permeability', 'CPA', (36, 63))	('affect', 'Reg', (14, 20))	('blood', 'MPA', (21, 26))	('impaired', 'NegReg', (129, 137))	('changes', 'Var', (6, 13))	('impaired', 'NegReg', (75, 83))	('oxygen', 'Chemical', 'MESH:D010100', (110, 116))	('fluid drainage', 'MPA', (138, 152))	('fluid drainage', 'Phenotype', 'HP:0000969', (138, 152))	('increased', 'PosReg', (157, 166))	('interstitial fluid pressure', 'MPA', (167, 194))	('impaired delivery', 'Phenotype', 'HP:0001787', (75, 92))
31685	24000989	The first-order covariance matrix, COV, was calculated according to:    A linear PCA transformation by solving lambdaE = COV E was then applied, yielding the eigenvectors E = {e1, e2 ... en_ j} and eigenvalues lambda = {lambda1, lambda2 ... lambdan-1}.	('COV', 'Disease', 'None', (121, 124))	('COV', 'Disease', (35, 38))	('COV', 'Disease', (121, 124))	('COV E', 'Disease', (121, 126))	('e2 ... en_ j}', 'Var', (180, 193))	('COV E', 'Disease', 'MESH:D016751', (121, 126))	('COV', 'Disease', 'None', (35, 38))
31740	22558599	Although the established histopathologic criteria distinguish invasive lobular from invasive ductal carcinoma, diagnostic difficulty occurs because of overlapping histopathologic features, particularly with invasive lobular carcinoma (ILC) variants and pleomorphic ILC.	('ductal carcinoma', 'Phenotype', 'HP:0030075', (93, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('variants', 'Var', (240, 248))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (84, 109))	('pleomorphic ILC', 'Disease', (253, 268))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (216, 233))	('invasive lobular carcinoma', 'Disease', (207, 233))	('invasive ductal carcinoma', 'Disease', (84, 109))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (207, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
31841	31665635	Mammary tumorigenesis in KEP mice resembles ILC in its pathology and progression, while mammary tumors arising in NeuT mice have previously been shown to resemble HER2+ breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('breast tumors', 'Disease', (169, 182))	('tumors', 'Disease', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('mice', 'Species', '10090', (29, 33))	('breast tumors', 'Phenotype', 'HP:0100013', (169, 182))	('breast tumor', 'Phenotype', 'HP:0100013', (169, 181))	('tumor', 'Disease', (176, 181))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('KEP', 'Var', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', (96, 101))	('breast tumors', 'Disease', 'MESH:D061325', (169, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mice', 'Species', '10090', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (176, 182))
31879	31665635	Notably, the cell cycle-related processes were significantly enriched only in KEP-TAMs which is in line with the phenotypical observations of Figures S1E and S1F.	('TAMs', 'Chemical', '-', (82, 86))	('enriched', 'PosReg', (61, 69))	('cell cycle-related processes', 'CPA', (13, 41))	('KEP-TAMs', 'Var', (78, 86))	('cell cycle', 'biological_process', 'GO:0007049', ('13', '23'))
31955	31665635	All single-cell suspensions were stained for 20 min at 4 C in the dark with anti-mouse F4/80 (1:200; BM8; eBioscience) and anti-mouse CD11b (1:200; M1/70; eBioscience) in IMDM supplemented with 2% FBS, 0.5% beta-mercaptoethanol, 0.5 mM EDTA, Pen/Strep.	('eBioscience', 'Disease', (155, 166))	('mouse', 'Species', '10090', (128, 133))	('CD11b', 'Gene', '16409', (134, 139))	('anti-mouse', 'Var', (123, 133))	('eBioscience', 'Disease', 'None', (155, 166))	('EDTA', 'Chemical', 'MESH:D004492', (236, 240))	('beta-mercaptoethanol', 'Chemical', 'MESH:D008623', (207, 227))	('Pen', 'Gene', '30052', (242, 245))	('CD11b', 'Gene', (134, 139))	('eBioscience', 'Disease', (106, 117))	('F4/80', 'Gene', '13733', (87, 92))	('Pen', 'Gene', (242, 245))	('FBS', 'Disease', (197, 200))	('M1/70', 'Gene', '22238', (148, 153))	('FBS', 'Disease', 'MESH:D005198', (197, 200))	('M1/70', 'Gene', (148, 153))	('F4/80', 'Gene', (87, 92))	('eBioscience', 'Disease', 'None', (106, 117))	('mouse', 'Species', '10090', (81, 86))
32045	25902937	Furthermore, E-cadherin gene mutations are present in more than 85% of invasive lobular carcinomas, likely reflecting characteristically low protein expression of E-cadherin.	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('E-cadherin', 'Gene', '999', (163, 173))	('protein expression', 'MPA', (141, 159))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (71, 98))	('mutations', 'Var', (29, 38))	('low', 'NegReg', (137, 140))	('cadherin', 'molecular_function', 'GO:0008014', ('165', '173'))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('invasive lobular carcinomas', 'Disease', (71, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (80, 97))	('E-cadherin', 'Gene', (163, 173))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (80, 98))
32108	24212814	The authors reported that ER/PR positivity was not associated with stage and not related to age, parity, menopausal status, or node metastases.	('PR', 'Gene', '5241', (29, 31))	('metastases', 'Disease', (132, 142))	('metastases', 'Disease', 'MESH:D009362', (132, 142))	('positivity', 'Var', (32, 42))	('menopausal status', 'Phenotype', 'HP:0008209', (105, 122))
32127	24212814	reported that genetic mutations in specific BRCA 1 (185delAG and 5382insC) and BRCA2 (6174delT) genes predispose to hereditary BC amongst the Ashkenazi Jewish population.	('185delAG', 'Mutation', 'c.185delAG', (52, 60))	('6174delT', 'Var', (86, 94))	('BRCA2', 'Gene', '675', (79, 84))	('hereditary BC', 'Disease', (116, 129))	('185delAG', 'Var', (52, 60))	('6174delT', 'Mutation', 'rs786204278', (86, 94))	('BC', 'Phenotype', 'HP:0003002', (127, 129))	('BRCA 1', 'Gene', (44, 50))	('BRCA2', 'Gene', (79, 84))	('5382insC', 'Mutation', 'c.5382insC', (65, 73))	('BRCA 1', 'Gene', '672', (44, 50))	('predispose', 'Reg', (102, 112))
32179	24212814	Of patients less than 50 years, 34% (17/50) were positive for Her-2 (3+), 42% were ER+ (21/50) and 48% (24/50) were PR+.	('Her-2', 'Gene', (62, 67))	('positive', 'Reg', (49, 57))	('ER+', 'Var', (83, 86))	('PR', 'Gene', '5241', (116, 118))	('patients', 'Species', '9606', (3, 11))	('Her-2', 'Gene', '2064', (62, 67))
32308	23247610	Short tandem repeat analysis performed at the University of Colorado Cancer Center Sequencing Core confirmed the human and unique genetic properties of the BCK4 cell line.	('Short tandem repeat', 'Var', (0, 19))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer', 'Disease', (69, 75))	('Cancer', 'Disease', 'MESH:D009369', (69, 75))	('BCK', 'molecular_function', 'GO:0047323', ('156', '159'))	('human', 'Species', '9606', (113, 118))
32341	23247610	The formal description:47,XX,del(1) (?p31;?q12),del(7)(q22),der(8)t(8;11)(p11;q13),11,der(16) t(1;16)(q12;q11.2)x2,+17:contains few anomalies.	('47,XX,del(1)', 'STRUCTURAL_ABNORMALITY', 'None', (23, 35))	('anomalies', 'Disease', 'MESH:D000014', (132, 141))	('p31', 'Gene', '529', (38, 41))	('der(8)t(8;11)(p11;q13', 'Var', (60, 81))	('der(8)t(8;11)(p11;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (60, 82))	('del(7)(q22', 'Var', (48, 58))	('t(1;16)(q12;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (94, 112))	('anomalies', 'Disease', (132, 141))	('p31', 'Gene', (38, 41))
32342	23247610	The BCK4 karyotype is much closer to normal than that of the commonly used T47D or MCF7 human breast cancer cells, which like 58 % of IDC with mucinous features are aneuploid.	('mucin', 'Gene', '100508689', (143, 148))	('BCK', 'molecular_function', 'GO:0047323', ('4', '7'))	('mucin', 'Gene', (143, 148))	('human', 'Species', '9606', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('aneuploid', 'Var', (165, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('T47D', 'CellLine', 'CVCL:0553', (75, 79))	('MCF7', 'CellLine', 'CVCL:0031', (83, 87))
32346	23247610	Additionally, single tandem repeat analysis of the patient's pleural effusion cells matched the BCK4 cell line (not shown).	('pleural effusion', 'Disease', (61, 77))	('pleural effusion', 'Phenotype', 'HP:0002202', (61, 77))	('BCK', 'molecular_function', 'GO:0047323', ('96', '99'))	('single tandem repeat analysis', 'Var', (14, 43))	('patient', 'Species', '9606', (51, 58))	('pleural effusion', 'Disease', 'MESH:D010996', (61, 77))
32372	23247610	3c, ethanol); much slower than that of other breast cancer cell lines, which tend to double in 24-48 h. However, BCK4 cell growth is accelerated by the synthetic AR R1881, the mixed AR/progestin/glucocorti-coid MPA, and by E2.	('ethanol', 'Chemical', 'MESH:D000431', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cell growth', 'biological_process', 'GO:0016049', ('118', '129'))	('MPA', 'Chemical', 'MESH:D017258', (211, 214))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('E2', 'Chemical', 'MESH:D004958', (223, 225))	('accelerated', 'PosReg', (133, 144))	('breast cancer', 'Disease', (45, 58))	('BCK4', 'Gene', (113, 117))	('R1881', 'Var', (165, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('BCK', 'molecular_function', 'GO:0047323', ('113', '116'))
32447	23247610	Further evidence that MBC differ from IDC NOS is based on the fact that MBC rarely contain mutations in phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) or v-akt murine thymoma viral oncogene homolog 1 (AKT1); both of which are commonly observed in IDC NOS.	('MBC', 'Disease', 'MESH:D001943', (72, 75))	('MBC', 'Disease', 'MESH:D001943', (22, 25))	('v-akt murine thymoma viral oncogene homolog 1', 'Gene', '207', (164, 209))	('MBC', 'Disease', (72, 75))	('thymoma', 'Phenotype', 'HP:0100522', (177, 184))	('AKT1', 'Gene', '11651', (211, 215))	('MBC', 'Disease', (22, 25))	('PIK3CA', 'Gene', '18706', (153, 159))	('mutations', 'Var', (91, 100))	('v-akt murine thymoma viral oncogene homolog 1', 'Gene', (164, 209))	('AKT1', 'Gene', (211, 215))	('PIK3CA', 'Gene', (153, 159))
32470	23247610	Of note is the loss of E-cadherin expression in the BCK4 cells which correlates with translocations in chromosome 16 of their karyotype (Fig.	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('expression', 'MPA', (34, 44))	('BCK', 'molecular_function', 'GO:0047323', ('52', '55'))	('loss', 'NegReg', (15, 19))	('E-cadherin', 'Gene', (23, 33))	('E-cadherin', 'Gene', '999', (23, 33))	('translocations', 'Var', (85, 99))	('cadherin', 'molecular_function', 'GO:0008014', ('25', '33'))
32569	30009102	Tumors that are negative cytokeratin (CK) 7 and positive CK20 suggest intestinal adenocarcinomas.	('negative', 'NegReg', (16, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('cytokeratin (CK) 7', 'Protein', (25, 43))	('intestinal adenocarcinomas', 'Disease', (70, 96))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('intestinal adenocarcinomas', 'Disease', 'MESH:D007414', (70, 96))	('positive', 'Var', (48, 56))	('CK20', 'Gene', (57, 61))	('CK20', 'Gene', '54474', (57, 61))	('intestinal adenocarcinomas', 'Phenotype', 'HP:0040273', (70, 96))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
32775	28560596	In a multivariate model (Table 3) including differentiation, PR status, and histology, which was limited to patients with complete data, histology was significantly associated with downstaging to BCS.	('downstaging', 'NegReg', (181, 192))	('histology', 'Var', (137, 146))	('BCS', 'Disease', (196, 199))	('PR', 'Gene', '5241', (61, 63))	('patients', 'Species', '9606', (108, 116))
32779	28560596	The greatest likelihood of downstaging in the breast was seen in the PR-/high grade or poorly differentiated tumors (62%) compared to 29% in the PR+/non-high grade, non-poorly differentiated tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('downstaging', 'NegReg', (27, 38))	('PR', 'Gene', '5241', (69, 71))	('PR', 'Gene', '5241', (145, 147))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('poorly', 'Var', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (191, 197))	('tumors', 'Disease', (109, 115))
32820	25713299	Nuclear p120-catenin regulates the anoikis resistance of mouse lobular breast cancer cells through Kaiso-dependent Wnt11 expression E-cadherin inactivation underpins the progression of invasive lobular breast carcinoma (ILC).	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('p120-catenin', 'Gene', '12388', (8, 20))	('Kaiso', 'Gene', (99, 104))	('regulates', 'Reg', (21, 30))	('lobular breast cancer', 'Disease', 'MESH:D013274', (63, 84))	('Wnt11', 'Gene', '22411', (115, 120))	('breast carcinoma', 'Phenotype', 'HP:0003002', (202, 218))	('anoikis resistance', 'CPA', (35, 53))	('p120-catenin', 'Gene', (8, 20))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (63, 84))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (185, 218))	('invasive lobular breast carcinoma', 'Disease', (185, 218))	('anoikis', 'biological_process', 'GO:0043276', ('35', '42'))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('inactivation', 'Var', (143, 155))	('Wnt11', 'Gene', (115, 120))	('lobular breast cancer', 'Disease', (63, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('mouse', 'Species', '10090', (57, 62))	('Kaiso', 'Gene', '56805', (99, 104))
32821	25713299	In ILC, p120-catenin (p120) translocates to the cytosol where it controls anchorage independence through the Rho-Rock signaling pathway, a key mechanism driving tumor growth and metastasis.	('p120-catenin', 'Gene', '12388', (8, 20))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('signaling pathway', 'biological_process', 'GO:0007165', ('118', '135'))	('anchorage independence', 'MPA', (74, 96))	('p120', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cytosol', 'cellular_component', 'GO:0005829', ('48', '55'))	('p120-catenin', 'Gene', (8, 20))	('tumor', 'Disease', (161, 166))
32825	25713299	Our findings thereby establish a mechanistic link between E-cadherin loss and subsequent control of Rho-driven anoikis resistance through p120- and Kaiso-dependent expression of Wnt11.	('cadherin', 'molecular_function', 'GO:0008014', ('60', '68'))	('anoikis', 'biological_process', 'GO:0043276', ('111', '118'))	('loss', 'NegReg', (69, 73))	('Kaiso-', 'Gene', (148, 154))	('Rho-driven anoikis resistance', 'MPA', (100, 129))	('Kaiso-', 'Gene', '56805', (148, 154))	('p120-', 'Var', (138, 143))	('E-cadherin', 'Protein', (58, 68))	('Wnt11', 'Gene', (178, 183))
32826	25713299	E-cadherin is the gatekeeper of epithelial integrity by linking its extracellular homotypic cis and trans interactions to the actin and microtubule cytoskeleton through beta-catenin, alpha-catenin and p120-catenin (p120) in cellular structures called adherens junctions (AJs) (reviewed in).	('gatekeeper', 'Species', '111938', (18, 28))	('p120-catenin', 'Gene', '12388', (201, 213))	('extracellular', 'cellular_component', 'GO:0005576', ('68', '81'))	('p120', 'Var', (215, 219))	('p120-catenin', 'Gene', (201, 213))	('microtubule cytoskeleton', 'cellular_component', 'GO:0015630', ('136', '160'))	('beta-catenin', 'Gene', (169, 181))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('beta-catenin', 'Gene', '12387', (169, 181))
32827	25713299	Loss of AJ function through inhibition of E-cadherin was linked to cancer cell invasiveness more than two decades ago, and these findings were further substantiated shortly thereafter by the discovery of inactivating germ line and somatic E-cadherin mutations in gastric carcinoma and breast cancer.	('gastric carcinoma', 'Disease', (263, 280))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (263, 280))	('linked', 'Reg', (57, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('cancer cell invasiveness', 'Disease', 'MESH:D009362', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('Loss', 'NegReg', (0, 4))	('cadherin', 'molecular_function', 'GO:0008014', ('241', '249'))	('breast cancer', 'Disease', 'MESH:D001943', (285, 298))	('inhibition', 'NegReg', (28, 38))	('breast cancer', 'Disease', (285, 298))	('cancer cell invasiveness', 'Disease', (67, 91))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('inactivating', 'Var', (204, 216))	('E-cadherin', 'Gene', (239, 249))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (250, 259))	('gastric carcinoma', 'Disease', 'MESH:D013274', (263, 280))	('E-cadherin', 'Protein', (42, 52))
32832	25713299	Although in normal epithelium p120 controls stability of the AJ through binding and stabilization of E-cadherin, loss of E-cadherin leads to translocation of p120 to the cytosol where it acts as an oncogene by regulating anchorage-independent tumor growth and metastasis through GTPase-dependent induction of resistance to anoikis (apoptosis that is induced through loss of cell-matrix adhesion).	('cell-matrix adhesion', 'biological_process', 'GO:0007160', ('374', '394'))	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('cytosol', 'cellular_component', 'GO:0005829', ('170', '177'))	('GTP', 'Chemical', 'MESH:D006160', (279, 282))	('apoptosis', 'biological_process', 'GO:0097194', ('332', '341'))	('regulating', 'Reg', (210, 220))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('binding', 'molecular_function', 'GO:0005488', ('72', '79'))	('loss', 'Var', (113, 117))	('cadherin', 'molecular_function', 'GO:0008014', ('123', '131'))	('metastasis', 'CPA', (260, 270))	('E-cadherin', 'Gene', (121, 131))	('apoptosis', 'biological_process', 'GO:0006915', ('332', '341'))	('anoikis', 'biological_process', 'GO:0043276', ('323', '330'))	('translocation', 'MPA', (141, 154))	('resistance to', 'CPA', (309, 322))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
32835	25713299	Unlike its BTB/POZ-ZF family members, Kaiso is thought to interact with target gene promoters through sequence-specific Kaiso-binding sites (KBSs; consensus sequence TCCTGCNA) and/or methylated CpG dinucleotides.	('Kaiso-', 'Gene', (120, 126))	('interact', 'Interaction', (58, 66))	('Kaiso-', 'Gene', '56805', (120, 126))	('methylated', 'Var', (183, 193))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))
32837	25713299	Binding to p120 relieves Kaiso-dependent transcriptional repression, suggesting that there is a crucial role for p120 in regulating gene expression.	('p120', 'Var', (11, 15))	('gene expression', 'biological_process', 'GO:0010467', ('132', '147'))	('relieves', 'NegReg', (16, 24))	('Binding', 'Var', (0, 7))	('Kaiso-', 'Gene', '56805', (25, 31))	('Kaiso-', 'Gene', (25, 31))
32843	25713299	Invasive lobular cancer (ILC) is a major breast cancer type that is characterized by a non-cohesive and infiltrative growth pattern due to E-cadherin (a transmembrane protein that controls cell-cell adhesion) inactivation and subsequent constitutive activation of Rho-Rock signaling.	('transmembrane', 'cellular_component', 'GO:0016021', ('153', '166'))	('activation', 'PosReg', (250, 260))	('signaling', 'biological_process', 'GO:0023052', ('273', '282'))	('transmembrane', 'cellular_component', 'GO:0044214', ('153', '166'))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('growth pattern', 'biological_process', 'GO:0007150', ('117', '131'))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('189', '207'))	('inactivation', 'Var', (209, 221))	('growth pattern', 'biological_process', 'GO:0040007', ('117', '131'))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('Invasive lobular cancer', 'Disease', (0, 23))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('Rho-Rock signaling', 'Pathway', (264, 282))	('breast cancer', 'Disease', (41, 54))	('E-cadherin', 'Protein', (139, 149))	('lobular cancer', 'Phenotype', 'HP:0030076', (9, 23))	('Invasive lobular cancer', 'Disease', 'MESH:D013274', (0, 23))	('cadherin', 'molecular_function', 'GO:0008014', ('141', '149'))
32850	25713299	The identification of a p120-Kaiso-Wnt11-dependent autocrine activation of RhoA that drives anchorage independence underpins the use of Rho-Rock targeting as a therapeutic strategy in the treatment of metastatic ILC.	('p120-Kaiso-Wnt11-dependent', 'Var', (24, 50))	('anchorage independence', 'MPA', (92, 114))	('metastatic ILC', 'Disease', (201, 215))	('RhoA', 'Gene', (75, 79))	('autocrine', 'MPA', (51, 60))	('RhoA', 'Gene', '11848', (75, 79))
32851	25713299	Here, we show that translocation of p120 inhibits Kaiso-mediated transcriptional repression in ILC.	('inhibits', 'NegReg', (41, 49))	('Kaiso-', 'Gene', '56805', (50, 56))	('p120', 'Var', (36, 40))	('Kaiso-', 'Gene', (50, 56))	('translocation', 'Var', (19, 32))
32852	25713299	Moreover, we were able to show that the nuclear pool of p120 is increased in anchorage-independent mouse ILC (mILC) cells, a mechanism which could induce Kaiso target gene expression specifically in anchorage-independent ILC.	('p120', 'Var', (56, 60))	('mouse', 'Species', '10090', (99, 104))	('anchorage-independent mouse ILC', 'Disease', (77, 108))	('nuclear pool', 'MPA', (40, 52))	('induce', 'PosReg', (147, 153))	('expression', 'MPA', (172, 182))	('increased', 'PosReg', (64, 73))	('gene expression', 'biological_process', 'GO:0010467', ('167', '182'))
32854	25713299	Previously, we have generated mouse models for human metastatic ILC based on tissue-specific inactivation of E-cadherin and p53 using either cytokeratin 14 or whey acidic protein promoter elements to drive Cre recombinase (K14cre;Cdh1F/F;Trp53F/F and WAPcre;Cdh1F/F;Trp53F/F).	('p53', 'Gene', (240, 243))	('p53', 'Gene', (124, 127))	('Trp53', 'Gene', '22059', (266, 271))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('cytokeratin 14', 'Gene', (141, 155))	('cytokeratin 14', 'Gene', '3861', (141, 155))	('p53', 'Gene', (268, 271))	('Trp53', 'Gene', '22059', (238, 243))	('p53', 'Gene', '7157', (240, 243))	('p53', 'Gene', '7157', (268, 271))	('p53', 'Gene', '7157', (124, 127))	('inactivation', 'Var', (93, 105))	('Trp53', 'Gene', (238, 243))	('cadherin', 'molecular_function', 'GO:0008014', ('111', '119'))	('human', 'Species', '9606', (47, 52))	('Trp53', 'Gene', (266, 271))	('mouse', 'Species', '10090', (30, 35))
32855	25713299	In these mouse models, loss of E-cadherin results in the translocation of p120 to the cytosol where it regulates anchorage-independent tumor growth and metastasis through p120-dependent activation of Rho-Rock signaling.	('E-cadherin', 'Protein', (31, 41))	('activation', 'PosReg', (186, 196))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('metastasis', 'CPA', (152, 162))	('Rho-Rock signaling', 'Pathway', (200, 218))	('tumor', 'Disease', (135, 140))	('mouse', 'Species', '10090', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('p120-dependent', 'Var', (171, 185))	('cytosol', 'cellular_component', 'GO:0005829', ('86', '93'))	('loss', 'NegReg', (23, 27))	('regulates', 'Reg', (103, 112))	('cadherin', 'molecular_function', 'GO:0008014', ('33', '41'))	('signaling', 'biological_process', 'GO:0023052', ('209', '218'))	('translocation', 'MPA', (57, 70))
32856	25713299	Because p120 has the ability to shuttle between the nucleus and the cytosol, we set out to determine a possible functional role for nuclear p120 in E-cadherin-negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('cytosol', 'cellular_component', 'GO:0005829', ('68', '75'))	('nucleus', 'cellular_component', 'GO:0005634', ('52', '59'))	('p120', 'Var', (8, 12))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('p120', 'Var', (140, 144))	('shuttle', 'MPA', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
32859	25713299	Immunofluorescence analysis of cells derived from pleural effusion fluids confirmed that p120 was also localized to the cytosol and nucleus in primary human metastatic ILC (hILC-2 and hILC-3; Fig.	('human', 'Species', '9606', (151, 156))	('pleural effusion', 'Disease', (50, 66))	('pleural effusion', 'Disease', 'MESH:D010996', (50, 66))	('pleural effusion', 'Phenotype', 'HP:0002202', (50, 66))	('nucleus', 'cellular_component', 'GO:0005634', ('132', '139'))	('p120', 'Var', (89, 93))	('cytosol', 'cellular_component', 'GO:0005829', ('120', '127'))
32862	25713299	1B,C, right panels) to emphasize that cytoplasmic and nuclear p120 is virtually absent in nonmetastatic breast cancer cells expressing a functional E-cadherin-based adherens junction.	('E-cadherin-based adherens junction', 'Protein', (148, 182))	('absent', 'NegReg', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('adherens junction', 'cellular_component', 'GO:0005912', ('165', '182'))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('p120', 'Var', (62, 66))
32863	25713299	To corroborate these findings in breast cancer, we validated the interaction between p120 and Kaiso in mILC-1 cells by co-immunoprecipitation (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('interaction', 'Interaction', (65, 76))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('p120', 'Var', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
32865	25713299	Indeed, Kaiso reporter activity was significantly higher in mILC cell lines compared to E-cadherin-expressing Trp53Delta/Delta cell lines, indicative of relief of Kaiso-mediated transcriptional repression (Fig.	('cadherin', 'molecular_function', 'GO:0008014', ('90', '98'))	('Kaiso-', 'Gene', '56805', (163, 169))	('higher', 'PosReg', (50, 56))	('Kaiso-', 'Gene', (163, 169))	('Trp53', 'Gene', (110, 115))	('Kaiso reporter activity', 'MPA', (8, 31))	('mILC', 'Var', (60, 64))	('Trp53', 'Gene', '22059', (110, 115))
32867	25713299	Indeed, basal Kaiso reporter activity in PMC-1 cells was significantly reduced compared to mILC cell lines, suggesting that p120 antagonizes Kaiso-mediated transcriptional repression (Fig.	('Kaiso-', 'Gene', (141, 147))	('Kaiso reporter activity', 'MPA', (14, 37))	('PMC-1', 'CellLine', 'CVCL:3773', (41, 46))	('reduced', 'NegReg', (71, 78))	('antagonizes', 'NegReg', (129, 140))	('Kaiso-', 'Gene', '56805', (141, 147))	('p120', 'Var', (124, 128))
32869	25713299	Taken together, these data demonstrate that translocation of p120 causes the inhibition of Kaiso-mediated transcriptional repression in E-cadherin-deficient ILC cells.	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('Kaiso-', 'Gene', '56805', (91, 97))	('inhibition', 'NegReg', (77, 87))	('p120', 'Var', (61, 65))	('Kaiso-', 'Gene', (91, 97))	('translocation', 'Var', (44, 57))
32870	25713299	Given the p120-dependent relief of Kaiso-mediated transcriptional repression in mILC cells, we reasoned that the nuclear influx of p120 could alter the subcellular localization of Kaiso.	('Kaiso-', 'Gene', (35, 41))	('p120', 'Var', (131, 135))	('subcellular localization', 'MPA', (152, 176))	('alter', 'Reg', (142, 147))	('localization', 'biological_process', 'GO:0051179', ('164', '176'))	('Kaiso-', 'Gene', '56805', (35, 41))	('p120-dependent', 'Var', (10, 24))
32871	25713299	To test this, we initially assessed localization of p120 and Kaiso in mILC-1 cells and the E-cadherin-expressing Trp53Delta/Delta-4 cell line using immunofluorescence microscopy.	('Trp53Delta/Delta-4', 'Gene', (113, 131))	('Trp53Delta/Delta-4', 'Gene', '54485', (113, 131))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('localization', 'biological_process', 'GO:0051179', ('36', '48'))	('p120', 'Var', (52, 56))
32875	25713299	By using immunofluorescence microscopy, we determined that colocalization of Kaiso and the active transcription marker H3K4me3 was significantly lower in mILC-1 cells when compared to Trp53Delta/Delta-4 cells (Fig.	('colocalization', 'MPA', (59, 73))	('Trp53Delta/Delta-4', 'Gene', (184, 202))	('Trp53Delta/Delta-4', 'Gene', '54485', (184, 202))	('lower', 'NegReg', (145, 150))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('mILC-1', 'Var', (154, 160))
32878	25713299	Given the fact that membrane-uncoupled p120 controls anchorage-independent tumor growth and metastasis of ILC, and nuclear p120 antagonizes Kaiso-dependent transcriptional repression in mILC cell lines, we hypothesized that Kaiso target genes could contribute to anchorage-independent survival of metastatic ILC.	('contribute', 'Reg', (249, 259))	('antagonizes', 'NegReg', (128, 139))	('metastasis', 'CPA', (92, 102))	('Kaiso-', 'Gene', '56805', (140, 146))	('p120', 'Var', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('membrane', 'cellular_component', 'GO:0016020', ('20', '28'))	('Kaiso-', 'Gene', (140, 146))	('tumor', 'Disease', (75, 80))
32881	25713299	Our results suggest a functional link between anoikis resistance and p120-dependent relief of Kaiso-mediated transcriptional repression.	('relief', 'NegReg', (84, 90))	('p120-dependent', 'Var', (69, 83))	('Kaiso-', 'Gene', (94, 100))	('anoikis resistance', 'Disease', (46, 64))	('anoikis', 'biological_process', 'GO:0043276', ('46', '53'))	('Kaiso-', 'Gene', '56805', (94, 100))
32882	25713299	To confirm that p120 is indeed regulating Wnt11 expression through Kaiso, we again made use of the E-cadherin-proficient Trp53Delta/Delta-4 cell line.	('Wnt11', 'Gene', (42, 47))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('Trp53Delta/Delta-4', 'Gene', (121, 139))	('expression', 'MPA', (48, 58))	('p120', 'Var', (16, 20))	('Trp53Delta/Delta-4', 'Gene', '54485', (121, 139))
32886	25713299	Ablation of Kaiso by administration of dox induced a threefold induction of Wnt11 expression (Fig.	('Wnt11', 'Gene', (76, 81))	('Ablation', 'Var', (0, 8))	('dox', 'Chemical', 'MESH:D004318', (39, 42))	('induction', 'PosReg', (63, 72))
32887	25713299	In summary, these results confirm the validity of Wnt11 as a genuine Kaiso target in mILC and demonstrate its regulation in E-cadherin-deficient breast cancer cells by nuclear p120.	('regulation', 'MPA', (110, 120))	('deficient breast cancer', 'Disease', (135, 158))	('deficient breast cancer', 'Disease', 'MESH:D001943', (135, 158))	('nuclear p120', 'Var', (168, 180))	('deficient breast', 'Phenotype', 'HP:0003187', (135, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('126', '134'))	('regulation', 'biological_process', 'GO:0065007', ('110', '120'))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Wnt11', 'Gene', (50, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
32888	25713299	To investigate whether the p120-dependent upregulation of Wnt11 in mILC promotes anoikis resistance, we transduced three mILC cell lines with a Wnt11-iKD construct and assayed the effect on anchorage-independent survival in absence or presence of dox.	('anoikis resistance', 'CPA', (81, 99))	('anoikis', 'biological_process', 'GO:0043276', ('81', '88'))	('promotes', 'PosReg', (72, 80))	('dox', 'Chemical', 'MESH:D004318', (247, 250))	('Wnt11', 'Gene', (58, 63))	('upregulation', 'PosReg', (42, 54))	('p120-dependent', 'Var', (27, 41))
32891	25713299	Although the inhibition of Mrip by p120 provided a rationale for increased Rho activity in the presence of cytosolic p120, it did not reveal the upstream signal that drives RhoA.	('increased', 'PosReg', (65, 74))	('p120', 'Var', (35, 39))	('Mrip', 'Gene', (27, 31))	('RhoA', 'Gene', (173, 177))	('RhoA', 'Gene', '11848', (173, 177))	('Rho', 'Enzyme', (75, 78))	('inhibition', 'NegReg', (13, 23))
32893	25713299	To address this, we assayed RhoA activity in the absence or presence of Wnt11-iKD and observed that Wnt11-iKD resulted in a marked reduction of active GTP-bound RhoA (Fig.	('reduction', 'NegReg', (131, 140))	('RhoA', 'Gene', '11848', (28, 32))	('GTP', 'Chemical', 'MESH:D006160', (151, 154))	('Wnt11-iKD', 'Var', (100, 109))	('RhoA', 'Gene', (161, 165))	('RhoA', 'Gene', '11848', (161, 165))	('RhoA', 'Gene', (28, 32))
32898	25713299	Here, we show that nuclear p120 exerts an oncogenic function by inhibiting Kaiso-mediated transcriptional repression and thereby induces expression of the Kaiso target gene Wnt11, a factor that drives Rho-dependent anoikis resistance in ILC.	('nuclear p120', 'Var', (19, 31))	('expression', 'MPA', (137, 147))	('anoikis', 'biological_process', 'GO:0043276', ('215', '222'))	('inhibiting', 'NegReg', (64, 74))	('Kaiso-', 'Gene', '56805', (75, 81))	('Wnt11', 'Gene', (173, 178))	('Kaiso-', 'Gene', (75, 81))	('induces', 'PosReg', (129, 136))
32899	25713299	Although it is still largely unknown how p120 transverses the nuclear pore and what factors mediate this transport, our observations support previous data showing that p120 relieves Kaiso-mediated transcriptional repression.	('Kaiso-', 'Gene', '56805', (182, 188))	('relieves', 'NegReg', (173, 181))	('Kaiso-', 'Gene', (182, 188))	('nuclear pore', 'cellular_component', 'GO:0005643', ('62', '74'))	('transport', 'biological_process', 'GO:0006810', ('105', '114'))	('p120', 'Var', (168, 172))
32900	25713299	Furthermore, we demonstrate that E-cadherin mutant breast cancer cells increase their nuclear p120 levels upon transfer to anchorage-independent conditions.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('E-cadherin', 'Protein', (33, 43))	('increase', 'PosReg', (71, 79))	('nuclear p120 levels', 'MPA', (86, 105))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('cadherin', 'molecular_function', 'GO:0008014', ('35', '43'))	('breast cancer', 'Disease', (51, 64))	('mutant', 'Var', (44, 50))
32901	25713299	Finally, our studies show that Kaiso is displaced from transcriptionally active genomic regions leading to increased endogenous Kaiso reporter activity in E-cadherin mutant breast cancer cells.	('E-cadherin', 'Protein', (155, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('increased', 'PosReg', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('endogenous Kaiso reporter activity', 'MPA', (117, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('mutant', 'Var', (166, 172))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Disease', (173, 186))
32904	25713299	Although the mode of action shared similarities, Kaiso did not associate with the p120-REST-CoREST complex, suggesting that nuclear p120 might have a broad function in the regulation of transcriptional repression.	('regulation', 'biological_process', 'GO:0065007', ('172', '182'))	('CoREST', 'Gene', '104383', (92, 98))	('nuclear p120', 'Var', (124, 136))	('CoREST', 'Gene', (92, 98))	('transcriptional repression', 'MPA', (186, 212))
32907	25713299	These data are in line with observations described here and by others that cytosolic and nuclear translocation of p120 can relieve Kaiso-mediated transcriptional repression.	('relieve', 'PosReg', (123, 130))	('Kaiso-', 'Gene', (131, 137))	('p120', 'Var', (114, 118))	('Kaiso-', 'Gene', '56805', (131, 137))
32908	25713299	In addition, we did not observe enrichment of genes harboring TCF/LEF-binding sites in their promoter regions confirming previous findings that the beta-catenin-dependent canonical Wnt signaling pathway is not activated by loss of E-cadherin.	('loss', 'Var', (223, 227))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('beta-catenin', 'Gene', (148, 160))	('canonical Wnt signaling pathway', 'biological_process', 'GO:0060070', ('171', '202'))	('cadherin', 'molecular_function', 'GO:0008014', ('233', '241'))	('E-cadherin', 'Protein', (231, 241))	('beta-catenin', 'Gene', '12387', (148, 160))
32910	25713299	Moreover, we demonstrate that p120-dependent derepression of the Kaiso target gene Wnt11 activates an autocrine Wnt11 signal that acts upstream of RhoA-dependent ILC anoikis resistance.	('p120-dependent derepression', 'Var', (30, 57))	('Wnt11', 'Gene', (83, 88))	('derepression', 'Var', (45, 57))	('autocrine Wnt11 signal', 'MPA', (102, 124))	('anoikis', 'biological_process', 'GO:0043276', ('166', '173'))	('RhoA', 'Gene', (147, 151))	('activates', 'PosReg', (89, 98))	('RhoA', 'Gene', '11848', (147, 151))
32914	25713299	In short, although the mechanism underlying Wnt11 expression differs between studies, it is clear that induction of Wnt11 expression results in (pro)metastatic behavior of breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('results in', 'Reg', (133, 143))	('induction', 'Var', (103, 112))	('breast cancer', 'Disease', (172, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('Wnt11', 'Gene', (116, 121))
32915	25713299	Taken together, we think our data have unraveled a mechanism whereby mutational inactivation of E-cadherin, and subsequent nuclear translocation of p120, leads to relief of Kaiso-mediated transcriptional repression of Wnt11 and subsequent anoikis resistance of ILC cells.	('E-cadherin', 'Protein', (96, 106))	('p120', 'Var', (148, 152))	('mutational', 'Var', (69, 79))	('Kaiso-', 'Gene', '56805', (173, 179))	('anoikis resistance', 'CPA', (239, 257))	('anoikis', 'biological_process', 'GO:0043276', ('239', '246'))	('Kaiso-', 'Gene', (173, 179))	('cadherin', 'molecular_function', 'GO:0008014', ('98', '106'))	('Wnt11', 'Gene', (218, 223))	('relief', 'PosReg', (163, 169))
32918	25713299	However, we believe that options for clinical interventions should be based on inhibition of Rho and Rock, because they represent the central hub in the regulation of anchorage-independent tumor growth and metastasis of E-cadherin mutant breast cancer.	('regulation', 'biological_process', 'GO:0065007', ('153', '163'))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cadherin', 'molecular_function', 'GO:0008014', ('222', '230'))	('Rho', 'Protein', (93, 96))	('mutant', 'Var', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))	('breast cancer', 'Disease', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('E-cadherin', 'Protein', (220, 230))
32919	25713299	In conclusion, our data establish a novel functional link between mutational inactivation of E-cadherin and subsequent p120-dependent relief of Kaiso-mediated transcriptional repression of Wnt11.	('relief', 'PosReg', (134, 140))	('E-cadherin', 'Protein', (93, 103))	('Kaiso-', 'Gene', '56805', (144, 150))	('p120-dependent', 'Var', (119, 133))	('Kaiso-', 'Gene', (144, 150))	('cadherin', 'molecular_function', 'GO:0008014', ('95', '103'))	('mutational', 'Var', (66, 76))	('Wnt11', 'Gene', (189, 194))
32920	25713299	In addition, we show that nucleocytoplasmic shuttling of p120 is the rate-limiting step in inhibition of Kaiso-mediated transcriptional repression.	('Kaiso-', 'Gene', '56805', (105, 111))	('inhibition', 'NegReg', (91, 101))	('p120', 'Var', (57, 61))	('nucleocytoplasmic shuttling', 'biological_process', 'GO:0006913', ('26', '53'))	('Kaiso-', 'Gene', (105, 111))
32923	25713299	Transduced cells were cultured for 4 days in the presence of 1.0 mug/ml doxycycline in order to induce p120-, Kaiso- and Wnt11-specific shRNA expression (iKD).	('Kaiso-', 'Gene', '56805', (110, 116))	('mug', 'molecular_function', 'GO:0043739', ('65', '68'))	('Kaiso-', 'Gene', (110, 116))	('induce', 'PosReg', (96, 102))	('p120-', 'Var', (103, 108))	('doxycycline', 'Chemical', 'MESH:D004318', (72, 83))
32973	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))
32981	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))
32985	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))
33023	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))
33043	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.	('gene expression', 'biological_process', 'GO:0010467', ('27', '42'))	('gene expression', 'biological_process', 'GO:0010467', ('264', '279'))	('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))
33045	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))
33048	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))	('chromosomal region', 'cellular_component', 'GO:0098687', ('122', '140'))	('gain', 'PosReg', (114, 118))	('chromosome', 'cellular_component', 'GO:0005694', ('89', '99'))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('amplification', 'Var', (151, 164))
33057	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))
33060	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))
33061	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))
33085	31888717	Since the vast majority of ER+ BC are IDCs (currently, invasive breast carcinoma NST), results obtained were dominated by this tumor subtype.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('ER+ BC', 'Var', (27, 33))	('tumor', 'Disease', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('breast carcinoma', 'Phenotype', 'HP:0003002', (64, 80))	('IDC', 'Gene', '4000', (38, 41))	('BC', 'Phenotype', 'HP:0003002', (31, 33))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('invasive breast carcinoma NST', 'Disease', (55, 84))	('IDC', 'Gene', (38, 41))	('invasive breast carcinoma NST', 'Disease', 'MESH:D001943', (55, 84))
33103	31888717	Factors included in multivariable regression analyses were histological grade (G1/G2, G3), T stage (pT1/2, pT3/4), nodal status (pN0, pN1/2/3), PgR (< 20% and >= 20%), Ki-67 (divided using institutional median value as < 20%, >= 20%), and HER2 overexpression (negative, positive).	('PgR', 'Gene', (144, 147))	('nodal', 'Gene', (115, 120))	('G1/G2', 'Var', (79, 84))	('nodal', 'Gene', '4838', (115, 120))	('HER2', 'Gene', (239, 243))	('HER2', 'Gene', '2064', (239, 243))	('overexpression', 'PosReg', (244, 258))	('PgR', 'Gene', '5241', (144, 147))
33129	31888717	In multivariable analysis, factors retaining significant and independent prognostic value for risk of late DM were nodal status, T stage, and Ki-67 LI (Table 2).	('DM', 'Disease', 'MESH:D009223', (107, 109))	('Ki-67 LI', 'Var', (142, 150))	('nodal', 'Gene', '4838', (115, 120))	('nodal', 'Gene', (115, 120))
33136	31888717	In lymph node-negative ILCs, tumors with Ki-67 >= 20% had a risk of late DM almost three times higher than those with Ki-67 < 20% (HR, 2.88; 95% CI, 1.29-6.45; Table 3).	('Ki-67 >= 20%', 'Var', (41, 53))	('higher', 'PosReg', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('DM', 'Disease', 'MESH:D009223', (73, 75))	('tumors', 'Disease', (29, 35))
33137	31888717	In lymph node-positive tumors, the risk of late DM was 50% higher in tumors with Ki-67 >= 20% (HR, 1.52; 95% CI, 0.85-2.72; Table 3).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('>= 20%', 'Var', (87, 93))	('DM', 'Disease', 'MESH:D009223', (48, 50))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('Ki-67', 'Gene', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
33138	31888717	In the group of lymph node-negative tumors with Ki-67 < 20% (701 of 1426 ILCs), there was a very low incidence of late DM (absolute distant recurrence risk in years 5 to 10, 2.5%; 95% CI, 1.3-4.3; Fig.	('DM', 'Disease', 'MESH:D009223', (119, 121))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('Ki-67', 'Var', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
33139	31888717	Lymph node-positive tumors with Ki-67 >= 20% displayed the highest incidence of late DM (absolute distant recurrence risk in years 5 to 10, 15.5%; 95% CI, 9.8-22.5; Fig.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('DM', 'Disease', 'MESH:D009223', (85, 87))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('Ki-67 >= 20%', 'Var', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
33141	31888717	These data show that in ILCs, KI-67 LI retained a significant and unchanged prognostic value for risk of DM in the late period of FUP as compared with the first 5 years after surgery, whereas positive nodal status had a significantly reduced prognostic value in late follow-up.	('nodal', 'Gene', (201, 206))	('nodal', 'Gene', '4838', (201, 206))	('DM', 'Disease', 'MESH:D009223', (105, 107))	('KI-67 LI', 'Var', (30, 38))
33146	31888717	Ki-67 LI was significantly associated with risk of DM only in the first 5 years of follow-up (HR, 2.73; 95% CI, 1.89-3.94; Additional file 1: Table S5) and lost its prognostic value in the subsequent period of FUP (HR, 1.57; 95% CI, 0.91-2.70; p heterogeneity 0.10; Additional file 1: Table S5).	('associated', 'Reg', (27, 37))	('Ki-67 LI', 'Var', (0, 8))	('DM', 'Disease', 'MESH:D009223', (51, 53))
33157	31888717	The group of patients with low KiCTS5 had a 1.9% (95% CI, 0.7-4.2) absolute risk of DM in years 5 to 10 of follow-up (Fig.	('DM', 'Disease', 'MESH:D009223', (84, 86))	('KiCTS5', 'Var', (31, 37))	('low KiCTS5', 'Var', (27, 37))	('patients', 'Species', '9606', (13, 21))
33159	31888717	Patients with ER-positive tumors continue to have a higher risk of relapse, including distant metastases, during years 5 to 25.	('ER-positive', 'Var', (14, 25))	('metastases', 'Disease', (94, 104))	('relapse', 'CPA', (67, 74))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
33171	31888717	In this regard, it has been demonstrated that alteration of the mechanisms that control cell cycle, and in particular of the cyclin D/cyclin-dependent kinases 4 and 6 (CDK4/6)/retinoblastoma (Rb) pathway, is one of the most relevant mechanisms of endocrine resistance in metastatic BCs, with some data obtained from neoadjuvant treatments.	('alteration', 'Var', (46, 56))	('retinoblastoma', 'Gene', '5925', (176, 190))	('metastatic BCs', 'Disease', (271, 285))	('retinoblastoma', 'Gene', (176, 190))	('Rb', 'Phenotype', 'HP:0009919', (192, 194))	('CDK', 'molecular_function', 'GO:0004693', ('168', '171'))	('BC', 'Phenotype', 'HP:0003002', (282, 284))	('retinoblastoma', 'Phenotype', 'HP:0009919', (176, 190))	('cyclin', 'molecular_function', 'GO:0016538', ('125', '131'))	('cyclin', 'molecular_function', 'GO:0016538', ('134', '140'))	('cell cycle', 'CPA', (88, 98))	('cell cycle', 'biological_process', 'GO:0007049', ('88', '98'))
33179	31888717	Obviously, further validation of the prognostic value of KiCST5 score in an independent cohort of patients with ILCs is needed, especially to evaluate whether and how much the reported interlaboratory variability in the assessment of Ki67-LI could limit the generalizability of the prognostic value of the KiCST5.	('patients', 'Species', '9606', (98, 106))	('Ki67-LI', 'Var', (234, 241))	('ILCs', 'Disease', (112, 116))
33372	24743323	These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0x10-10; P-het for ILC vs IDC ER+ tumors = 1.8x10-4).	('rs11977670', 'Mutation', 'rs11977670', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('rs11977670', 'Var', (58, 68))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (149, 155))	('ILC', 'Disease', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))
33374	24743323	Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04).	('associations', 'Interaction', (172, 184))	('rs1752911', 'Mutation', 'rs1752911', (243, 252))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('ILC', 'Disease', (56, 59))	('MAP3K', 'molecular_function', 'GO:0004709', ('125', '130'))	('MAP3K1', 'Gene', (125, 131))	('MAP3K1', 'Gene', '4214', (125, 131))	('FGFR2', 'Gene', (87, 92))	('rs2981579', 'Mutation', 'rs2981579', (71, 80))	('rs889312', 'Mutation', 'rs889312', (111, 119))	('associations', 'Interaction', (39, 51))	('LGR6', 'Gene', '59352', (219, 223))	('rs6678914', 'Mutation', 'rs6678914', (204, 213))	('rs1752911/6q14', 'Var', (243, 257))	('LGR6', 'Gene', (219, 223))	('stronger', 'PosReg', (30, 38))	('LCIS', 'Disease', (189, 193))	('FGFR2', 'Gene', '2263', (87, 92))	('stronger', 'PosReg', (163, 171))
33375	24743323	In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7).	('CDCA7', 'Gene', (351, 356))	('rs10941679', 'Mutation', 'rs10941679', (280, 290))	('rs10995190', 'Mutation', 'rs10995190', (215, 225))	('FGFR2', 'Gene', '2263', (205, 210))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('ILC', 'Disease', (167, 170))	('rs1550623', 'Mutation', 'rs1550623', (336, 345))	('rs11249433', 'Mutation', 'rs11249433', (172, 182))	('FGFR', 'molecular_function', 'GO:0005007', ('205', '209'))	('RAD51L1', 'Gene', '5890', (308, 315))	('ZNF365', 'Gene', (232, 238))	('rs6472903/8q21', 'Var', (317, 331))	('CDCA7', 'Gene', '83879', (351, 356))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('rs2588809', 'Mutation', 'rs2588809', (292, 301))	('rs2981579', 'Mutation', 'rs2981579', (189, 198))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('rs11249433/1p11', 'Var', (172, 187))	('RAD', 'biological_process', 'GO:1990116', ('308', '311'))	('tumors', 'Disease', (83, 89))	('IDC', 'Disease', (270, 273))	('FGFR2', 'Gene', (205, 210))	('RAD51L1', 'Gene', (308, 315))	('rs6472903', 'Mutation', 'rs6472903', (317, 326))	('ZNF365', 'Gene', '22891', (232, 238))	('associations', 'Reg', (150, 162))
33382	24743323	We also ascertained which of the known variants predisposes specifically to lobular breast cancer and show for the first time that some of these loci are also associated with lobular carcinoma in situ, a non-obligate precursor of breast cancer and also a risk factor for contralateral breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('breast cancer', 'Disease', (230, 243))	('associated', 'Reg', (159, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (285, 298))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (271, 298))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('breast cancer', 'Disease', 'MESH:D001943', (285, 298))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('lobular breast cancer', 'Disease', (76, 97))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (175, 192))	('lobular carcinoma in situ', 'Disease', 'MESH:D000071960', (175, 200))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (175, 200))	('variants', 'Var', (39, 47))	('lobular breast cancer', 'Disease', 'MESH:D013274', (76, 97))	('contralateral breast cancer', 'Disease', (271, 298))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (76, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (183, 200))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lobular carcinoma in situ', 'Disease', (175, 200))
33393	24743323	Women who have had LCIS are 2.4 times more likely to develop invasive breast cancer compared to the general population, with an excess of ILC (23-80% of cases).	('LCIS', 'Var', (19, 23))	('Women', 'Species', '9606', (0, 5))	('invasive breast cancer', 'Disease', 'MESH:D001943', (61, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('develop', 'PosReg', (53, 60))	('invasive breast cancer', 'Disease', (61, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ILC', 'Disease', (138, 141))
33396	24743323	Unlike DCIS, LCIS is also a risk factor for developing invasive cancer in the contralateral breast.	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('invasive cancer', 'Disease', 'MESH:D009362', (55, 70))	('LCIS', 'Var', (13, 17))	('invasive cancer', 'Disease', (55, 70))
33406	24743323	In order to identify new loci that predispose to lobular carcinoma, we selected six uncorrelated SNPs (rs11977670, rs2121783, rs2747652, rs3909680, rs9948182, rs7034265) that were only weakly correlated (r2<0.25) with known loci and that showed the best evidence of association (P between 5x10-8 and 5x10-5) in the overall lobular case-control analysis (ILC and LCIS).	('rs2121783', 'Mutation', 'rs2121783', (115, 124))	('rs9948182', 'Var', (148, 157))	('lobular carcinoma', 'Disease', 'MESH:D018275', (49, 66))	('rs11977670', 'Mutation', 'rs11977670', (103, 113))	('rs9948182', 'Mutation', 'rs9948182', (148, 157))	('lobular carcinoma', 'Disease', (49, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('rs11977670', 'Var', (103, 113))	('rs7034265', 'Mutation', 'rs7034265', (159, 168))	('rs2121783', 'Var', (115, 124))	('rs7034265', 'Var', (159, 168))	('rs2747652', 'Mutation', 'rs2747652', (126, 135))	('rs3909680', 'Var', (137, 146))	('rs3909680', 'Mutation', 'rs3909680', (137, 146))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (49, 66))	('rs2747652', 'Var', (126, 135))
33408	24743323	rs11977670 showed a similar association with LCIS (P-het for ILC vs LCIS = 0.198), and a very weak or no association with IDC (OR = 1.02, 95%CI = 1.00-1.05, P = 0.070; P-het for ILC vs IDC = 1.3x10-5), indicating that this is a lobular specific predisposition locus (Table 2).	('rs11977670', 'Mutation', 'rs11977670', (0, 10))	('IDC', 'Disease', (122, 125))	('LCIS', 'Disease', (45, 49))	('rs11977670', 'Var', (0, 10))
33409	24743323	rs11977670 was not significantly associated with age at onset of ILC (Ptrend = 0.16) and risk alleles were not significantly over-represented in cases with a positive family history (FH) (P = 0.90, FH+ vs FH-).	('rs11977670', 'Mutation', 'rs11977670', (0, 10))	('ILC', 'Disease', (65, 68))	('rs11977670', 'Var', (0, 10))
33410	24743323	None of the other 5 SNPs genotyped were associated with lobular breast cancer at a genome-wide significance level, with the strongest association being for rs2121783 at 3p13 (OR = 1.11, 95%CI = 1.07-1.15, P = 4.5x10-7; Table S4).	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('rs2121783', 'Mutation', 'rs2121783', (156, 165))	('lobular breast cancer', 'Disease', (56, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('rs2121783', 'Var', (156, 165))	('lobular breast cancer', 'Disease', 'MESH:D013274', (56, 77))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (56, 77))
33411	24743323	rs11977670 at 7q34 (position:139942304, GRCh Build 37) is intergenic, 65 kb from the nearest gene, JHDM1D, a histone demethylase and 500 kb from BRAF, a gene frequently mutated in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('BRAF', 'Gene', (145, 149))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('rs11977670', 'Mutation', 'rs11977670', (0, 10))	('rs11977670', 'Var', (0, 10))	('JHDM1D', 'Gene', (99, 105))	('BRAF', 'Gene', '673', (145, 149))	('JHDM1D', 'Gene', '80853', (99, 105))
33412	24743323	ENCODE data on normal human mammary epithelial cells (HMEC), and breast carcinoma (MCF-7), were used to establish chromatin states in the region and showed that rs11977670 lies in region marked by H3K27 acetylation, Figure S3.	('rs11977670', 'Mutation', 'rs11977670', (161, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('human', 'Species', '9606', (22, 27))	('MCF-7', 'CellLine', 'CVCL:0031', (83, 88))	('rs11977670', 'Var', (161, 171))	('breast carcinoma', 'Disease', 'MESH:D001943', (65, 81))	('breast carcinoma', 'Disease', (65, 81))	('H3K27', 'Protein', (197, 202))	('chromatin', 'cellular_component', 'GO:0000785', ('114', '123'))	('acetylation', 'MPA', (203, 214))	('breast carcinoma', 'Phenotype', 'HP:0003002', (65, 81))
33413	24743323	Using expression data from the Cancer Genome Atlas Network (TCGA database), we assessed expression of the nine genes within 0.5 Mb of rs11977670 by breast cancer subtype (ER+ ILC, 40 cases; ER+ IDC, 341 cases; and ER-negative IDC, 108 cases; Figure S4).	('ER+ IDC', 'Disease', (190, 197))	('rs11977670', 'Var', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('expression', 'MPA', (88, 98))	('rs11977670', 'Mutation', 'rs11977670', (134, 144))
33416	24743323	To further investigate which genes may be influenced by SNPs tagged by rs11977670, germline genotype data for rs13225058 (A/G), a surrogate for rs11977670 (G/A) (r2 = 0.79) was taken from the TCGA database (SNP6.0 Affymetrix array) and compared to expression of these genes, correcting for copy number variation, in 335 ER+ primary breast cancers where both genotype and expression data was available.	('breast cancers', 'Disease', (332, 346))	('rs11977670', 'Mutation', 'rs11977670', (144, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (332, 345))	('rs13225058', 'Mutation', 'rs13225058', (110, 120))	('cancers', 'Phenotype', 'HP:0002664', (339, 346))	('breast cancers', 'Phenotype', 'HP:0003002', (332, 346))	('influenced', 'Reg', (42, 52))	('rs11977670', 'Mutation', 'rs11977670', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('breast cancers', 'Disease', 'MESH:D001943', (332, 346))	('rs11977670', 'Var', (71, 81))
33418	24743323	There was no evidence of copy number variation around rs11977670 and no evidence of an excess of somatic mutations in JHDM1D, SLC37A3 or BRAF in ILC.	('JHDM1D', 'Gene', (118, 124))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('SLC37A3', 'Gene', (126, 133))	('JHDM1D', 'Gene', '80853', (118, 124))	('rs11977670', 'Mutation', 'rs11977670', (54, 64))	('SLC37A3', 'Gene', '84255', (126, 133))	('rs11977670', 'Var', (54, 64))
33420	24743323	The strongest associations were with SNPs close to FGFR2 (rs2981579, OR = 1.38, P = 5.1x10-52), TOX3 (rs3803662, OR = 1.33, P = 1.1x10-35), at 1p11.2 (rs11249433, OR = 1.25, P = 2.7x10-25) and 11q13.3 (rs554219, OR = 1.33, P = 1.6x10-22).	('rs11249433', 'Mutation', 'rs11249433', (151, 161))	('associations', 'Interaction', (14, 26))	('rs2981579', 'Var', (58, 67))	('rs11249433', 'Var', (151, 161))	('FGFR2', 'Gene', (51, 56))	('FGFR2', 'Gene', '2263', (51, 56))	('rs3803662', 'Mutation', 'rs3803662', (102, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('rs554219', 'Var', (202, 210))	('TOX3', 'Gene', (96, 100))	('rs2981579', 'Mutation', 'rs2981579', (58, 67))	('TOX3', 'Gene', '27324', (96, 100))	('rs554219', 'Mutation', 'rs554219', (202, 210))	('rs3803662', 'Var', (102, 111))
33421	24743323	All 13 loci had previously been shown to be associated with ER+ breast cancer and one locus, rs11249433 (1p11.2), with lobular histology in subgroup analysis.	('associated', 'Reg', (44, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('rs11249433', 'Mutation', 'rs11249433', (93, 103))	('rs11249433', 'Var', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
33422	24743323	Of the remaining 19 SNPs with P>=0.05, 18 had ORs in the same direction as previously reported for overall breast cancer (Sign test P = 0.0001), suggesting that these SNPs are also likely to predispose to LCIS.	('SNPs', 'Var', (167, 171))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('predispose', 'Reg', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('LCIS', 'Disease', (205, 209))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
33425	24743323	For the 75 known breast cancer susceptibility loci, case-control analysis for the 401 cases of pure LCIS (without invasion) and 24,045 controls, revealed 15 out of 75 SNPs associated with LCIS at P<0.05 (Table 3).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('SNPs', 'Var', (167, 171))	('breast cancer', 'Disease', (17, 30))	('associated', 'Reg', (172, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('LCIS', 'Disease', (188, 192))	('pure', 'molecular_function', 'GO:0034023', ('95', '99'))
33426	24743323	The strongest associations were for rs865686 (9q31.2, P = 2.2x10-5); rs3803662 (TOX3, P = 1.2x10-4), c11_pos69088342/rs75915166 (11q13.3, P = 7.8x10-4) and rs1243482 (MLLT10, 10p12.31, P = 7.8x10-4) that is partially correlated (r2 = 0.69) with rs7072776, a recently identified ER+ breast cancer predisposition locus that showed a weaker association with LCIS (OR = 1.17, 95%CI = 1.00-1.36, P = 0.05; Table S5).	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('rs865686', 'Var', (36, 44))	('rs865686', 'Mutation', 'rs865686', (36, 44))	('rs3803662', 'Var', (69, 78))	('MLLT10', 'Gene', '8028', (167, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (282, 295))	('TOX3', 'Gene', '27324', (80, 84))	('TOX3', 'Gene', (80, 84))	('breast cancer', 'Disease', 'MESH:D001943', (282, 295))	('rs7072776', 'Var', (245, 254))	('rs3803662', 'Mutation', 'rs3803662', (69, 78))	('breast cancer', 'Disease', (282, 295))	('c11_pos69088342/rs75915166', 'Var', (101, 127))	('rs75915166', 'Mutation', 'rs75915166', (117, 127))	('MLLT10', 'Gene', (167, 173))	('rs1243482', 'Var', (156, 165))	('LCIS', 'Disease', (355, 359))	('rs7072776', 'Mutation', 'rs7072776', (245, 254))	('rs1243482', 'Mutation', 'rs1243482', (156, 165))
33427	24743323	Two loci showed stronger associations with ILC than pure LCIS: rs2981579, FGFR2 (P-het = 0.02); and rs889312, 5q11.2 (P-het = 0.03).	('associations', 'Interaction', (25, 37))	('rs889312', 'Mutation', 'rs889312', (100, 108))	('pure', 'molecular_function', 'GO:0034023', ('52', '56'))	('rs2981579', 'Var', (63, 72))	('FGFR2', 'Gene', (74, 79))	('FGFR2', 'Gene', '2263', (74, 79))	('ILC', 'Disease', (43, 46))	('rs2981579', 'Mutation', 'rs2981579', (63, 72))	('rs889312', 'Var', (100, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
33428	24743323	Case-only analysis also suggested that two ER-negative specific SNPs were more strongly associated with LCIS than ILC: rs6678914, 1q32.1 (P-het = 0.0007) and rs17529111, 6q14.1 (P-het = 0.04) Table 3.	('rs6678914', 'Var', (119, 128))	('LCIS', 'Disease', (104, 108))	('rs6678914', 'Mutation', 'rs6678914', (119, 128))	('rs17529111', 'Mutation', 'rs17529111', (158, 168))	('associated', 'Reg', (88, 98))	('rs17529111', 'Var', (158, 168))
33430	24743323	At P<0.05, a further two loci were associated more strongly with ILC than IDC: rs2981579, FGFR2 (P-het = 5.3x10-3) and rs10995190, 10q21.2 (P-het = 0.002).	('rs10995190', 'Var', (119, 129))	('FGFR2', 'Gene', (90, 95))	('FGFR2', 'Gene', '2263', (90, 95))	('rs2981579', 'Var', (79, 88))	('rs10995190', 'Mutation', 'rs10995190', (119, 129))	('rs2981579', 'Mutation', 'rs2981579', (79, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('ILC', 'Disease', (65, 68))
33431	24743323	This analysis also identified four IDC-specific SNPs at P<0.05: rs10941679, 5p12 (P-het = 1.5x10-4); rs2588809, RAD51L1 (P-het = 0.001); rs6472903, 8q21.11 (P-het = 0.004); rs1550623, CDCA7 (P-het = 0.031) Table S6.	('CDCA7', 'Gene', (184, 189))	('rs10941679', 'Var', (64, 74))	('rs2588809', 'Var', (101, 110))	('RAD', 'biological_process', 'GO:1990116', ('112', '115'))	('rs2588809', 'Mutation', 'rs2588809', (101, 110))	('rs6472903', 'Mutation', 'rs6472903', (137, 146))	('RAD51L1', 'Gene', '5890', (112, 119))	('rs1550623', 'Var', (173, 182))	('rs10941679', 'Mutation', 'rs10941679', (64, 74))	('rs1550623', 'Mutation', 'rs1550623', (173, 182))	('RAD51L1', 'Gene', (112, 119))	('rs6472903', 'Var', (137, 146))	('CDCA7', 'Gene', '83879', (184, 189))
33433	24743323	The top hits were at FGFR2 (rs2981579, OR = 1.37, P = 1.6x10-7), rs941764 (CCDC88C, OR = 1.25, P = 3.6x10-4) and rs10995190 (ZNF365, OR = 0.74, P = 3.9x10-4).	('rs10995190', 'Var', (113, 123))	('CCDC88C', 'Gene', '440193', (75, 82))	('FGFR2', 'Gene', (21, 26))	('FGFR2', 'Gene', '2263', (21, 26))	('rs941764', 'Mutation', 'rs941764', (65, 73))	('rs2981579', 'Var', (28, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('rs10995190', 'Mutation', 'rs10995190', (113, 123))	('CCDC88C', 'Gene', (75, 82))	('rs2981579', 'Mutation', 'rs2981579', (28, 37))	('ZNF365', 'Gene', '22891', (125, 131))	('ZNF365', 'Gene', (125, 131))	('rs941764', 'Var', (65, 73))
33434	24743323	The case-only analysis above showed that two of these SNPs are more strongly associated with ILC than IDC (rs2981579, rs10995190).	('ILC', 'Disease', (93, 96))	('rs10995190', 'Mutation', 'rs10995190', (118, 128))	('rs2981579', 'Var', (107, 116))	('rs10995190', 'Var', (118, 128))	('rs2981579', 'Mutation', 'rs2981579', (107, 116))	('associated', 'Reg', (77, 87))
33435	24743323	rs941764 showed no association with ILC and only weak association with ER+ IDC, Table S6.	('ILC', 'Disease', (36, 39))	('rs941764', 'Mutation', 'rs941764', (0, 8))	('ER+ IDC', 'Disease', (71, 78))	('rs941764', 'Var', (0, 8))
33436	24743323	Our analyses of a total of 6,539 lobular cancers (including 436 cases of pure LCIS) and 35,710 controls has identified for the first time a lobular-specific SNP, rs11977670 (JHDM1D; OR = 1.13 P = 4.2x10-10, that showed little evidence of association with IDC (P = 0.07) or DCIS (P = 0.23).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('pure', 'molecular_function', 'GO:0034023', ('73', '77'))	('JHDM1D', 'Gene', '80853', (174, 180))	('rs11977670', 'Mutation', 'rs11977670', (162, 172))	('lobular cancer', 'Phenotype', 'HP:0030076', (33, 47))	('rs11977670', 'Var', (162, 172))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('JHDM1D', 'Gene', (174, 180))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('DCIS', 'Disease', (273, 277))	('cancers', 'Disease', (41, 48))	('IDC', 'Disease', (255, 258))
33437	24743323	The preliminary in silico functional analysis suggests that SNPs in this region may be influencing expression of JHDM1D (a histone demethylase) and SLC37A3 (a sugar-phosphate exchanger).	('expression', 'MPA', (99, 109))	('SNPs', 'Var', (60, 64))	('SLC37A3', 'Gene', '84255', (148, 155))	('influencing', 'Reg', (87, 98))	('exchanger', 'molecular_function', 'GO:0015297', ('175', '184'))	('JHDM1D', 'Gene', (113, 119))	('SLC37A3', 'Gene', (148, 155))	('JHDM1D', 'Gene', '80853', (113, 119))
33443	24743323	However, none of the 56 SNPs in CDH1 that were typed on the iCOGS chip showed any association with lobular cancer at P<0.05.	('association', 'Interaction', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CDH1', 'Gene', (32, 36))	('SNPs', 'Var', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('lobular cancer', 'Phenotype', 'HP:0030076', (99, 113))	('CDH1', 'Gene', '999', (32, 36))	('cancer', 'Disease', (107, 113))
33448	24743323	However, some loci were only associated with ER+ IDC and not with ILC, particularly rs10941679 at 5p12, previously shown to predispose more strongly to ER-positive, lower-grade cancers, P-het = 2.7x10-8.	('rs10941679', 'Mutation', 'rs10941679', (84, 94))	('ER-positive', 'Disease', (152, 163))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('ER+ IDC', 'Disease', (45, 52))	('rs10941679', 'Var', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
33449	24743323	Others showed a much stronger association with ILC than IDC, particularly rs11249433 at 1p11.2, as previously described.	('rs11249433', 'Var', (74, 84))	('ILC', 'Disease', (47, 50))	('rs11249433', 'Mutation', 'rs11249433', (74, 84))
33453	24743323	Specifically, rs6678914 at 1q32.1 (LGR6), known to be an ER-negative specific SNP, that appeared to be associated with LCIS but not ILC (P-het = 0.0007), and rs17529111 at 6q14 preferentially associated with ER-negative tumors that had a stronger association with LCIS than ILC (P-het = 0.04).	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('rs6678914', 'Var', (14, 23))	('rs17529111 at', 'Var', (158, 171))	('associated', 'Reg', (192, 202))	('associated', 'Reg', (103, 113))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('LGR6', 'Gene', (35, 39))	('LCIS', 'Disease', (264, 268))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('rs6678914', 'Mutation', 'rs6678914', (14, 23))	('rs17529111', 'Mutation', 'rs17529111', (158, 168))	('LCIS', 'Disease', (119, 123))	('LGR6', 'Gene', '59352', (35, 39))
33454	24743323	We also identified SNPs in FGFR2 and at 5q11.2 (MAP3K1) that appear only to predispose to ILC, but have little effect on LCIS suggesting that SNPs affect different parts of the lobular carcinoma pathway.	('SNPs', 'Var', (19, 23))	('FGFR2', 'Gene', (27, 32))	('FGFR2', 'Gene', '2263', (27, 32))	('predispose', 'Reg', (76, 86))	('lobular carcinoma', 'Disease', (177, 194))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (177, 194))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('MAP3K1', 'Gene', (48, 54))	('MAP3K1', 'Gene', '4214', (48, 54))	('lobular carcinoma', 'Disease', 'MESH:D018275', (177, 194))	('MAP3K', 'molecular_function', 'GO:0004709', ('48', '53'))	('ILC', 'Disease', (90, 93))	('affect', 'Reg', (147, 153))
33455	24743323	Some of the SNPs associated with both ILC and LCIS showed a stronger effect size in LCIS compared to ILC (for example SNPs at TOX3, 9q31.2, 11q13.3, ZNF365 and MLLT10).	('MLLT10', 'Gene', (160, 166))	('SNPs', 'Var', (118, 122))	('MLLT10', 'Gene', '8028', (160, 166))	('TOX3', 'Gene', (126, 130))	('ZNF365', 'Gene', '22891', (149, 155))	('11q13.3', 'Var', (140, 147))	('TOX3', 'Gene', '27324', (126, 130))	('LCIS', 'Disease', (84, 88))	('9q31.2', 'Var', (132, 138))	('ZNF365', 'Gene', (149, 155))
33458	24743323	One SNP, rs1243182 (MLLT10), that showed a strong association with LCIS (LCIS: P = 7.8x10-4, OR = 1.29; ILC: P = 6.1x10-9,OR = 1.14; ILC+LCIS: P = 3x10-10,OR = 1.15, IDC: P = 1.4x10-5,OR = 1.07, is partially correlated (r2 = 0.69) with rs7072776, a recently identified ER+ breast cancer predisposition locus, which showed no association with LCIS in this study.	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('LCIS', 'Disease', (67, 71))	('MLLT10', 'Gene', (20, 26))	('rs1243182', 'Var', (9, 18))	('rs7072776', 'Mutation', 'rs7072776', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('MLLT10', 'Gene', '8028', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('rs1243182', 'Mutation', 'rs1243182', (9, 18))	('rs7072776', 'Var', (236, 245))	('breast cancer', 'Disease', (273, 286))
33459	24743323	It is also strongly correlated with rs1243180 (r2 = 0.80), an ovarian cancer predisposition variant and rs11012732 (r2 = 0.57), which predisposes to meningioma.	('meningioma', 'Phenotype', 'HP:0002858', (149, 159))	('correlated', 'Interaction', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('rs11012732', 'Var', (104, 114))	('rs11012732', 'Mutation', 'rs11012732', (104, 114))	('rs1243180', 'Var', (36, 45))	('rs1243180', 'Mutation', 'rs1243180', (36, 45))	('meningioma', 'Disease', (149, 159))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))
33460	24743323	The ovarian SNP, rs1243180, also showed a strong association with lobular cancer (ILC+LCIS: P = 5.54x10-10; OR = 1.13).	('rs1243180', 'Mutation', 'rs1243180', (17, 26))	('lobular cancer', 'Phenotype', 'HP:0030076', (66, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('rs1243180', 'Var', (17, 26))
33485	24743323	Expression data from the Cancer Genome Atlas Network for each gene within a 1 Mb window of rs11977670 was analyzed looking for differential expression in each breast cancer subtype (ER+ ILC, 40 cases; ER+ IDC, 341 cases; and ER-negative IDC, 108 cases).	('rs11977670', 'Var', (91, 101))	('ER+', 'Disease', (201, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('rs11977670', 'Mutation', 'rs11977670', (91, 101))
33489	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))	('cancers', 'Disease', (80, 87))	('cancer', 'Disease', (44, 50))	('malignancy', 'Disease', (202, 212))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('BRCA2', 'Gene', '675', (148, 153))	('BRCA1', 'Gene', '672', (139, 144))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('BRCA1', 'Gene', (139, 144))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
33495	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))
33505	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))	('signaling', 'biological_process', 'GO:0023052', ('255', '264'))	('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))
33526	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))
33527	30258937	The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 gene.	('BRCA1', 'Gene', (82, 87))	('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))	('BRCA2', 'Gene', '675', (91, 96))	('BRCA1', 'Gene', '672', (82, 87))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (25, 49))	('cause', 'Reg', (16, 21))
33528	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))
33529	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))
33530	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))
33531	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))
33532	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))
33533	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))
33534	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))
33535	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', (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))	('men', 'Species', '9606', (85, 88))	('BRCA2', 'Gene', (95, 100))	('BRCA1', 'Gene', '672', (12, 17))	('breast cancers', 'Phenotype', 'HP:0003002', (57, 71))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('BRCA1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (18, 27))
33536	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))	('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))
33537	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))	('protein', 'cellular_component', 'GO:0003675', ('938', '945'))	('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))	('breast cancer', 'Disease', (1031, 1044))	('cancer', 'Disease', (223, 229))	('ovaries', 'Disease', (606, 613))	('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))	('STK11', 'molecular_function', 'GO:0033868', ('741', '746'))	('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))	('breast cancer', 'Disease', 'MESH:D001943', (860, 873))	('cancer', 'Disease', 'MESH:D009369', (509, 515))	('CHEK2', 'Gene', (308, 313))	('cancer', 'Disease', 'MESH:D009369', (842, 848))	('CHEK2', 'Gene', '11200', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (519, 524))	('protein', 'cellular_component', 'GO:0003675', ('906', '913'))	('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))	('cancerous tumors', 'Disease', (509, 525))	('PALB2', 'Gene', (887, 892))	('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))
33538	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', (153, 157))	('BRCA1', 'Gene', (69, 74))	('women', 'Species', '9606', (161, 166))	('men', 'Species', '9606', (270, 273))	('TP53', 'Gene', '7157', (153, 157))	('BRCA2', 'Gene', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('breast cancer', 'Disease', 'MESH:D001943', (249, 262))
33553	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))	('ADH', 'molecular_function', 'GO:0047636', ('186', '189'))	('ductal hyperplasia (ADH) and atypical lobular hyperplasia', 'Disease', 'MESH:D006965', (166, 223))	('ADH', 'molecular_function', 'GO:0004022', ('186', '189'))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('increase breast cancer', 'Disease', (101, 123))
33563	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))	('aging', 'biological_process', 'GO:0007568', ('79', '84'))	('cancers', 'Disease', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('caused by', 'Reg', (21, 30))
33566	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))
33588	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))
33672	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))
33675	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))
33701	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))	('ALDH', 'molecular_function', 'GO:0004030', ('208', '212'))	('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))	('CD10', 'molecular_function', 'GO:0004245', ('199', '203'))	('EpCAM', 'Gene', (192, 197))	('CD10', 'Gene', (199, 203))	('SSEA4', 'Gene', (217, 222))
33714	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))
33736	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))	('p53', 'Gene', (17, 20))	('formation', 'biological_process', 'GO:0009058', ('47', '56'))	('mammary tumors', 'Disease', 'MESH:D001943', (60, 74))	('mammary tumors', 'Disease', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sped up', 'PosReg', (79, 86))	('mouse', 'Species', '10090', (30, 35))	('knockout', 'Var', (107, 115))	('Esr2', 'Gene', (119, 123))
33744	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.	('binding', 'molecular_function', 'GO:0005488', ('7', '14'))	('HER2', 'Gene', '2064', (121, 125))	('binding', 'Interaction', (7, 14))	('activation', 'PosReg', (142, 152))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))	('intracellular', 'cellular_component', 'GO:0005622', ('97', '110'))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('dimerization', 'Var', (30, 42))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('MAPK', 'molecular_function', 'GO:0004707', ('241', '245'))	('PI3K', 'molecular_function', 'GO:0016303', ('303', '307'))	('HER2', 'Gene', (121, 125))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('phosphorylation', 'MPA', (53, 68))
33747	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))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('cell proliferation', 'biological_process', 'GO:0008283', ('93', '111'))	('signaling', 'biological_process', 'GO:0023052', ('5', '14'))	('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))
33760	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))
33763	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.	('GSK-3beta', 'Gene', (14, 23))	('CBP', 'Gene', '1387', (202, 205))	('nucleus', 'cellular_component', 'GO:0005634', ('119', '126'))	('CREB binding protein', 'Gene', (180, 200))	('CBP', 'Gene', (202, 205))	('Inhibition of GSK', 'biological_process', 'GO:1902948', ('0', '17'))	('CREB binding protein', 'Gene', '1387', (180, 200))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('CREB binding', 'molecular_function', 'GO:0008140', ('180', '192'))	('MYC', 'Gene', (317, 320))	('translocation', 'MPA', (96, 109))	('GSK', 'molecular_function', 'GO:0050321', ('14', '17'))	('accumulation', 'PosReg', (46, 58))	('Inhibition', 'Var', (0, 10))	('transcription', 'biological_process', 'GO:0006351', ('261', '274'))	('GSK-3beta', 'Gene', '2931', (14, 23))	('CCND1', 'Gene', '595', (322, 327))	('CBP', 'molecular_function', 'GO:0008140', ('202', '205'))	('beta-catenin', 'Protein', (33, 45))	('CCND1', 'Gene', (322, 327))	('MYC', 'Gene', '4609', (317, 320))	('cytoplasm', 'cellular_component', 'GO:0005737', ('66', '75'))
33764	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).	('mammary gland development', 'biological_process', 'GO:0030879', ('50', '75'))	('MMTV', 'Species', '11757', (237, 241))	('Wnt1', 'Gene', (215, 219))	('mouse', 'Species', '10090', (164, 169))	('men', 'Species', '9606', (71, 74))	('mammalian', 'Species', '9606', (118, 127))	('insertion', 'Var', (202, 211))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('oncogenesis', 'biological_process', 'GO:0007048', ('178', '189'))	('MMTV', 'Species', '11757', (151, 155))
33766	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))
33769	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))
33773	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))	('signaling', 'biological_process', 'GO:0023052', ('23', '32'))	('stabilized beta-catenin', 'MPA', (162, 185))
33777	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))	('APC', 'cellular_component', 'GO:0005680', ('31', '34'))	('hypermethylation', 'Var', (133, 149))
33780	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))	('DNA methylation', 'biological_process', 'GO:0006306', ('165', '180'))	('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))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('breast tumors', 'Disease', (66, 79))
33783	30258937	The expression of Wnt1 in human mammary epithelial cells increased stem cell self-renewal, resistance to apoptosis and failure to senescence.	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('senescence', 'biological_process', 'GO:0010149', ('130', '140'))	('resistance to apoptosis', 'CPA', (91, 114))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '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))
33787	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))	('mammary tumors', 'Disease', 'MESH:D001943', (135, 149))	('beta-catenin', 'Var', (62, 74))	('transgenic mice', 'Species', '10090', (153, 168))	('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))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('Neu', 'Gene', (180, 183))	('Neu', 'Gene', '13866', (180, 183))
33788	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))	('APC', 'cellular_component', 'GO:0005680', ('33', '36'))	('mammary tumors', 'Disease', (142, 156))	('tumor', 'Disease', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('APC', 'cellular_component', 'GO:0005680', ('177', '180'))	('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))
33790	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.	('GSK', 'molecular_function', 'GO:0050321', ('28', '31'))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('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))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('suppression', 'NegReg', (13, 24))	('protein kinase D1', 'Gene', '5587', (87, 104))
33793	30258937	These include CDKs (Cyclin dependent kinase), Notch, SHH, PI3K/Akt/mTOR, and others.	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('Notch', 'Disease', (46, 51))	('Cyclin', 'Gene', '5111', (20, 26))	('Cyclin', 'molecular_function', 'GO:0016538', ('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))
33797	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))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('amplification', 'Var', (10, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('Cyclin D1', 'Gene', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
33800	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))	('CDK', 'molecular_function', 'GO:0004693', ('9', '12'))	('HER2', 'Gene', '2064', (133, 137))	('palbocyclib', 'Chemical', '-', (203, 214))	('ER', 'Gene', '2099', (134, 136))	('ER', 'Gene', '2099', (88, 90))	('amplification', 'Var', (138, 151))	('cell cycle', 'biological_process', 'GO:0007049', ('65', '75'))
33807	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))	('morphogenesis', 'biological_process', 'GO:0009653', ('158', '171'))	('Disruption', 'Var', (0, 10))
33808	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))
33811	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))	('BRK', 'Gene', '5753', (13, 16))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('breast cancer', 'Disease', (20, 33))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('Depletion', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('EGFR', 'Gene', '1956', (60, 64))	('impair', 'NegReg', (53, 59))	('EGFR', 'Gene', (60, 64))
33814	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.	('human', 'Species', '9606', (123, 128))	('PIK3CA', 'Gene', '5290', (96, 102))	('PI3K', 'molecular_function', 'GO:0016303', ('84', '88'))	('attain multi-lineage potential', 'CPA', (245, 275))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('mTOR', 'Gene', (9, 13))	('AKT', 'Gene', (5, 8))	('luminal or basal mammary progenitor cells', 'CPA', (185, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('mTOR', 'Gene', '2475', (9, 13))	('dedifferentiation', 'CPA', (164, 181))	('PIK3CA', 'Gene', (96, 102))	('mutation', 'Var', (72, 80))	('dedifferentiation', 'biological_process', 'GO:0043696', ('164', '181'))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('lead to', 'Reg', (152, 159))	('breast cancer', 'Disease', (129, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Gene', (84, 88))	('AKT', 'Gene', '207', (5, 8))
33819	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))
33821	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).	('BRCA1', 'Gene', (136, 141))	('BRCA2', 'Gene', (145, 150))	('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))
33823	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))
33824	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))	('to 14', 'Species', '2282628', (32, 37))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('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))
33825	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))
33827	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))	('DNA repair', 'biological_process', 'GO:0006281', ('85', '95'))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('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))
33828	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))
33830	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))
33833	30258937	A latest update report of the CIMBA dataset summarized a total of 1650 and 1731 unique mutations in BRCA1 and BRCA2 respectively.	('BRCA1', 'Gene', '672', (100, 105))	('BRCA2', 'Gene', (110, 115))	('BRCA1', 'Gene', (100, 105))	('BRCA2', 'Gene', '675', (110, 115))	('mutations', 'Var', (87, 96))
33834	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))	('functional proteins', 'MPA', (191, 210))	('frameshift', 'Var', (47, 57))	('BRCA2', 'Gene', (30, 35))	('BRCA1', 'Gene', '672', (20, 25))	('premature stop codons', 'MPA', (114, 135))	('BRCA2', 'Gene', '675', (30, 35))
33835	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))
33844	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.	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('membrane', 'cellular_component', 'GO:0016020', ('199', '207'))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('PI3K', 'molecular_function', 'GO:0016303', ('171', '175'))	('tyrosine', 'Chemical', 'MESH:D014443', (68, 76))	('recruited', 'PosReg', (182, 191))	('interaction', 'Interaction', (115, 126))	('PI3K signaling', 'biological_process', 'GO:0014065', ('0', '14'))	('PI3K', 'Var', (171, 175))
33845	30258937	Activated PI3K subsequently activates critical downstream mediators AKT and mTOR, leading to enhanced growth, anti-apoptosis, cell-cycle progression, and translation.	('cell-cycle', 'biological_process', 'GO:0007049', ('126', '136'))	('mTOR', 'Gene', (76, 80))	('PI3K', 'Var', (10, 14))	('mTOR', 'Gene', '2475', (76, 80))	('PI3K', 'molecular_function', 'GO:0016303', ('10', '14'))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('110', '124'))	('cell-cycle progression', 'CPA', (126, 148))	('anti-apoptosis', 'CPA', (110, 124))	('translation', 'CPA', (154, 165))	('translation', 'biological_process', 'GO:0006412', ('154', '165'))	('AKT', 'Gene', '207', (68, 71))	('enhanced', 'PosReg', (93, 101))	('activates', 'PosReg', (28, 37))	('AKT', 'Gene', (68, 71))	('growth', 'CPA', (102, 108))
33847	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))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('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))	('PI3K', 'molecular_function', 'GO:0016303', ('20', '24'))	('PIK3CA', 'Gene', '5290', (155, 161))
33848	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))
33850	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))	('dysfunction', 'Disease', (109, 120))	('PI3K', 'molecular_function', 'GO:0016303', ('54', '58'))	('HER2', 'Gene', (89, 93))	('mutations', 'Var', (22, 31))	('AKT', 'Gene', '207', (134, 137))	('activating', 'PosReg', (139, 149))	('HER2', 'Gene', '2064', (89, 93))	('PIK3CA', 'Gene', (15, 21))
33851	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', (13, 19))	('PIK3R1', 'Gene', '5295', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('p110alpha', 'Gene', '5290', (172, 181))	('stabilizing', 'PosReg', (160, 171))	('PIK3R1', 'Gene', '5295', (13, 19))	('PIK3R1', 'Gene', (98, 104))	('p110alpha', 'Gene', (172, 181))	('p85alpha', 'Gene', '5295', (118, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('tumor', 'Disease', (135, 140))	('p85alpha', 'Gene', (118, 126))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Disease', (44, 57))
33852	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))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('E17K', 'Mutation', 'p.E17K', (16, 20))	('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))
33853	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))
33854	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))	('dedifferentiation', 'biological_process', 'GO:0043696', ('48', '65'))	('PIK3CA', 'Gene', '5290', (10, 16))	('mutations', 'Var', (17, 26))
33855	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))	('HER2', 'Gene', (124, 128))	('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))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))	('IGF-1R', 'Gene', (132, 138))	('ER', 'Gene', '2099', (234, 236))	('downregulation', 'NegReg', (82, 96))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('acquired resistance', 'CPA', (190, 209))	('upregulate', 'PosReg', (15, 25))
33856	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))
33858	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))
33859	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))
33861	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))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('damaged DNA repair', 'MPA', (181, 199))	('ataxia telangiectasia', 'Disease', (121, 142))	('ATM', 'Gene', '472', (113, 116))	('participates', 'Reg', (165, 177))	('DNA repair', 'biological_process', 'GO:0006281', ('189', '199'))	('ATM', 'Gene', (148, 151))
33864	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))
33865	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))
33867	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))
33869	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))
33870	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))
33872	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))	('STK11', 'molecular_function', 'GO:0033868', ('0', '5'))	('hamartomatous polyps', 'Disease', 'MESH:D011127', (180, 200))	('men', 'Species', '9606', (227, 230))	('autosomal dominant disorder', 'Disease', (135, 162))	('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))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (135, 162))	('LKB1', 'Gene', '6794', (115, 119))
33874	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))	('PALB2', 'Gene', '79728', (49, 54))	('FANCN', 'Gene', '79728', (70, 75))	('loss-of-function', 'NegReg', (19, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (207, 224))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	("Fanconi's anemia", 'Disease', 'MESH:D005199', (83, 99))	('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))
33875	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))
33877	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))
33881	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.	('histone modification', 'biological_process', 'GO:0016570', ('78', '98'))	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('men', 'Species', '9606', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('aberrant', 'Var', (49, 57))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('DNA methylation', 'biological_process', 'GO:0006306', ('58', '73'))	('cancer', 'Disease', (377, 383))	('cancer', 'Disease', 'MESH:D009369', (377, 383))
33882	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))
33884	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', 'molecular_function', 'GO:0005488', ('37', '44'))	('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))	('demethylation', 'biological_process', 'GO:0070988', ('16', '29'))
33886	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))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('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))	('binding', 'molecular_function', 'GO:0005488', ('44', '51'))	('resistance', 'MPA', (86, 96))
33898	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))
33899	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))	('gene expression', 'biological_process', 'GO:0010467', ('40', '55'))	('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))
33900	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))
33903	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))	('TP53', 'Gene', '7157', (155, 159))	('OBSCN', 'Gene', '84033', (145, 150))	('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))
33904	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))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('NF1', 'Gene', (254, 257))	('ATM', 'Gene', (224, 227))	('genetic variations', 'Var', (25, 43))	('variations', 'Var', (33, 43))	('IGF1R', 'Gene', '3480', (247, 252))	('cancer', 'Disease', (190, 196))	('ATR', 'Gene', (228, 231))	('regulation', 'MPA', (176, 186))	('TOP2A', 'Gene', (271, 276))	('IGF1R', 'Gene', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('FGFR', 'molecular_function', 'GO:0005007', ('233', '237'))	('FGFR1', 'Gene', '2260', (233, 238))	('NF1', 'Gene', '4763', (254, 257))	('TOP2A', 'Gene', '7153', (271, 276))	('phosphorylation', 'MPA', (126, 141))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('FOXA1', 'Gene', '3169', (240, 245))	('protein-protein interaction', 'MPA', (143, 170))	('NOTCH2', 'Gene', '4853', (259, 265))	('ATM', 'Gene', '472', (224, 227))	('FOXA1', 'Gene', (240, 245))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('ATR', 'Gene', '545', (228, 231))	('regulation', 'biological_process', 'GO:0065007', ('176', '186'))	('FGFR1', 'Gene', (233, 238))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('impact', 'Reg', (115, 121))
33906	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))	('cell-cycle', 'biological_process', 'GO:0007049', ('338', '348'))
33908	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))	('RNA', 'cellular_component', 'GO:0005562', ('135', '138'))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
33911	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))
33925	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))	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('12p', 'CPA', (178, 181))	('gain', 'PosReg', (160, 164))	('tumors', 'Disease', (27, 33))	('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))
33933	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))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('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))
33935	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))	('JNK', 'molecular_function', 'GO:0004705', ('763', '766'))	('Notch pathway', 'Pathway', (748, 761))	('mTOR', 'Gene', (361, 365))	('cell-cycle', 'biological_process', 'GO:0007049', ('635', '645'))	('EGFR', 'Gene', '1956', (404, 408))	('CCND1', 'Gene', '595', (613, 618))	('FGFR', 'molecular_function', 'GO:0005007', ('397', '401'))	('amplification', 'Var', (663, 676))	('FGFR1', 'Gene', (397, 402))	('deletions', 'Var', (568, 577))	('JAK', 'molecular_function', 'GO:0004713', ('680', '683'))	('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))	('JAK', 'molecular_function', 'GO:0004713', ('692', '695'))	('BRCA1', 'Gene', (210, 215))	('DNA', 'cellular_component', 'GO:0005574', ('225', '228'))	('EGFR', 'molecular_function', 'GO:0005006', ('404', '408'))	('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))	('DNA repair', 'biological_process', 'GO:0006281', ('225', '235'))	('PI3K', 'molecular_function', 'GO:0016303', ('356', '360'))	('EGFR', 'Gene', (404, 408))	('CDK', 'molecular_function', 'GO:0004693', ('607', '610'))	('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))	('AP-1', 'cellular_component', 'GO:0005907', ('767', '771'))
33936	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))
33949	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))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('128', '161'))	('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))	('EMT', 'biological_process', 'GO:0001837', ('163', '166'))	('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))
33957	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))	('cell proliferation', 'biological_process', 'GO:0008283', ('264', '282'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
33975	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))	('JAK2', 'Gene', '3717', (275, 279))	('inactivating', 'NegReg', (250, 262))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('metastases', 'Disease', 'MESH:D009362', (26, 36))	('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))	('JAK', 'molecular_function', 'GO:0004713', ('275', '278'))
33990	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))	('carcinoma metastasis', 'Disease', 'MESH:D009362', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('CTCs', 'Gene', (147, 151))	('carcinoma metastasis', 'Disease', (105, 125))	('increase', 'PosReg', (196, 204))	('patient', 'Species', '9606', (228, 235))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
34008	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))
34009	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))	('aging', 'biological_process', 'GO:0007568', ('170', '175'))
34016	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))
34021	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))
34022	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))
34032	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))
34033	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))
34046	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))	('tumor', 'Disease', (156, 161))	('patient', 'Species', '9606', (77, 84))
34049	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))
34052	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))
34057	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))
34062	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))
34063	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))
34064	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))	('cadherin', 'molecular_function', 'GO:0008014', ('131', '139'))	('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))	('catenin complex', 'cellular_component', 'GO:0016342', ('140', '155'))	('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))
34067	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))
34068	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))
34069	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.	('higher', 'PosReg', (97, 103))	('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))
34085	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))
34090	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))
34091	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))
34092	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))	('higher', 'PosReg', (192, 198))	('truncal', 'Var', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
34099	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))	('MAP3K', 'molecular_function', 'GO:0004709', ('0', '5'))	('MAP3K1', 'Gene', '4214', (0, 6))	('ARID1A', 'Gene', '8289', (32, 38))	('RUNX1', 'Gene', (18, 23))	('ARID1A', 'Gene', (32, 38))	('NCOR1', 'Gene', (25, 30))
34105	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))	('aging', 'biological_process', 'GO:0007568', ('142', '147'))	('C>G transversions', 'Var', (153, 170))	('cytosine', 'Chemical', 'MESH:D003596', (273, 281))	('DNA', 'cellular_component', 'GO:0005574', ('269', '272'))	('cytosine deaminase activity', 'molecular_function', 'GO:0004131', ('273', '300'))	('APOBEC', 'cellular_component', 'GO:0030895', ('262', '268'))
34109	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))	('APOBEC', 'cellular_component', 'GO:0030895', ('209', '215'))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('aging', 'biological_process', 'GO:0007568', ('263', '268'))	('APOBEC', 'cellular_component', 'GO:0030895', ('120', '126'))	('mutations', 'Var', (137, 146))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('cancer', 'Disease', (150, 156))	('APOBEC', 'cellular_component', 'GO:0030895', ('29', '35'))	('cytosine', 'Chemical', 'MESH:D003596', (45, 53))	('APOBEC', 'Disease', (209, 215))	('APOBEC3B', 'Gene', (29, 37))	('mutational', 'Var', (216, 226))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mRNA levels', 'MPA', (14, 25))
34112	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))	('APOBEC', 'cellular_component', 'GO:0030895', ('23', '29'))	('intra-tumor', 'Disease', 'MESH:D009369', (103, 114))
34113	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))	('APOBEC', 'cellular_component', 'GO:0030895', ('40', '46'))	('APOBEC3B', 'Gene', '9582', (102, 110))	('APOBEC3B', 'Gene', (102, 110))	('mutation', 'Var', (47, 55))	('APOBEC', 'cellular_component', 'GO:0030895', ('102', '108'))	('expression levels', 'MPA', (81, 98))
34116	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))
34118	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))	('FOXA1', 'Gene', (169, 174))	('TBX3', 'Gene', (179, 183))	('PIK3CA', 'Gene', '5290', (161, 167))	('CDH1', 'Gene', (64, 68))	('FOXA1', 'Gene', '3169', (169, 174))
34120	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 suppressor', 'biological_process', 'GO:0051726', ('362', '378'))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('ILC', 'Disease', (424, 427))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('362', '378'))	('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))
34121	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))
34239	29273958	Heterogeneous amplification, although uncommon in breast carcinomas compared with gastric tumours, often raises doubts about quantification.	('breast carcinomas', 'Phenotype', 'HP:0003002', (50, 67))	('Heterogeneous amplification', 'Var', (0, 27))	('gastric tumours', 'Disease', (82, 97))	('breast carcinoma', 'Phenotype', 'HP:0003002', (50, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('breast carcinomas', 'Disease', 'MESH:D001943', (50, 67))	('gastric tumours', 'Disease', 'MESH:D013274', (82, 97))	('breast carcinomas', 'Disease', (50, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))
34272	29273958	Whereas MAP3K1/TP53, GATA3/TP53, CDH1/TP53, and CDH1/GATA3 mutations were mutually exclusive, concomitant mutations of MAP3K1/PIK3CA, CDH1/PIK3CA were frequently observed.	('CDH1', 'Gene', '999', (134, 138))	('CDH1', 'Gene', (48, 52))	('TP53', 'Gene', (38, 42))	('PIK3CA', 'Gene', (139, 145))	('MAP3K1', 'Gene', (8, 14))	('CDH1', 'Gene', (134, 138))	('TP53', 'Gene', (27, 31))	('MAP3K1', 'Gene', '4214', (8, 14))	('MAP3K1', 'Gene', (119, 125))	('PIK3CA', 'Gene', '5290', (126, 132))	('MAP3K1', 'Gene', '4214', (119, 125))	('TP53', 'Gene', '7157', (15, 19))	('GATA3', 'Gene', '2625', (53, 58))	('TP53', 'Gene', '7157', (38, 42))	('GATA3', 'Gene', '2625', (21, 26))	('GATA3', 'Gene', (53, 58))	('MAP3K', 'molecular_function', 'GO:0004709', ('8', '13'))	('GATA3', 'Gene', (21, 26))	('CDH1', 'Gene', '999', (33, 37))	('TP53', 'Gene', '7157', (27, 31))	('PIK3CA', 'Gene', '5290', (139, 145))	('PIK3CA', 'Gene', (126, 132))	('observed', 'Reg', (162, 170))	('CDH1', 'Gene', (33, 37))	('CDH1', 'Gene', '999', (48, 52))	('TP53', 'Gene', (15, 19))	('MAP3K', 'molecular_function', 'GO:0004709', ('119', '124'))	('mutations', 'Var', (106, 115))
34273	29273958	Regarding intrinsic breast cancer subtypes, mutations in PIK3CA were observed in 43-57% of Luminal A and in 31-35% of Luminal B carcinomas, respectively.	('PIK3CA', 'Gene', '5290', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('breast cancer', 'Disease', (20, 33))	('Luminal A', 'Disease', (91, 100))	('carcinomas', 'Disease', (128, 138))	('carcinomas', 'Disease', 'MESH:D002277', (128, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('mutations', 'Var', (44, 53))	('observed', 'Reg', (69, 77))	('PIK3CA', 'Gene', (57, 63))
34274	29273958	The most important difference between both types of tumours was the frequency of TP53 mutations, which was 11-12% in Luminal A, but 24-29% in Luminal B breast carcinomas.	('breast carcinomas', 'Phenotype', 'HP:0003002', (152, 169))	('mutations', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('breast carcinoma', 'Phenotype', 'HP:0003002', (152, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumours', 'Disease', 'MESH:D009369', (52, 59))	('breast carcinomas', 'Disease', 'MESH:D001943', (152, 169))	('breast carcinomas', 'Disease', (152, 169))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('Luminal A', 'Disease', (117, 126))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
34275	29273958	TP53 and PIK3CA mutations have been detected in approximately 70 and 40% of HER2-enriched breast carcinomas and in 89 and 16% of basal breast carcinomas, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('detected', 'Reg', (36, 44))	('breast carcinomas', 'Disease', 'MESH:D001943', (90, 107))	('breast carcinomas', 'Disease', (90, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('breast carcinoma', 'Phenotype', 'HP:0003002', (90, 106))	('TP53', 'Gene', '7157', (0, 4))	('HER2', 'Gene', (76, 80))	('mutations', 'Var', (16, 25))	('breast carcinomas', 'Disease', 'MESH:D001943', (135, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('PIK3CA', 'Gene', (9, 15))	('breast carcinomas', 'Phenotype', 'HP:0003002', (90, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('basal breast carcinomas', 'Disease', (129, 152))	('breast carcinomas', 'Phenotype', 'HP:0003002', (135, 152))	('TP53', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (76, 80))	('breast carcinoma', 'Phenotype', 'HP:0003002', (135, 151))	('basal breast carcinomas', 'Disease', 'MESH:D001943', (129, 152))	('PIK3CA', 'Gene', '5290', (9, 15))
34277	29273958	The most frequent mutations were detected in CDH1 (65%), PIK3CA (48%), RUNX1 (10%), TBX3 (9%), PTEN (8%), TP53 (8%), FOXA1 (7%), MAP3K1 (6%), and GATA3 (5%).	('PIK3CA', 'Gene', '5290', (57, 63))	('MAP3K', 'molecular_function', 'GO:0004709', ('129', '134'))	('CDH1', 'Gene', '999', (45, 49))	('TBX3', 'Gene', (84, 88))	('MAP3K1', 'Gene', (129, 135))	('MAP3K1', 'Gene', '4214', (129, 135))	('PTEN', 'Gene', '5728', (95, 99))	('FOXA1', 'Gene', '3169', (117, 122))	('CDH1', 'Gene', (45, 49))	('FOXA1', 'Gene', (117, 122))	('TP53', 'Gene', (106, 110))	('PIK3CA', 'Gene', (57, 63))	('GATA3', 'Gene', '2625', (146, 151))	('GATA3', 'Gene', (146, 151))	('TBX3', 'Gene', '6926', (84, 88))	('RUNX1', 'Gene', (71, 76))	('PTEN', 'Gene', (95, 99))	('RUNX1', 'Gene', '861', (71, 76))	('TP53', 'Gene', '7157', (106, 110))	('mutations', 'Var', (18, 27))
34279	29273958	The lower incidence of GATA3 and the higher incidence of FOXA1 mutations in ILC, and their roles as regulators of ER activity, suggest that GATA3 and FOXA1 regulate the ER receptor by alternative mechanisms.	('mutations', 'Var', (63, 72))	('FOXA1', 'Gene', (150, 155))	('FOXA1', 'Gene', '3169', (57, 62))	('GATA3', 'Gene', (23, 28))	('FOXA1', 'Gene', '3169', (150, 155))	('ER', 'Gene', '2099', (169, 171))	('ER', 'Gene', '2099', (114, 116))	('GATA3', 'Gene', (140, 145))	('GATA3', 'Gene', '2625', (23, 28))	('FOXA1', 'Gene', (57, 62))	('GATA3', 'Gene', '2625', (140, 145))	('regulate', 'Reg', (156, 164))
34281	29273958	Finally, 14% of ILC showed PTEN inactivation, compared to 3% of IDC, either by homozygous deletions or mutations, and were mutually exclusive with PIK3CA.	('mutations', 'Var', (103, 112))	('PIK3CA', 'Gene', (147, 153))	('PIK3CA', 'Gene', '5290', (147, 153))	('inactivation', 'NegReg', (32, 44))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))
34283	29273958	A recent consensus group has suggested that for selecting breast cancer patients for clinical trials investigating new drugs, an optimal gene panel should detect AKT1, PIK3CA, PTEN, ESR1 mutations and FGFR1 amplification, in addition to the study of ER, PR, HER2 and BRCA1/2.	('FGFR1', 'Gene', (201, 206))	('ESR1', 'Gene', (182, 186))	('PIK3CA', 'Gene', '5290', (168, 174))	('HER2', 'Gene', (258, 262))	('BRCA1/2', 'Gene', '672;675', (267, 274))	('AKT1', 'Gene', '207', (162, 166))	('ER', 'Gene', '2099', (259, 261))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PTEN', 'Gene', (176, 180))	('FGFR1', 'Gene', '2260', (201, 206))	('PIK3CA', 'Gene', (168, 174))	('ER', 'Gene', '2099', (250, 252))	('AKT1', 'Gene', (162, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('201', '205'))	('HER2', 'Gene', '2064', (258, 262))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('PTEN', 'Gene', '5728', (176, 180))	('mutations', 'Var', (187, 196))	('breast cancer', 'Disease', (58, 71))	('BRCA1/2', 'Gene', (267, 274))	('ESR1', 'Gene', '2099', (182, 186))	('patients', 'Species', '9606', (72, 80))
34286	29273958	CTCs have been proved to be a significant prognostic factor in both early and metastatic breast cancer.	('early', 'Disease', (68, 73))	('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))	('CTCs', 'Var', (0, 4))
34287	29273958	In fact, CTC positivity constitutes an individual risk factor for breast cancer relapse/death not inferior to the usual prognostic factors (size, grade, proliferation or node status) that are currently taken into account for adjuvant treatment decision.	('CTC positivity', 'Var', (9, 23))	('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))
34290	29273958	Another potential use of ctDNA is to detect ESR1 mutations, which predict resistance to aromatase inhibitors (but not fulvestrant) in advanced ER-positive breast cancer or PI3K mutations, which may predict the benefit of some PI3K inhibitors; these are under development.	('predict', 'Reg', (66, 73))	('mutations', 'Var', (49, 58))	('PI3K', 'molecular_function', 'GO:0016303', ('226', '230'))	('ESR1', 'Gene', '2099', (44, 48))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('resistance to aromatase inhibitors', 'MPA', (74, 108))	('PI3K', 'molecular_function', 'GO:0016303', ('172', '176'))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('ESR1', 'Gene', (44, 48))	('ER', 'Gene', '2099', (143, 145))
34316	29263698	P-ILC is associated with worse prognostic factors (i.e., larger tumor size, more frequent axillary metastasis) compared with other lobular carcinomas (LCs), and this explains the higher risk of recurrence and decreased survival rate often reported in literature, although in some reports, no differences are noted.	('lobular carcinomas', 'Phenotype', 'HP:0030076', (131, 149))	('tumor', 'Disease', (64, 69))	('lobular carcinomas', 'Disease', (131, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('lobular carcinomas', 'Disease', 'MESH:D018275', (131, 149))	('P-ILC', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (131, 148))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('LCs', 'Phenotype', 'HP:0030076', (151, 154))	('decreased', 'NegReg', (209, 218))
34342	29263698	Absolute values of Ki67 were higher for HG-IDC and lower for C-ILC, while P-ILC showed intermediate results (P<0.01).	('higher', 'PosReg', (29, 35))	('IDC', 'Gene', '4000', (43, 46))	('IDC', 'Gene', (43, 46))	('lower', 'NegReg', (51, 56))	('C-ILC', 'Disease', (61, 66))	('Ki67', 'Var', (19, 23))
34355	29263698	Ki67 in P-ILC was intermediate between those of C-ILC (usually very low, below 15%) and HG-IDC (usually high; in any case >20%, and frequently as high as 90%), as shown in Figure 1E.	('IDC', 'Gene', '4000', (91, 94))	('Ki67', 'Var', (0, 4))	('IDC', 'Gene', (91, 94))
34366	29263698	Additionally, it has been argued that P-ILC may develop through a molecular pathway similar to that of C-ILC, with the acquisition of further molecular alterations, more typical of high-grade ductal carcinomas, such as gain of HER2/neu, c-myc, p53 positivity and amplification of 8q24, 12q13 and 20q13.	('HER2/neu', 'Gene', '2064', (227, 235))	('8q24', 'Gene', (280, 284))	('HER2/neu', 'Gene', (227, 235))	('p53', 'Gene', (244, 247))	('p53', 'Gene', '7157', (244, 247))	('c-myc', 'Gene', '4609', (237, 242))	('gain', 'PosReg', (219, 223))	('c-myc', 'Gene', (237, 242))	('amplification', 'Var', (263, 276))	('positivity', 'Var', (248, 258))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (192, 208))	('12q13', 'Gene', (286, 291))	('ductal carcinomas', 'Disease', 'MESH:D044584', (192, 209))	('20q13', 'Gene', (296, 301))	('ductal carcinomas', 'Disease', (192, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
34379	25980321	A total of 466 ILC patients received NAC compared with 3622 IDC patients.	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (64, 72))	('ILC', 'Disease', (15, 18))	('NAC', 'Var', (37, 40))	('NAC', 'Chemical', '-', (37, 40))	('NAC', 'cellular_component', 'GO:0005854', ('37', '40'))
34381	25980321	Breast-conserving surgery was performed for 24.4 % of the patients with ILC receiving NAC versus 39.4 % of the patients with IDC.	('NAC', 'Var', (86, 89))	('ILC', 'Disease', (72, 75))	('NAC', 'Chemical', '-', (86, 89))	('NAC', 'cellular_component', 'GO:0005854', ('86', '89'))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (111, 119))
34384	25980321	The patients with ILC receiving NAC were less likely to experience a pCR and less likely to undergo BCS than the patients with IDC.	('BCS', 'Disease', (100, 103))	('pCR', 'Disease', (69, 72))	('patients', 'Species', '9606', (113, 121))	('NAC', 'cellular_component', 'GO:0005854', ('32', '35'))	('less', 'NegReg', (77, 81))	('NAC', 'Var', (32, 35))	('NAC', 'Chemical', '-', (32, 35))	('patients', 'Species', '9606', (4, 12))	('less', 'NegReg', (41, 45))	('ILC', 'Disease', (18, 21))
34418	25980321	Of the 6401 patients with ILC, 466 (7.3 %) received NAC versus 3622 (8.1 %) of the 44,597 patients with IDC (P = 0.02).	('patients', 'Species', '9606', (12, 20))	('NAC', 'cellular_component', 'GO:0005854', ('52', '55'))	('ILC', 'Disease', (26, 29))	('NAC', 'Var', (52, 55))	('NAC', 'Chemical', '-', (52, 55))	('patients', 'Species', '9606', (90, 98))
34423	25980321	Of all the ILC patients treated with NAC, 218 (46.8 %) experienced downstaging of their tumor compared with 2355 of the IDC patients (65 %) (P < 0.0001).	('NAC', 'cellular_component', 'GO:0005854', ('37', '40'))	('patients', 'Species', '9606', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ILC', 'Disease', (11, 14))	('downstaging', 'NegReg', (67, 78))	('NAC', 'Var', (37, 40))	('NAC', 'Chemical', '-', (37, 40))	('tumor', 'Disease', (88, 93))	('patients', 'Species', '9606', (124, 132))
34443	25980321	The patients who underwent NAC presented with significantly larger tumors than the patients who underwent primary surgery without NAC.	('NAC', 'Var', (27, 30))	('NAC', 'Chemical', '-', (27, 30))	('NAC', 'Chemical', '-', (130, 133))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('NAC', 'cellular_component', 'GO:0005854', ('27', '30'))	('larger', 'PosReg', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (83, 91))	('NAC', 'cellular_component', 'GO:0005854', ('130', '133'))	('tumors', 'Disease', (67, 73))
34446	25980321	Of all the patients with cT3 or cT4 breast cancer, the proportion that underwent primary surgery without NAC was 7.7 % for those with ILC and 2 % for those with IDC (Table 4).	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('cT3', 'Gene', (25, 28))	('NAC', 'cellular_component', 'GO:0005854', ('105', '108'))	('cT4', 'Var', (32, 35))	('cT3', 'Gene', '285782', (25, 28))	('ILC', 'Disease', (134, 137))	('NAC', 'Chemical', '-', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('patients', 'Species', '9606', (11, 19))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
34449	25980321	Among the patients with IDC, BCS was achieved in 55.7 % of those with cT2 tumors receiving NAC compared with 44.0 % of those who had cT2 tumors without NAC (P < 0.0001).	('tumors', 'Disease', (137, 143))	('cT2', 'Gene', (70, 73))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cT2', 'Gene', '30848', (70, 73))	('NAC', 'cellular_component', 'GO:0005854', ('152', '155'))	('NAC', 'cellular_component', 'GO:0005854', ('91', '94'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('NAC', 'Chemical', '-', (152, 155))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('NAC', 'Var', (91, 94))	('cT2', 'Gene', (133, 136))	('NAC', 'Chemical', '-', (91, 94))	('patients', 'Species', '9606', (10, 18))	('cT2', 'Gene', '30848', (133, 136))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', (74, 80))
34477	25980321	Our study showed that despite a significantly lower pCR among patients with ILC than among those who underwent surgery without NAC, patients with cT2 and cT3 breast cancer still can benefit from NAC regarding the chance of BCS, although the NNT remains high in this group.	('NAC', 'Var', (195, 198))	('NAC', 'Chemical', '-', (127, 130))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('NAC', 'Chemical', '-', (195, 198))	('cT2', 'Gene', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('cT2', 'Gene', '30848', (146, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('pCR', 'MPA', (52, 55))	('NAC', 'cellular_component', 'GO:0005854', ('195', '198'))	('cT3', 'Gene', '285782', (154, 157))	('lower', 'NegReg', (46, 51))	('BCS', 'Disease', (223, 226))	('NAC', 'cellular_component', 'GO:0005854', ('127', '130'))	('cT3', 'Gene', (154, 157))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (132, 140))
34496	31205468	The indicators of aggressivity were age (over 60), advanced stage (from IIIA to IV), E-cadherin negativity, and vimentin positivity.	('positivity', 'Var', (121, 131))	('vimentin', 'Gene', (112, 120))	('cadherin', 'molecular_function', 'GO:0008014', ('87', '95'))	('E-cadherin', 'Gene', (85, 95))	('E-cadherin', 'Gene', '999', (85, 95))	('vimentin', 'Gene', '7431', (112, 120))	('vimentin', 'cellular_component', 'GO:0045099', ('112', '120'))	('negativity', 'NegReg', (96, 106))	('vimentin', 'cellular_component', 'GO:0045098', ('112', '120'))
34497	31205468	The immunoprofile indicated unfavorable prognosis for mesenchymal-type carcinomas (negativity for E-cadherin and positivity for vimentin, with membrane to nuclear translocation or negativity of beta-catenin).	('positivity', 'Var', (113, 123))	('vimentin', 'Protein', (128, 136))	('negativity', 'NegReg', (180, 190))	('mesenchymal-type carcinomas', 'Disease', (54, 81))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('vimentin', 'cellular_component', 'GO:0045098', ('128', '136'))	('beta-catenin', 'Gene', (194, 206))	('membrane to nuclear translocation', 'CPA', (143, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('E-cadherin', 'Protein', (98, 108))	('mesenchymal-type carcinomas', 'Disease', 'MESH:C535700', (54, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('mesenchymal-type carcinoma', 'Disease', 'MESH:C535700', (54, 80))	('beta-catenin', 'Gene', '1499', (194, 206))	('negativity', 'Var', (83, 93))	('vimentin', 'cellular_component', 'GO:0045099', ('128', '136'))	('membrane', 'cellular_component', 'GO:0016020', ('143', '151'))
34519	31205468	The colonic origin was proved by positivity of tumor cells for CK20 and inconstant positivity for CDX2.	('colonic', 'Disease', (4, 11))	('CDX2', 'Gene', (98, 102))	('CDX2', 'Gene', '1045', (98, 102))	('CK20', 'Var', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))
34522	31205468	Metastases from a lobular carcinoma of the breast were based on negativity for Estrogen and Progesteron receptors (ER, PgR) and also negativity for mammaglobin, endothelial transcription factor 3 (GATA 3), and gross cystic disease fluid protein 15 (GCDFP-15).	('protein', 'cellular_component', 'GO:0003675', ('237', '244'))	('transcription factor', 'molecular_function', 'GO:0000981', ('173', '193'))	('ER', 'Gene', (115, 117))	('negativity', 'Var', (133, 143))	('GCDFP-15', 'Gene', '5304', (249, 257))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (26, 49))	('gross cystic disease fluid protein 15', 'Gene', '5304', (210, 247))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (18, 35))	('lobular carcinoma', 'Disease', (18, 35))	('PgR', 'Gene', (119, 122))	('gross cystic disease fluid protein 15', 'Gene', (210, 247))	('PgR', 'Gene', '5241', (119, 122))	('Metastases', 'CPA', (0, 10))	('GCDFP-15', 'Gene', (249, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('transcription', 'biological_process', 'GO:0006351', ('173', '186'))	('GATA 3', 'Gene', '2625', (197, 203))	('GATA 3', 'Gene', (197, 203))
34523	31205468	S100 and HMB45 negativity excluded a metastatic melanoma (Tables 3 and 4).	('melanoma', 'Disease', (48, 56))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('S100', 'Gene', (0, 4))	('HMB45', 'Protein', (9, 14))	('negativity', 'Var', (15, 25))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
34526	31205468	Negativity for maspin was an indicator of high risk for distant metastases.	('Negativity', 'Var', (0, 10))	('maspin', 'Gene', (15, 21))	('distant metastases', 'CPA', (56, 74))	('maspin', 'Gene', '5268', (15, 21))
34532	31205468	It is positive for urothelial carcinoma but can also mark the gastric and colorectal carcinomas, especially those with microsatellite status or with serrated pathway and BRAF mutations.	('colorectal carcinomas', 'Disease', (74, 95))	('BRAF', 'Gene', (170, 174))	('gastric', 'Disease', (62, 69))	('urothelial carcinoma', 'Disease', (19, 39))	('microsatellite status', 'Var', (119, 140))	('mutations', 'Var', (175, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('BRAF', 'Gene', '673', (170, 174))
34533	31205468	E-cadherin is negative in over 75% of invasive lobular carcinoma of the breast, as a result of mutations of the CDH1 gene.	('result', 'Reg', (85, 91))	('invasive lobular carcinoma of the breast', 'Disease', (38, 78))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (47, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('negative', 'NegReg', (14, 22))	('invasive lobular carcinoma of the breast', 'Disease', 'MESH:D018275', (38, 78))	('mutations', 'Var', (95, 104))	('CDH1', 'Gene', (112, 116))	('CDH1', 'Gene', '999', (112, 116))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (55, 78))
34535	31205468	Whereas HER-2, ER and PR are used as predictive factors, c-MET aberrations (mutations or amplification) are indicators of high-grade invasive breast lobular carcinomas with increased metastatic risk and are commonly identified in triple negative basal-like cases that represent below 2% of all invasive lobular carcinomas of the breast.	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('aberrations', 'Var', (63, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (311, 321))	('c-MET', 'Gene', (57, 62))	('invasive lobular carcinomas', 'Disease', (294, 321))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (294, 321))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (149, 167))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (303, 320))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (311, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('invasive breast lobular carcinomas', 'Disease', (133, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('invasive breast lobular carcinomas', 'Disease', 'MESH:D018275', (133, 167))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (149, 166))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (303, 321))
34543	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))
34650	26224116	Other physical properties, such as dense appearance on mammogram as well as hypo-reflectivity in ultrasound, establish the first line of screening and diagnosis of breast disease.	('breast disease', 'Disease', 'MESH:D001941', (164, 178))	('hypo-reflectivity', 'Var', (76, 93))	('breast disease', 'Disease', (164, 178))
34727	26224116	Proliferation index was low by Ki67.	('Proliferation index', 'CPA', (0, 19))	('Ki67', 'Var', (31, 35))	('low', 'NegReg', (24, 27))	('Ki67', 'Chemical', '-', (31, 35))
34743	26224116	As cancer progresses, the tissue becomes softer and the resistance of the tissue also changes (6.83 +- 0.86 kPa to 6.98 +- 0.72 kPa and 753.84 +- 0.46 kOmega to 754.26 +- 0.47 kOmega in case of ILC).	('ILC', 'Disease', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('changes', 'Reg', (86, 93))	('753.84', 'Var', (136, 142))	('resistance', 'MPA', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
34797	30796653	Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not.	('BC', 'Phenotype', 'HP:0003002', (46, 48))	('Ki67', 'Var', (13, 17))	('PR', 'Gene', '5241', (90, 92))	('NHG', 'Var', (22, 25))	('BCM', 'Chemical', '-', (46, 49))	('BCM', 'Disease', (46, 49))	('prognostic', 'Reg', (31, 41))
34804	30796653	The prognostic role of AR in BC is still unclear with some studies showing that AR positivity is associated with better prognosis and others showing non-prognostic results.	('AR', 'Gene', '367', (80, 82))	('better', 'PosReg', (113, 119))	('AR', 'Gene', '367', (23, 25))	('positivity', 'Var', (83, 93))	('BC', 'Phenotype', 'HP:0003002', (29, 31))
34807	30796653	AIB1 is often expressed in BC and high AIB1 is implicated to be a negative prognostic factor and at the same time a predictive factor for response to endocrine therapy, although the findings are not unanimous.	('AIB1', 'Gene', '63897', (0, 4))	('high', 'Var', (34, 38))	('negative', 'NegReg', (66, 74))	('BC', 'Phenotype', 'HP:0003002', (27, 29))	('AIB1', 'Gene', (39, 43))	('AIB1', 'Gene', '63897', (39, 43))	('AIB1', 'Gene', (0, 4))
34810	30796653	Furthermore, lack of GPER in the plasma membrane (PM GPER-negativity) has been identified as a good prognostic feature in ER-positive BC.	('BC', 'Phenotype', 'HP:0003002', (134, 136))	('GPER', 'Gene', (53, 57))	('GPER', 'Gene', '2852', (21, 25))	('lack', 'Var', (13, 17))	('ER', 'Gene', '2099', (55, 57))	('plasma membrane', 'cellular_component', 'GO:0005886', ('33', '48'))	('GPER', 'Gene', (21, 25))	('ER', 'Gene', '2099', (122, 124))	('GPER', 'Gene', '2852', (53, 57))	('ER', 'Gene', '2099', (23, 25))
34834	30796653	Ki67 (Clone MIB-1, M7240 DAKO 1:200) proliferation index was considered high if >= 24% cells were stained.	('M7240', 'Var', (19, 24))	('MIB-1', 'Gene', '57534', (12, 17))	('MIB-1', 'Gene', (12, 17))
34835	30796653	The cut-off value was set at this level to mimic the fraction of high Ki67 tumors (7.8%) in our previous whole tissue section analyses of ILC.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('high Ki67', 'Var', (65, 74))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
34837	30796653	A value of IHC 3+ was considered as HER2 positive.	('HER2', 'Gene', '2064', (36, 40))	('IHC 3+', 'Var', (11, 17))	('HER2', 'Gene', (36, 40))
34851	30796653	Proportional hazard assumptions were checked graphically for each biomarker, and were found to be violated for, e.g., high vs. low AIB1 (Fig.	('high', 'Var', (118, 122))	('low', 'Var', (127, 130))	('AIB1', 'Gene', (131, 135))	('AIB1', 'Gene', '63897', (131, 135))
34865	30796653	The associations between these three factors and other prognostic factors were also in general weak with strongest evidence for a positive association between AIB1 and Ki67 (P = 0.002) and for a negative association between AR expression and grade (P < 0.001) (Table 3).	('negative', 'NegReg', (195, 203))	('Ki67', 'Var', (168, 172))	('AIB1', 'Gene', (159, 163))	('AIB1', 'Gene', '63897', (159, 163))	('AR', 'Gene', '367', (224, 226))	('associations', 'Interaction', (4, 16))
34869	30796653	(Table 4; Online Resource 1) Ki67 (high vs. low) and NHG (3 vs. 1 + 2) were prognostic for BCM with 10- and 25-year FU, whereas PR (positive vs. negative) was not (Table 4).	('BC', 'Phenotype', 'HP:0003002', (91, 93))	('PR', 'Gene', '5241', (128, 130))	('BCM', 'Chemical', '-', (91, 94))	('NHG', 'Gene', (53, 56))	('Ki67', 'Var', (29, 33))	('BCM', 'Disease', (91, 94))
34873	30796653	High AIB1 expression was associated with worse outcome (HR > > 1.00) in two out of the three datasets (METABRIC (HR 3.1, 95% CI 1.3-7.4, P = 0.01), Metzger Filho et al.	('expression', 'MPA', (10, 20))	('AIB1', 'Gene', '63897', (5, 9))	('AIB1', 'Gene', (5, 9))	('High', 'Var', (0, 4))
34885	30796653	In line with other studies, AIB1 was also associated with high Ki67 but in contrast, AIB1 was not associated with NHG 3.	('AIB1', 'Gene', (28, 32))	('AIB1', 'Gene', '63897', (28, 32))	('Ki67', 'Var', (63, 67))	('AIB1', 'Gene', (85, 89))	('high Ki67', 'Var', (58, 67))	('AIB1', 'Gene', '63897', (85, 89))
34891	30796653	High expression of AIB1 was a negative prognostic factor in two out of three datasets (HR 3.1 and HR 3.6, respectively).	('AIB1', 'Gene', (19, 23))	('AIB1', 'Gene', '63897', (19, 23))	('High expression', 'Var', (0, 15))
34942	20534162	Involvement of the latter can result in ureteral obstruction and hydronephrosis is a not infrequent complication.	('Involvement', 'Var', (0, 11))	('ureteral obstruction', 'Phenotype', 'HP:0006000', (40, 60))	('result in', 'Reg', (30, 39))	('ureteral obstruction and hydronephrosis', 'Disease', 'MESH:D006869', (40, 79))	('hydronephrosis', 'Phenotype', 'HP:0000126', (65, 79))
35071	28039597	The absence of e-cadherin expression and ERalpha positivity in a gastric biopsy can establish metastatic breast cancer in ER positive patients.	('cadherin', 'molecular_function', 'GO:0008014', ('17', '25'))	('ERalpha', 'Gene', (41, 48))	('positivity', 'Var', (49, 59))	('patients', 'Species', '9606', (134, 142))	('e-cadherin', 'Gene', (15, 25))	('ERalpha', 'Gene', '2099', (41, 48))	('absence', 'NegReg', (4, 11))	('e-cadherin', 'Gene', '999', (15, 25))	('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))
35087	31620363	Additionally, activation of the interferon-alpha response, interferon-gamma response, and TNF-alpha signaling via the NFkappaB pathway was observed in the low-risk score subtype, which indicated T cell activation and may be responsible for significantly favorable outcomes in IDC patients.	('interferon-alpha response', 'MPA', (32, 57))	('activation', 'PosReg', (14, 24))	('IDC', 'Gene', (276, 279))	('patients', 'Species', '9606', (280, 288))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('59', '75'))	('low-risk score', 'Var', (155, 169))	('TNF-alpha', 'Gene', '7124', (90, 99))	('interferon-gamma', 'Gene', '3458', (59, 75))	('TNF-alpha', 'Gene', (90, 99))	('T cell activation', 'biological_process', 'GO:0042110', ('195', '212'))	('NFkappaB', 'Gene', (118, 126))	('activation', 'PosReg', (202, 212))	('interferon-gamma', 'Gene', (59, 75))	('IDC', 'Gene', '4000', (276, 279))	('NFkappaB', 'Gene', '4790', (118, 126))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))
35093	31620363	HER2 overexpression or amplification is detected in 20% of these tumors.	('amplification', 'Var', (23, 36))	('overexpression', 'PosReg', (5, 19))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
35096	31620363	The loss of CDH1 leads to the discohesive morphology in ILCs, whereas IDCs maintain intact cell adhesion.	('leads to', 'Reg', (17, 25))	('ILC', 'Disease', (56, 59))	('cell adhesion', 'biological_process', 'GO:0007155', ('91', '104'))	('discohesive', 'MPA', (30, 41))	('CDH1', 'Gene', (12, 16))	('CDH1', 'Gene', '999', (12, 16))	('IDC', 'Gene', '4000', (70, 73))	('cell adhesion', 'CPA', (91, 104))	('IDC', 'Gene', (70, 73))	('ILC', 'Disease', 'MESH:D018275', (56, 59))	('loss', 'Var', (4, 8))
35099	31620363	Genetic and epigenetic changes contribute to the progression of tumor progression and recurrence in different cancer types.	('cancer', 'Disease', (110, 116))	('tumor', 'Disease', (64, 69))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('contribute', 'Reg', (31, 41))	('epigenetic changes', 'Var', (12, 30))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
35136	31620363	To confirm our findings in the IDC cohort, we validated the prognostic function of the immune signature in two independent GEO cohorts (GSE20685 and GSE86948).	('GSE20685', 'Var', (136, 144))	('GSE86948', 'Var', (149, 157))	('IDC', 'Gene', '4000', (31, 34))	('IDC', 'Gene', (31, 34))
35143	31620363	The TIS (p < 0.0001 and p < 0.0001, respectively) (Figures 3D,G), interferon-gamma signature (p < 0.0001 and p < 0.0001, respectively) (Figures 3E,H), and CYT (p < 0.0001 and p < 0.0001, respectively) (Figures 3F,I) were increased in the low-risk score group and high infiltration group.	('interferon-gamma', 'Gene', (66, 82))	('increased', 'PosReg', (221, 230))	('TIS', 'CPA', (4, 7))	('interferon-gamma', 'Gene', '3458', (66, 82))	('CYT', 'CPA', (155, 158))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('66', '82'))	('low-risk score', 'Disease', (238, 252))	('high infiltration', 'Var', (263, 280))
35156	31620363	The risk score from the immune signature had a positive correlation with total mutations in IDC patients (Figure 6A).	('IDC', 'Gene', (92, 95))	('patients', 'Species', '9606', (96, 104))	('IDC', 'Gene', '4000', (92, 95))	('mutations', 'Var', (79, 88))
35169	31620363	Furthermore, the mean expression of PD-1, PDL-1, and CTLA-4 was significantly increased in the high-infiltration group, indicating a potentially enhanced response to the corresponding anticancer antibody for IDCs with high immune infiltration status.	('IDC', 'Gene', (208, 211))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('enhanced', 'PosReg', (145, 153))	('antibody', 'cellular_component', 'GO:0019814', ('195', '203'))	('PDL-1', 'Gene', '29126', (42, 47))	('antibody', 'molecular_function', 'GO:0003823', ('195', '203'))	('antibody', 'cellular_component', 'GO:0042571', ('195', '203'))	('cancer', 'Disease', (188, 194))	('expression', 'MPA', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CTLA-4', 'Gene', '1493', (53, 59))	('response to', 'MPA', (154, 165))	('high-infiltration', 'Var', (95, 112))	('increased', 'PosReg', (78, 87))	('PDL-1', 'Gene', (42, 47))	('CTLA-4', 'Gene', (53, 59))	('antibody', 'cellular_component', 'GO:0019815', ('195', '203'))	('PD-1', 'Gene', (36, 40))	('IDC', 'Gene', '4000', (208, 211))
35185	31620363	Hence, the increased T cell infiltration score, interferon-gamma signature, and cytotoxic activity score may lead to an anti-tumor effect in the high-infiltration group.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('high-infiltration', 'Var', (145, 162))	('increased', 'PosReg', (11, 20))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('48', '64'))	('cytotoxic activity score', 'CPA', (80, 104))	('T cell infiltration score', 'CPA', (21, 46))	('increased T cell', 'Phenotype', 'HP:0100828', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('interferon-gamma', 'Gene', '3458', (48, 64))	('interferon-gamma', 'Gene', (48, 64))
35210	31620363	The total mutations showed a positive correlation with the risk score in IDC patients.	('mutations', 'Var', (10, 19))	('IDC', 'Gene', '4000', (73, 76))	('IDC', 'Gene', (73, 76))	('patients', 'Species', '9606', (77, 85))
35214	31620363	Mutations in GATA3 are more frequent in luminal A IDC and are mutually exclusive with FOXA1 events.	('IDC', 'Gene', (50, 53))	('FOXA1', 'Gene', (86, 91))	('Mutations', 'Var', (0, 9))	('frequent', 'Reg', (28, 36))	('FOXA1', 'Gene', '3169', (86, 91))	('GATA3', 'Gene', (13, 18))	('GATA3', 'Gene', '2625', (13, 18))	('IDC', 'Gene', '4000', (50, 53))
35215	31620363	The differential expression level and enrichment for mutations of GATA3 in IDCs and of FOXA1 in ILC indicates a preferential requirement for the distinct regulation of ER activity in ILC and IDC.	('ILC', 'Disease', (183, 186))	('GATA3', 'Gene', (66, 71))	('ILC', 'Disease', 'MESH:D018275', (183, 186))	('IDC', 'Gene', (75, 78))	('FOXA1', 'Gene', (87, 92))	('GATA3', 'Gene', '2625', (66, 71))	('mutations', 'Var', (53, 62))	('FOXA1', 'Gene', '3169', (87, 92))	('expression level', 'MPA', (17, 33))	('ILC', 'Disease', (96, 99))	('ILC', 'Disease', 'MESH:D018275', (96, 99))	('IDC', 'Gene', '4000', (191, 194))	('regulation', 'biological_process', 'GO:0065007', ('154', '164'))	('IDC', 'Gene', '4000', (75, 78))	('IDC', 'Gene', (191, 194))
35216	31620363	Previous studies revealed that the GATA3 mutation correlates with increased expression, which is associated with the immune response.	('GATA3', 'Gene', (35, 40))	('increased', 'PosReg', (66, 75))	('immune response', 'biological_process', 'GO:0006955', ('117', '132'))	('GATA3', 'Gene', '2625', (35, 40))	('mutation', 'Var', (41, 49))	('expression', 'MPA', (76, 86))
35217	31620363	Our analysis further confirms the correlation of the GATA3 mutation with immune infiltration.	('GATA3', 'Gene', (53, 58))	('mutation', 'Var', (59, 67))	('GATA3', 'Gene', '2625', (53, 58))	('immune infiltration', 'Disease', (73, 92))
35226	31620363	In our analysis, the expression of PD1, PDL-1, and CTLA-4 was significantly increased in the high-infiltration group.	('high-infiltration', 'Var', (93, 110))	('PDL-1', 'Gene', '29126', (40, 45))	('PD1', 'Gene', (35, 38))	('CTLA-4', 'Gene', (51, 57))	('PDL-1', 'Gene', (40, 45))	('increased', 'PosReg', (76, 85))	('expression', 'MPA', (21, 31))	('CTLA-4', 'Gene', '1493', (51, 57))	('PD1', 'Gene', '5133', (35, 38))
35276	29262543	Corresponding to the UVA results, PR positive patients showed better OS than PR negative ones (HR = 0.513, 95% CI 0.312-0.843 P = 0.008), while no significant effects on OS of ER status (P = 0.335) nor histopathological grade (P = 0.562) was observed.	('positive', 'Var', (37, 45))	('patients', 'Species', '9606', (46, 54))	('OS', 'Chemical', '-', (69, 71))	('ER', 'Gene', '2099', (176, 178))	('better', 'PosReg', (62, 68))	('OS', 'Chemical', '-', (170, 172))	('PR', 'Gene', '5241', (77, 79))	('PR', 'Gene', '5241', (34, 36))
35282	29262543	In another paper, the authors demonstrated that patients with LCIS had a subsequent 10-year incidence of IBC development of 7.1%.	('patients', 'Species', '9606', (48, 56))	('IBC', 'Chemical', '-', (105, 108))	('IBC development', 'Disease', (105, 120))	('LCIS', 'Var', (62, 66))
35294	29262543	It was reported that after 12 years' follow-up, the incidence of subsequent ipsilateral IBC within the population of low and high grade DCIS was 14.4% and 24.6% (P = 0.003), respectively.	('low', 'Var', (117, 120))	('IBC', 'Chemical', '-', (88, 91))	('high grade', 'Var', (125, 135))	('ipsilateral IBC', 'Disease', (76, 91))
35371	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))
35409	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))
35459	32257726	Besides clonal theory, change of expression can occur after adjuvant therapy due to the elimination and growth of PR-positive or ER-negative cells or due to gene mutations .	('change', 'Reg', (23, 29))	('PR', 'Gene', '5241', (114, 116))	('ER', 'Gene', '2099', (129, 131))	('expression', 'MPA', (33, 43))	('gene mutations', 'Var', (157, 171))
35500	32117586	We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the K14-cre;Cdh1Flox/Flox;Trp53Flox/Flox (KEP) mouse model of metastatic ILC.	('mammalian target of rapamycin', 'Gene', '2475', (78, 107))	('mammalian target of rapamycin', 'Gene', (78, 107))	('mouse', 'Species', '10090', (166, 171))	('Cdh1', 'Gene', (131, 135))	('Cdh1', 'Gene', '12550', (131, 135))	('AZD8055', 'Chemical', 'MESH:C546624', (53, 60))	('AZD8055', 'Var', (53, 60))
35501	32117586	Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease.	('blocked', 'NegReg', (29, 36))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('mTOR signaling', 'Pathway', (14, 28))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('Inhibition', 'Var', (0, 10))	('growth', 'MPA', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
35505	32117586	Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naive immunocompetent hosts.	('AZD8055-resistant', 'Var', (80, 97))	('KEP', 'Disease', (98, 101))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('AZD8055', 'Chemical', 'MESH:C546624', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
35514	32117586	Activating mutations in the PI3K signaling pathway are more common in ILC than in other breast cancer types, offering a potentially promising therapeutic target.	('PI3K', 'molecular_function', 'GO:0016303', ('28', '32'))	('ILC', 'Disease', (70, 73))	('PI3K signaling pathway', 'Pathway', (28, 50))	('Activating mutations', 'Var', (0, 20))	('signaling pathway', 'biological_process', 'GO:0007165', ('33', '50'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('28', '42'))	('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))
35515	32117586	In this study, we used the K14-cre;Cdh1Flox/Flox;Trp53Flox/Flox (KEP) mouse model with tissue-specific inactivation of E-cadherin (Cdh1) and p53 (Trp53) driving the formation of metastatic mouse ILC, or mILC.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '22059', (51, 54))	('p53', 'Gene', (141, 144))	('mouse', 'Species', '10090', (189, 194))	('p53', 'Gene', '22059', (141, 144))	('p53', 'Gene', (148, 151))	('formation', 'biological_process', 'GO:0009058', ('165', '174'))	('E-cadherin', 'Gene', (119, 129))	('inactivation', 'Var', (103, 115))	('E-cadherin', 'Gene', '12550', (119, 129))	('Cdh1', 'Gene', (35, 39))	('Cdh1', 'Gene', '12550', (35, 39))	('mouse', 'Species', '10090', (70, 75))	('Cdh1', 'Gene', (131, 135))	('Cdh1', 'Gene', '12550', (131, 135))	('p53', 'Gene', '22059', (148, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('121', '129'))
35518	32117586	Inhibiting PI3K signaling might, therefore, influence the crosstalk between cancer cells and the host immune system.	('Inhibiting', 'Var', (0, 10))	('PI3K signaling', 'Pathway', (11, 25))	('crosstalk', 'Interaction', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('influence', 'Reg', (44, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('11', '15'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('11', '25'))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
35520	32117586	To assess the prevalence of aberrant PI3K signaling in invasive lobular carcinoma (ILC), we used publicly available data on the cBioPortal for Cancer Genomics (http://www.cbioportal.org/).	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('invasive lobular carcinoma', 'Disease', (55, 81))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (64, 81))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (55, 81))	('aberrant', 'Var', (28, 36))	('PI3K', 'molecular_function', 'GO:0016303', ('37', '41'))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PI3K signaling', 'biological_process', 'GO:0014065', ('37', '51'))
35524	32117586	The majority of human ILCs were also found to be positive for phosphorylated S6K1-T389 (70% of the cases) and phosphorylated AKT-T308 (59%, Figure 1(a), Supplementary Figure 1).	('S6K1-T389', 'Var', (77, 86))	('phosphorylated', 'Var', (110, 124))	('human', 'Species', '9606', (16, 21))
35525	32117586	In KEP mice, the vast majority of mILCs were positive for phosphorylated 4EBP1-, AKT-S473, and phosphorylated S6-S235/236, while normal mammary gland had very low expression of these signaling markers (Figure 1(a,b)).	('4EBP1-', 'Var', (73, 79))	('phosphorylated', 'Var', (95, 109))	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('mice', 'Species', '10090', (7, 11))	('positive', 'Reg', (45, 53))	('AKT-S473', 'Var', (81, 89))
35533	32117586	Treatment of both adherently and non-adherently growing KEP cells with 500 nM AZD8055 for 24 h caused potent reduction of phosphoprotein levels of AKT-S473, p70S6K-T389, S6-T235/236, and 4EBP1-T37/46.	('AZD8055', 'Chemical', 'MESH:C546624', (78, 85))	('p70S6K', 'Gene', '72508', (157, 163))	('phosphoprotein levels', 'MPA', (122, 143))	('p70S6K', 'Gene', (157, 163))	('reduction', 'NegReg', (109, 118))	('4EBP1-T37/46', 'Var', (187, 199))	('S6-T235/236', 'Var', (170, 181))	('AZD8055', 'Var', (78, 85))
35536	32117586	Wildtype FVB/n mice bearing an orthotopically transplanted primary KEP tumor were treated with AZD8055 for 28 days when tumors reached a diameter of 5 mm (Figure 2(a)).	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('AZD8055', 'Chemical', 'MESH:C546624', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', (71, 76))	('AZD8055', 'Var', (95, 102))	('tumor', 'Disease', (120, 125))
35537	32117586	During treatment, mTOR inhibition effectively suppressed primary tumor growth, leading to tumor stasis.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor stasis', 'Disease', (90, 102))	('inhibition', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor stasis', 'Disease', 'MESH:D018589', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mTOR', 'Protein', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('suppressed', 'NegReg', (46, 56))
35540	32117586	The primary KEP tumors in vehicle-treated control mice and AZD8055-treated mice were surgically removed when they reached a diameter of 15 mm, and animals were subsequently monitored for the development of metastatic disease.	('mice', 'Species', '10090', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('KEP', 'Gene', (12, 15))	('AZD8055', 'Chemical', 'MESH:C546624', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('mice', 'Species', '10090', (50, 54))	('tumors', 'Disease', (16, 22))	('AZD8055-treated', 'Var', (59, 74))
35543	32117586	Altogether, these results show that mTOR inhibition can block the growth of primary KEP tumors and spontaneous metastases in vivo.	('metastases', 'Disease', (111, 121))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mTOR', 'Protein', (36, 40))	('growth', 'CPA', (66, 72))	('block', 'NegReg', (56, 61))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('inhibition', 'Var', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
35545	32117586	To this end, we transplanted mice orthotopically with pieces from the same KEP tumor and monitored tumor outgrowth to a size of 15 mm, at which point we surgically removed the primary tumor and started 28 days of adjuvant treatment with AZD8055 (Figure 2(e), red arrow).	('tumor', 'Disease', (99, 104))	('AZD8055', 'Var', (237, 244))	('AZD8055', 'Chemical', 'MESH:C546624', (237, 244))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mice', 'Species', '10090', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
35548	32117586	Weekly X-ray computed tomography (CT) scans of the thorax in a subgroup of the mice demonstrated a slowdown in disease progression in the AZD8055-treated group compared to controls (Supplementary Fig.	('AZD8055-treated', 'Var', (138, 153))	('slowdown', 'NegReg', (99, 107))	('disease progression', 'CPA', (111, 130))	('mice', 'Species', '10090', (79, 83))	('AZD8055', 'Chemical', 'MESH:C546624', (138, 145))
35553	32117586	We harvested metastatic tumor tissue from the lungs of mice from the chronic treatment group and assessed activity of mTOR signaling by measuring the levels of phosphorylated AKT (S473), p70SK (T389), S6 (S235/235), and 4EBP1 (T37/46) (Figure 2(h)).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('p70SK (T389', 'Var', (187, 198))	('tumor', 'Disease', (24, 29))	('S473', 'Var', (180, 184))	('mice', 'Species', '10090', (55, 59))	('activity', 'MPA', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
35554	32117586	Strikingly, signaling was still effectively inhibited in all AZD8055-treated lung metastases at the endpoint of chronic treatment.	('AZD8055', 'Chemical', 'MESH:C546624', (61, 68))	('signaling', 'biological_process', 'GO:0023052', ('12', '21'))	('inhibited', 'NegReg', (44, 53))	('AZD8055-treated', 'Var', (61, 76))	('lung metastases', 'Disease', (77, 92))	('lung metastases', 'Disease', 'MESH:D009362', (77, 92))
35557	32117586	Continued neoadjuvant treatment with AZD8055 resulted in prolonged growth arrest of primary KEP tumors, but eventually all tumors progressed.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('growth', 'MPA', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('AZD8055', 'Chemical', 'MESH:C546624', (37, 44))	('growth arrest', 'Phenotype', 'HP:0001510', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('AZD8055', 'Var', (37, 44))
35558	32117586	AZD8055-resistant KEP tumors grew fast, with growth rates comparable to untreated control tumors (Figure 3(b)).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('KEP', 'Disease', (18, 21))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('grew', 'CPA', (29, 33))	('AZD8055-resistant', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (90, 96))	('growth', 'MPA', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', (22, 28))
35559	32117586	The median progression-free survival benefit was 47.5 days in the AZD8055-treated group versus control mice (54 vs 6.5 days, respectively, p < .0001, Figure 3(c)).	('mice', 'Species', '10090', (103, 107))	('AZD8055-treated', 'Var', (66, 81))	('progression-free survival', 'CPA', (11, 36))	('AZD8055', 'Chemical', 'MESH:C546624', (66, 73))
35564	32117586	Since development of resistance to AZD8055 in KEP tumors was not associated with reactivation of mTOR signaling, we set out to explore which other biological processes might play a role in the dynamics of therapy response and resistance after long-term mTOR inhibition.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('AZD8055', 'Var', (35, 42))	('AZD8055', 'Chemical', 'MESH:C546624', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
35567	32117586	Immunohistochemical quantification of Ki-67 and cleaved caspase 3 (CC3) positive cells in tumor sections showed that after 5 days of AZD8055 treatment, mTOR inhibition suppressed proliferation of cancer cells, while the number of apoptotic cells was unchanged compared to control tumors (Figure 4(b,c)).	('AZD8055', 'Chemical', 'MESH:C546624', (133, 140))	('CC3', 'Gene', '12367', (67, 70))	('inhibition suppressed', 'NegReg', (157, 178))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('mTOR', 'MPA', (152, 156))	('Ki-67', 'Gene', '17345', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (280, 286))	('cleaved caspase 3', 'Gene', (48, 65))	('tumor', 'Disease', (90, 95))	('cleaved caspase 3', 'Gene', '12367', (48, 65))	('tumor', 'Disease', (280, 285))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('proliferation', 'CPA', (179, 192))	('Ki-67', 'Gene', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('cancer', 'Disease', (196, 202))	('CC3', 'Gene', (67, 70))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('AZD8055', 'Var', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumors', 'Disease', (280, 286))
35569	32117586	Unsupervised hierarchical clustering using the expression of 136 epitopes separated AZD8055-treated tumors from untreated control tumors but did not separate AZD8055-resistant tumors from AZD8055-sensitive tumors (Supplementary Fig.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('AZD8055', 'Chemical', 'MESH:C546624', (84, 91))	('AZD8055-resistant tumors', 'Disease', 'MESH:D060467', (158, 182))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('AZD8055-sensitive tumors', 'Disease', (188, 212))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('AZD8055-sensitive tumors', 'Disease', 'MESH:D009369', (188, 212))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('AZD8055-treated', 'Var', (84, 99))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', (130, 136))	('AZD8055', 'Chemical', 'MESH:C546624', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('AZD8055-resistant tumors', 'Disease', (158, 182))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (176, 182))	('AZD8055', 'Chemical', 'MESH:C546624', (188, 195))
35580	32117586	To further investigate changes in the immune system induced by mTOR inhibition, we performed flow cytometry analysis on tumor tissue and blood from untreated control animals and neoadjuvant-treated animals with resistant primary tumors (15 mm diameter), for a panel of immune cell markers (CD45, B220, CD3, CD4, CD8, gammadeltaTCR, FOXP3, CD11b, Ly6G, Ly6C, c-KIT, and F4/80).	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('B220', 'Gene', '19264', (296, 300))	('F4/80', 'Gene', '13733', (369, 374))	('FOXP3', 'Gene', '20371', (332, 337))	('Ly6G', 'Gene', '546644', (346, 350))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('primary tumors', 'Disease', 'MESH:D001932', (221, 235))	('CD4', 'Gene', (307, 310))	('F4/80', 'Gene', (369, 374))	('Ly6G', 'Gene', (346, 350))	('B220', 'Gene', (296, 300))	('CD4', 'Gene', (290, 293))	('Ly6C', 'Gene', '17067', (352, 356))	('tumor', 'Disease', (120, 125))	('KIT', 'molecular_function', 'GO:0005020', ('360', '363'))	('CD11b', 'Gene', '16409', (339, 344))	('c-KIT', 'Gene', '16590', (358, 363))	('CD45', 'Gene', '19264', (290, 294))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CD4', 'Gene', '12504', (307, 310))	('tumor', 'Disease', (229, 234))	('CD3', 'Gene', (302, 305))	('primary tumors', 'Disease', (221, 235))	('Ly6C', 'Gene', (352, 356))	('CD4', 'Gene', '12504', (290, 293))	('FOXP3', 'Gene', (332, 337))	('CD11b', 'Gene', (339, 344))	('gammadeltaTCR', 'Var', (317, 330))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('c-KIT', 'Gene', (358, 363))	('CD45', 'Gene', (290, 294))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CD3', 'Gene', '12501', (302, 305))
35587	32117586	These results show that the response of primary KEP tumors to treatment with AZD8055 is associated with MHCII upregulation in the primary tumor immune environment, as well as upregulated transcription of genes related to antigen presentation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('upregulation', 'PosReg', (110, 122))	('transcription', 'biological_process', 'GO:0006351', ('187', '200'))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (52, 57))	('AZD8055', 'Chemical', 'MESH:C546624', (77, 84))	('tumors', 'Disease', (52, 58))	('upregulated', 'PosReg', (175, 186))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('transcription of genes', 'MPA', (187, 209))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('AZD8055', 'Var', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('antigen presentation', 'biological_process', 'GO:0019882', ('221', '241'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
35600	32117586	mTOR inhibition slowed down tumor growth in both cohorts, but the median tumor-related survival (time until tumors reached a diameter of 15 mm) was 17.5 days shorter for the AZD8055-treated Rag1-/- cohort compared to the AZD8055-treated wildtype mice (p = .049, Figure 5(d)).	('tumor', 'Disease', (28, 33))	('inhibition', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (108, 113))	('AZD8055-treated', 'Var', (174, 189))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (73, 78))	('tumors', 'Disease', (108, 114))	('AZD8055', 'Chemical', 'MESH:C546624', (174, 181))	('shorter', 'NegReg', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('Rag1', 'Gene', '19373', (190, 194))	('AZD8055', 'Chemical', 'MESH:C546624', (221, 228))	('Rag1', 'Gene', (190, 194))	('mice', 'Species', '10090', (246, 250))
35601	32117586	Thus, therapeutic efficacy of AZD8055 was significantly reduced in the absence of a functional adaptive immune system.	('therapeutic efficacy', 'CPA', (6, 26))	('reduced', 'NegReg', (56, 63))	('AZD8055', 'Var', (30, 37))	('AZD8055', 'Chemical', 'MESH:C546624', (30, 37))
35606	32117586	Activation of the adaptive immune system is induced by AZD8055 in therapy-responsive tumors and eventually lost upon acquisition of resistance.	('adaptive immune system', 'CPA', (18, 40))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('AZD8055', 'Chemical', 'MESH:C546624', (55, 62))	('AZD8055', 'Var', (55, 62))	('Activation', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
35612	32117586	We found that AZD8055 effectively suppressed mTOR signaling in KEP tumors, and that activation of the adaptive immune system contributed to the therapeutic response to mTOR inhibition.	('mTOR signaling', 'MPA', (45, 59))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('suppressed', 'NegReg', (34, 44))	('KEP', 'Disease', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('AZD8055', 'Var', (14, 21))	('AZD8055', 'Chemical', 'MESH:C546624', (14, 21))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
35614	32117586	While suppression of mTOR signaling continued to be effective during AZD8055 treatment, therapy-associated activation of the adaptive immune system seemed to be transient, and its decline coincided with the development of therapy resistance in mouse ILC.	('adaptive immune', 'CPA', (125, 140))	('suppression', 'NegReg', (6, 17))	('mouse', 'Species', '10090', (244, 249))	('mTOR', 'MPA', (21, 25))	('decline', 'NegReg', (180, 187))	('AZD8055', 'Var', (69, 76))	('AZD8055', 'Chemical', 'MESH:C546624', (69, 76))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('activation', 'PosReg', (107, 117))
35617	32117586	In the current study, however, mTOR inhibition with AZD8055 led to an increase in MHCII expression and activation of transcriptional programs related to antigen presentation through MHCII.	('increase', 'PosReg', (70, 78))	('inhibition', 'NegReg', (36, 46))	('antigen presentation', 'biological_process', 'GO:0019882', ('153', '173'))	('MHCII', 'Gene', (82, 87))	('mTOR', 'MPA', (31, 35))	('AZD8055', 'Var', (52, 59))	('AZD8055', 'Chemical', 'MESH:C546624', (52, 59))	('transcriptional programs', 'MPA', (117, 141))	('activation', 'PosReg', (103, 113))	('expression', 'MPA', (88, 98))
35618	32117586	In line with our findings, others have reported increased expression of MHCII on macrophages and dendritic cells after a combination treatment with AZD8055 and an agonist CD40 antibody.	('increased', 'PosReg', (48, 57))	('antibody', 'cellular_component', 'GO:0042571', ('176', '184'))	('expression', 'MPA', (58, 68))	('antibody', 'cellular_component', 'GO:0019815', ('176', '184'))	('AZD8055', 'Var', (148, 155))	('AZD8055', 'Chemical', 'MESH:C546624', (148, 155))	('antibody', 'cellular_component', 'GO:0019814', ('176', '184'))	('antibody', 'molecular_function', 'GO:0003823', ('176', '184'))	('CD40', 'Gene', '21939', (171, 175))	('combination', 'Interaction', (121, 132))	('MHCII', 'Gene', (72, 77))	('CD40', 'Gene', (171, 175))
35621	32117586	Previous studies indicate that mTOR inhibition, on the one hand, enhances immune-stimulatory function in existing differentiated DCs, but on the other hand impairs dendritic cell development, maturation, and survival.	('hand impairs', 'Phenotype', 'HP:0001155', (151, 163))	('inhibition', 'Var', (36, 46))	('impairs dendritic', 'Disease', 'MESH:D007635', (156, 173))	('immune-stimulatory function', 'MPA', (74, 101))	('impairs dendritic', 'Disease', (156, 173))	('maturation', 'CPA', (192, 202))	('enhances', 'PosReg', (65, 73))	('survival', 'CPA', (208, 216))	('cell development', 'biological_process', 'GO:0048468', ('174', '190'))	('mTOR', 'Protein', (31, 35))
35628	32117586	Indeed, others have combined AZD8055 with an agonist CD40 antibody in a model of metastatic renal cell carcinoma, resulting in an improved antitumor immune response which included increased numbers of dendritic cells.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('antibody', 'molecular_function', 'GO:0003823', ('58', '66'))	('AZD8055', 'Chemical', 'MESH:C546624', (29, 36))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('increased', 'PosReg', (180, 189))	('renal cell carcinoma', 'Disease', (92, 112))	('CD40', 'Gene', '21939', (53, 57))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (92, 112))	('antibody', 'cellular_component', 'GO:0042571', ('58', '66'))	('CD40', 'Gene', (53, 57))	('antibody', 'cellular_component', 'GO:0019815', ('58', '66'))	('immune response', 'biological_process', 'GO:0006955', ('149', '164'))	('AZD8055', 'Var', (29, 36))	('antibody', 'cellular_component', 'GO:0019814', ('58', '66'))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('improved', 'PosReg', (130, 138))
35639	32117586	Mouse ILC (mILC) tumors were harvested from the established K14-cre;Cdh1Flox/Flox;Trp53Flox/Flox (KEP) model,18 bred to an FVB/N genetic background.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Cdh1', 'Gene', '12550', (68, 72))	('Mouse', 'Species', '10090', (0, 5))	('Trp53Flox/Flox', 'Var', (82, 96))	('Cdh1', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
35653	32117586	Triplicate cores from these 66 invasive lobular carcinomas were incorporated into the TMA, and immunohistochemically stained with the following antibodies: Cell Signaling 9206 (phospho-S6K1 T389), 2965 (phospho-AKT T308), and 9456 (phospho-4EBP1 S65).	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('Signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('9456', 'Var', (226, 230))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (40, 58))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (40, 57))	('phospho-S6K1 T389', 'Var', (177, 194))	('invasive lobular carcinomas', 'Disease', (31, 58))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (31, 58))	('phospho-AKT', 'Var', (203, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
35657	32117586	The following primary antibodies were used: Cell Signaling 4060 (phospho-AKT S473, clone D9E), 9272 (AKT), 9234 (phospho-p70S6K T389, clone 108D2), 2708 (p70S6K, clone 49D7), 4858 (phospho-S6 S235/236, clone D57.2.2E), 2217 (S6, clone 5G10), 2855 (phospho-4EBP1 T37/46, clone 236B4), 9644 (4EBP1, clone 53H11), and Sigma A1978 (beta-actin, clone AC-15).	('p70S6K', 'Gene', (154, 160))	('D9E', 'Mutation', 'p.D9E', (89, 92))	('beta-actin', 'Gene', (328, 338))	('Signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('p70S6K', 'Gene', '72508', (154, 160))	('Sigma A1978', 'Var', (315, 326))	('p70S6K', 'Gene', (121, 127))	('beta-actin', 'Gene', '11461', (328, 338))	('p70S6K', 'Gene', '72508', (121, 127))
35661	32117586	The authors thank AstraZeneca for providing the AZD8055 compound, and the following core facilities of The Netherlands Cancer Institute (NKI) for their contributions: the Core Facility Molecular Pathology and Biobanking (CFMPB) for their contribution to the analysis of tumors from patients, the Flow Cytometry Facility, the Experimental Animal Pathology Facility for the processing and staining of mouse tissues, and the Laboratory Animal Facility for animal care and support of the animal experiments.	('tumors', 'Disease', (270, 276))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('core', 'cellular_component', 'GO:0019013', ('84', '88'))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('AZD8055', 'Chemical', 'MESH:C546624', (48, 55))	('AZD8055', 'Var', (48, 55))	('mouse', 'Species', '10090', (399, 404))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('patients', 'Species', '9606', (282, 290))
35662	32117586	AstraZeneca provided the mTOR inhibitor AZD8055.	('AZD8055', 'Var', (40, 47))	('mTOR inhibitor', 'MPA', (25, 39))	('AZD8055', 'Chemical', 'MESH:C546624', (40, 47))
35730	33926574	Cancer is a multi-step process that encompasses the accumulation of mutations that result in the hallmark of the malignant state.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (68, 77))	('result in', 'Reg', (83, 92))
35731	33926574	The goal of cancer research is to identify these mutations and correlate them with the underlying tumorigenic process.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', (98, 103))
35734	33926574	Inspired with bacterial immune system, CRISPR/Cas9 came into existence as a revolutionizing powerful tool that facilitates correction, insertion, or deletion of genetic material both in vitro and in vivo systems.	('deletion', 'Var', (149, 157))	('correction', 'Var', (123, 133))	('Cas', 'Gene', (46, 49))	('Cas', 'Gene', '1500', (46, 49))	('CRISPR', 'Gene', (39, 45))	('Cas', 'cellular_component', 'GO:0005650', ('46', '49'))	('insertion', 'Var', (135, 144))	('CRISPR', 'Gene', '70873', (39, 45))
35735	33926574	Upon transfecting cells, Cas9/gRNA complex can find its way to the target sequence (with the help of gRNA) to delete or insert a segment of DNA (with the aid of Cas9 enzyme).	('DNA', 'Gene', (140, 143))	('Cas', 'cellular_component', 'GO:0005650', ('161', '164'))	('delete', 'Var', (110, 116))	('insert', 'Reg', (120, 126))	('Cas', 'cellular_component', 'GO:0005650', ('25', '28'))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('Cas', 'Gene', (161, 164))	('Cas', 'Gene', (25, 28))	('Cas', 'Gene', '1500', (161, 164))	('Cas', 'Gene', '1500', (25, 28))
35753	33926574	Truncating APC tumor suppressor gene in gut cells was successful representative for a well-developed early event in colorectal cancer development.	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('APC tumor', 'Disease', 'MESH:D011125', (11, 20))	('colorectal cancer', 'Disease', (116, 133))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('APC', 'cellular_component', 'GO:0005680', ('11', '14'))	('APC tumor', 'Disease', (11, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('Truncating', 'Var', (0, 10))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))
35755	33926574	Other approaches involve creating cells with activated KRAS oncogene along with loss-of-function mutation.	('KRAS', 'Gene', (55, 59))	('loss-of-function', 'NegReg', (80, 96))	('KRAS', 'Gene', '3845', (55, 59))	('mutation', 'Var', (97, 105))
35760	33926574	Chen, Peng recorded a massive growth of tumor and lung metastasis upon inoculating the modified cells into immunodeficient mice.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('lung metastasis', 'CPA', (50, 65))	('modified', 'Var', (87, 95))	('tumor', 'Disease', (40, 45))	('mice', 'Species', '10090', (123, 127))
35779	33926574	Meanwhile, CRISPR/Cas9-mediated deletion of miRNA-binding site located in the UTR (un-translated region) of F1H1:the gene that regulate angiogenesis in NSCLC cells: resulted in recovering the vascular abnormalities that characterize lung cancer.	('deletion', 'Var', (32, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('UTR', 'Gene', (78, 81))	('Cas', 'Gene', (18, 21))	('Cas', 'cellular_component', 'GO:0005650', ('18', '21'))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('vascular abnormalities', 'Disease', 'MESH:D000783', (192, 214))	('UTR', 'Gene', '2837', (78, 81))	('lung cancer', 'Disease', (233, 244))	('angiogenesis', 'biological_process', 'GO:0001525', ('136', '148'))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('vascular abnormalities', 'Phenotype', 'HP:0002597', (192, 214))	('F1H1', 'Gene', (108, 112))	('Cas', 'Gene', '1500', (18, 21))	('CRISPR', 'Gene', (11, 17))	('vascular abnormalities', 'Disease', (192, 214))	('NSCLC', 'Disease', (152, 157))	('CRISPR', 'Gene', '70873', (11, 17))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('recovering', 'PosReg', (177, 187))	('miRNA-binding', 'molecular_function', 'GO:0035198', ('44', '57'))
35780	33926574	The oncogene HER2 exons are also a target for CRISPR intervention, where a mutation in the exon12 of HER2 resulted in a dominant negative mutant phenotype.	('CRISPR', 'Gene', '70873', (46, 52))	('HER2', 'Gene', (101, 105))	('HER2', 'Gene', '2064', (101, 105))	('HER2', 'Gene', (13, 17))	('CRISPR', 'Gene', (46, 52))	('HER2', 'Gene', '2064', (13, 17))	('mutation in the', 'Var', (75, 90))
35781	33926574	The mutant HER2 was found to inhibit the MAPK/ERK axis of HER2 signaling pathway required for the proliferation of breast cancer cells.	('ERK', 'Gene', '5594', (46, 49))	('HER2', 'Gene', (11, 15))	('mutant', 'Var', (4, 10))	('rat', 'Species', '10116', (105, 108))	('ERK', 'Gene', (46, 49))	('HER2 signaling pathway', 'biological_process', 'GO:0038128', ('58', '80'))	('inhibit', 'NegReg', (29, 36))	('MAPK', 'molecular_function', 'GO:0004707', ('41', '45'))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('ERK', 'molecular_function', 'GO:0004707', ('46', '49'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('HER2', 'Gene', (58, 62))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('HER2', 'Gene', '2064', (58, 62))	('HER2', 'Gene', '2064', (11, 15))
35782	33926574	Controlling breast cancer via CRISPR-mediated editing of HER2 is enhanced in the presence of PARP inhibitors that is involved in DNA repair and cell death.	('breast cancer', 'Disease', (12, 25))	('editing', 'Var', (46, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('PARP', 'Gene', '142', (93, 97))	('HER2', 'Gene', (57, 61))	('CRISPR', 'Gene', '70873', (30, 36))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('enhanced', 'PosReg', (65, 73))	('HER2', 'Gene', '2064', (57, 61))	('cell death', 'biological_process', 'GO:0008219', ('144', '154'))	('DNA repair', 'biological_process', 'GO:0006281', ('129', '139'))	('CRISPR', 'Gene', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('PARP', 'Gene', (93, 97))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('death', 'Disease', 'MESH:D003643', (149, 154))	('death', 'Disease', (149, 154))
35791	33926574	It has been indicated that breast cancer proliferation is controlled by a site-specific proteasome phosphorylation process, and the interfering and disruption of this process might be of value in controlling the disease.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('disruption', 'Var', (148, 158))	('proteasome', 'cellular_component', 'GO:0000502', ('88', '98'))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('proteasome', 'molecular_function', 'GO:0004299', ('88', '98'))	('rat', 'Species', '10116', (48, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))
35796	33926574	Antiestrogen resistance of the mutant cells was found to be associated with upregulation of the protein response that reduces the ERalpha degradation.	('Antiestrogen', 'Disease', (0, 12))	('mutant', 'Var', (31, 37))	('upregulation', 'PosReg', (76, 88))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('degradation', 'biological_process', 'GO:0009056', ('138', '149'))	('protein response', 'MPA', (96, 112))	('reduces', 'NegReg', (118, 125))	('ERalpha', 'Gene', '2099', (130, 137))	('ERalpha', 'Gene', (130, 137))
35799	33926574	Using CRISPR/Cas9, a targeted deletion in this gene effectively led to repeal its expression and hence to control the disease spearing.	('CRISPR', 'Gene', (6, 12))	('expression', 'MPA', (82, 92))	('repeal', 'PosReg', (71, 77))	('deletion', 'Var', (30, 38))	('control', 'Reg', (106, 113))	('CRISPR', 'Gene', '70873', (6, 12))	('Cas', 'Gene', (13, 16))	('Cas', 'Gene', '1500', (13, 16))	('Cas', 'cellular_component', 'GO:0005650', ('13', '16'))
35801	33926574	Mutations in PTEN (phosphatase and tensin homolog) gene, are fundamental step in the carcinogenesis process.	('phosphatase', 'molecular_function', 'GO:0016791', ('19', '30'))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('19', '49'))	('carcinogenesis', 'Disease', (85, 99))	('Mutations', 'Var', (0, 9))	('phosphatase and tensin homolog', 'Gene', '5728', (19, 49))	('PTEN', 'Gene', (13, 17))
35809	33926574	Taking into consideration that the endogenous TCRs might compete with engineered one, endogenous TCR-beta was knocked out in the recipient cells via CRISPR/Cas9.	('Cas', 'cellular_component', 'GO:0005650', ('156', '159'))	('TCR', 'Gene', (97, 100))	('Cas', 'Gene', (156, 159))	('TCR', 'Gene', (46, 49))	('Cas', 'Gene', '1500', (156, 159))	('CRISPR', 'Gene', (149, 155))	('rat', 'Species', '10116', (19, 22))	('TCR', 'cellular_component', 'GO:0042101', ('97', '100'))	('TCR', 'biological_process', 'GO:0006283', ('97', '100'))	('TCR', 'Gene', '6962', (97, 100))	('TCR', 'Gene', '6962', (46, 49))	('knocked', 'Var', (110, 117))	('CRISPR', 'Gene', '70873', (149, 155))
35812	33926574	CRISPR/Cas9-mediated epigenome editing is one of the potential tools to treat several cancers including breast cancer.	('CRISPR', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('Cas', 'cellular_component', 'GO:0005650', ('7', '10'))	('epigenome editing', 'Var', (21, 38))	('CRISPR', 'Gene', '70873', (0, 6))	('breast cancer', 'Disease', (104, 117))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cancers', 'Disease', (86, 93))	('Cas', 'Gene', (7, 10))	('Cas', 'Gene', '1500', (7, 10))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
35815	33926574	Cancer cells normally contain a wide variety of genetic mutations either in TSGs or in oncogenes.	('mutations', 'Var', (56, 65))	('TSGs', 'Gene', (76, 80))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('oncogenes', 'Gene', (87, 96))
35816	33926574	Using CRISPR/Cas9, specific loss-of-function or gain-of-function mutations could be achieved.	('CRISPR', 'Gene', (6, 12))	('loss-of-function', 'NegReg', (28, 44))	('CRISPR', 'Gene', '70873', (6, 12))	('Cas', 'Gene', (13, 16))	('gain-of-function', 'PosReg', (48, 64))	('Cas', 'Gene', '1500', (13, 16))	('Cas', 'cellular_component', 'GO:0005650', ('13', '16'))	('mutations', 'Var', (65, 74))
35821	33926574	Using CRISPR/Cas9-based epigenetic, silencing of SRC-1 resulted in a poor expression of the proliferation- and differentiation-associated genes, which might control the progression of breast cancer and/or tumor metastasis.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('SRC-1', 'Gene', (49, 54))	('Cas', 'Gene', '1500', (13, 16))	('progression', 'CPA', (169, 180))	('expression', 'MPA', (74, 84))	('breast cancer', 'Disease', (184, 197))	('SRC-1', 'Gene', '8648', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('control', 'Reg', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Cas', 'cellular_component', 'GO:0005650', ('13', '16'))	('epigenetic', 'Var', (24, 34))	('CRISPR', 'Gene', (6, 12))	('rat', 'Species', '10116', (99, 102))	('CRISPR', 'Gene', '70873', (6, 12))	('silencing', 'Var', (36, 45))	('Cas', 'Gene', (13, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('tumor', 'Disease', (205, 210))	('poor', 'NegReg', (69, 73))
35822	33926574	Molecular barcoding using mutations induced by Cas9 is an influential method for recording biological information on real time, however, its applications in mammalian systems is relatively limited.	('mutations', 'Var', (26, 35))	('mammalian', 'Species', '9606', (157, 166))	('Cas', 'Gene', (47, 50))	('Cas', 'cellular_component', 'GO:0005650', ('47', '50'))	('Cas', 'Gene', '1500', (47, 50))
35823	33926574	Breast cancer progression and proper response to treatments are major aspects being affected with the large count of mutations accumulated in malignant cells.	('mutations', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Breast cancer', 'Disease', (0, 13))
35826	33926574	This approach has been used in different malignant cells to introduce nonsense or missense mutations in TP53, resulting in an inactive or a dominant-negative form of this TSG.	('nonsense', 'Var', (70, 78))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('missense mutations', 'Var', (82, 100))
35842	33926574	Supported by the high membrane-penetrating capability of the polypeptide, P-HNPs attained competent cellular internalization and endosomal escape, which is considered an efficient way to system delivery.	('membrane', 'cellular_component', 'GO:0016020', ('22', '30'))	('endosomal escape', 'CPA', (129, 145))	('rat', 'Species', '10116', (36, 39))	('cellular internalization', 'CPA', (100, 124))	('P-HNPs', 'Var', (74, 80))
35859	33926574	Other approach involves mutating the Cas9 active domain to alter its cleavage function aiming to enforce it to use two-enzyme unite to make double stand break (DSB).	('cleavage function', 'MPA', (69, 86))	('mutating', 'Var', (24, 32))	('stand break', 'Phenotype', 'HP:0003698', (147, 158))	('Cas', 'Gene', (37, 40))	('alter', 'Reg', (59, 64))	('Cas', 'Gene', '1500', (37, 40))	('Cas', 'cellular_component', 'GO:0005650', ('37', '40'))
35868	33926574	Results also indicated that miR-27b could have tumor suppressive activity under certain circumstances.	('miR-27b', 'Var', (28, 35))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
35869	33926574	A knock-in mice with Cre-conditional expression of a cytidine base editor was generated to test the utility for precise somatic engineering of missense mutations in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('missense mutations', 'Var', (143, 161))	('mice', 'Species', '10090', (11, 15))	('rat', 'Species', '10116', (82, 85))	('cytidine', 'Chemical', 'MESH:D003562', (53, 61))
35870	33926574	A designed sgRNA-encoding vector was delivered to induce point mutation to assess the effect of defined allelic variants on mammary tumorigenesis.	('point mutation', 'Var', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))
35889	33926574	Nevertheless, one can argue that, for example, correcting the faulty version of the MYBPC3 gene that causes hypertrophic cardiomyopathy in fetus might help in the selection of the healthy embryos for implantation as a potential therapeutic intervention to treat monogenic inherited disorders.	('inherited disorders', 'Disease', 'MESH:D030342', (272, 291))	('causes', 'Reg', (101, 107))	('hypertrophic cardiomyopathy', 'Phenotype', 'HP:0001639', (108, 135))	('faulty', 'Var', (62, 68))	('MYBPC3', 'Gene', '4607', (84, 90))	('inherited disorders', 'Disease', (272, 291))	('hypertrophic cardiomyopathy', 'Disease', (108, 135))	('MYBPC3', 'Gene', (84, 90))	('hypertrophic cardiomyopathy', 'Disease', 'MESH:D002312', (108, 135))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (121, 135))
35964	21698015	Multi-spectral images of 14 breast cancer specimens acquired before and after incubation with 2-NBDG demonstrated increased fluorescent signal in all of the malignant tissue due to increased 2-NBDG consumption.	('2-NBDG', 'Chemical', 'MESH:C098340', (94, 100))	('2-NBDG consumption', 'Var', (191, 209))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('increased', 'PosReg', (114, 123))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('fluorescent signal', 'MPA', (124, 142))	('2-NBDG', 'Chemical', 'MESH:C098340', (191, 197))
36001	21698015	For example, the differences at 580 nm for the cancerous tissue from each patient (excluding patient #10) were placed into one group and the differences at 580 nm for the normal control tissues were also placed into a group.	('patient', 'Species', '9606', (74, 81))	('differences', 'Var', (17, 28))	('cancerous', 'Disease', (47, 56))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancerous', 'Disease', 'MESH:D009369', (47, 56))
36163	26271749	Several studies have demonstrated a strong correlation between Oncotype Dx RS and the risk of both local and distant recurrences, and risk of death from breast carcinoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (153, 169))	('breast carcinoma', 'Phenotype', 'HP:0003002', (153, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('Oncotype Dx RS', 'Var', (63, 77))	('death', 'Disease', 'MESH:D003643', (142, 147))	('death', 'Disease', (142, 147))	('breast carcinoma', 'Disease', (153, 169))
36192	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))	('cadherin', 'molecular_function', 'GO:0008014', ('263', '271'))	('loss', 'Var', (221, 225))	('LCIS', 'Phenotype', 'HP:0030076', (282, 286))	('LCIS', 'Phenotype', 'HP:0030076', (159, 163))	('E-cadherin', 'Gene', (261, 271))	('cadherin', 'molecular_function', 'GO:0008014', ('203', '211'))	('truncating mutations', 'Var', (173, 193))
36197	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))
36208	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))
36219	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))
36220	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))	('cadherin', 'molecular_function', 'GO:0008014', ('71', '79'))	('clonal', 'MPA', (118, 124))	('drops', 'NegReg', (176, 181))	('E-cadherin', 'Gene', (69, 79))	('PIK3CA', 'Gene', (85, 91))
36223	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))
36224	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))
36226	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))
36230	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))
36231	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))
36244	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))
36245	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))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('LCIS', 'Phenotype', 'HP:0030076', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CDH1', 'Gene', (57, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('CDH1', 'Gene', '999', (57, 61))
36246	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))
36252	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))
36265	25848941	Germline mutations in BRCA1 and TP53 are predominantly associated with invasive ductal carcinoma, while BRCA2 mutations are associated with both ductal and lobular cancers.	('Germline mutations', 'Var', (0, 18))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (80, 96))	('BRCA2', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (71, 96))	('TP53', 'Gene', '7157', (32, 36))	('associated', 'Reg', (55, 65))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('lobular cancers', 'Disease', 'MESH:D013274', (156, 171))	('BRCA2', 'Gene', '675', (104, 109))	('associated', 'Reg', (124, 134))	('BRCA1', 'Gene', '672', (22, 27))	('TP53', 'Gene', (32, 36))	('invasive ductal carcinoma', 'Disease', (71, 96))	('BRCA1', 'Gene', (22, 27))	('lobular cancers', 'Disease', (156, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
36266	25848941	CDH1, the gene coding for the E-cadherin adhesion protein, is of special interest as mutations are associated with invasive lobular carcinoma, but never with ductal carcinoma.	('invasive lobular carcinoma', 'Disease', (115, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('CDH1', 'Gene', '999', (0, 4))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (115, 141))	('ductal carcinoma', 'Disease', 'MESH:D044584', (158, 174))	('E-cadherin', 'Gene', (30, 40))	('ductal carcinoma', 'Disease', (158, 174))	('E-cadherin', 'Gene', '999', (30, 40))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (124, 141))	('mutations', 'Var', (85, 94))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (158, 174))	('CDH1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cadherin', 'molecular_function', 'GO:0008014', ('32', '40'))	('associated', 'Reg', (99, 109))
36268	25848941	The risk of invasive lobular carcinoma is high in female mutation carriers, as about 50% are expected to develop the disease.	('mutation', 'Var', (57, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('invasive lobular carcinoma', 'Disease', (12, 38))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (21, 38))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (12, 38))
36273	25848941	As for genetic risk factors, we show that ILC is often underrepresented in patients carrying mutations in the best-known breast cancer susceptibility genes (BRCA1, TP53), but that it is the only invasive histological type associated with CDH1, the diffuse gastric cancer susceptibility gene.	('TP53', 'Gene', '7157', (164, 168))	('TP53', 'Gene', (164, 168))	('mutations', 'Var', (93, 102))	('BRCA1', 'Gene', (157, 162))	('gastric cancer', 'Disease', (256, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('patients', 'Species', '9606', (75, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (256, 270))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('BRCA1', 'Gene', '672', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('CDH1', 'Gene', (238, 242))	('breast cancer', 'Disease', (121, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (256, 270))	('CDH1', 'Gene', '999', (238, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('ILC', 'Disease', (42, 45))
36282	25848941	In particular, reproductive factors associated with increased exposure to endogenous estrogens produced by the ovaries, such as earlier menarche, late menopause, low parity, and late age at first birth, are recognized breast cancer risk factors.	('breast cancer', 'Disease', (218, 231))	('menarche', 'biological_process', 'GO:0042696', ('136', '144'))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('increased', 'PosReg', (52, 61))	('low parity', 'Var', (162, 172))	('menopause', 'biological_process', 'GO:0042697', ('151', '160'))	('ovaries', 'Disease', 'MESH:D010051', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('late menopause', 'Phenotype', 'HP:0008209', (146, 160))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('ovaries', 'Disease', (111, 118))	('earlier menarche', 'Phenotype', 'HP:0012569', (128, 144))
36287	25848941	On the contrary, excess weight is associated with a decrease in risk in premenopausal women.	('excess weight', 'Var', (17, 30))	('women', 'Species', '9606', (86, 91))	('decrease', 'NegReg', (52, 60))
36296	25848941	This reduction in risk is consistent with preclinical, cellular and animal models showing that low-dose estradiol can cause tumor regression and apoptosis after prior estrogen deprivation.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('low-dose', 'Var', (95, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('apoptosis', 'CPA', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
36308	25848941	Associations with other reproductive factors, such as parity and breastfeeding, were in general not markedly different between ILC and IDC, although a few studies reported stronger associations with parity for IDC than for ILC.	('associations', 'Interaction', (181, 193))	('IDC', 'Gene', (135, 138))	('IDC', 'Gene', '4000', (210, 213))	('IDC', 'Gene', (210, 213))	('ILC', 'Disease', (127, 130))	('IDC', 'Gene', '4000', (135, 138))	('parity', 'Var', (199, 205))
36320	25848941	About 90 genes or genetic loci are involved in breast cancer susceptibility in general, through rare, moderate to high penetrance mutations (lifetime risk >20%), the penetrance being the risk for a mutation carrier of developing a disease, or through common variants associated with risks that are only slightly increased compared with the wild-type allele (RR = 1 to 1.5).	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('variants', 'Var', (258, 266))	('carrier', 'molecular_function', 'GO:0005215', ('207', '214'))	('mutations', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
36323	25848941	Germline mutations in BRCA1 and TP53 are predominantly associated with IDC, BRCA2 mutations are associated with both ductal and lobular tumors, while mutations in CDH1 are exclusively associated with ILC.	('Germline mutations', 'Var', (0, 18))	('IDC', 'Gene', (71, 74))	('associated', 'Reg', (96, 106))	('TP53', 'Gene', '7157', (32, 36))	('BRCA2', 'Gene', '675', (76, 81))	('ductal', 'Disease', (117, 123))	('associated', 'Reg', (55, 65))	('CDH1', 'Gene', '999', (163, 167))	('CDH1', 'Gene', (163, 167))	('lobular tumors', 'Disease', 'MESH:D018275', (128, 142))	('TP53', 'Gene', (32, 36))	('lobular tumors', 'Disease', (128, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('BRCA2', 'Gene', (76, 81))	('mutations', 'Var', (82, 91))	('BRCA1', 'Gene', '672', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('associated', 'Reg', (184, 194))	('IDC', 'Gene', '4000', (71, 74))	('BRCA1', 'Gene', (22, 27))
36324	25848941	Mutations in PTEN and STK11 cause, respectively, Cowden and Peutz-Jaeger syndrome, and breast cancer risk is also high in affected females.	('STK11', 'molecular_function', 'GO:0033868', ('22', '27'))	('STK11', 'Gene', '6794', (22, 27))	('Peutz-Jaeger syndrome', 'Disease', 'MESH:C536955', (60, 81))	('Cowden', 'Disease', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cause', 'Reg', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('PTEN', 'Gene', (13, 17))	('Peutz-Jaeger syndrome', 'Disease', (60, 81))	('PTEN', 'Gene', '5728', (13, 17))	('STK11', 'Gene', (22, 27))
36327	25848941	Mutations confer a high risk of breast and ovarian cancer with estimated breast cancer penetrances of 60% for BRCA1 and 55% for BRCA2 by age 70 years.	('BRCA2', 'Gene', (128, 133))	('BRCA1', 'Gene', '672', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (32, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Mutations', 'Var', (0, 9))	('BRCA1', 'Gene', (110, 115))	('breast cancer', 'Disease', (73, 86))	('BRCA2', 'Gene', '675', (128, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (43, 57))
36328	25848941	However, not all breast and breast-ovarian cancer families carry a mutation in BRCA1 or BRCA2.	('BRCA1', 'Gene', '672', (79, 84))	('mutation', 'Var', (67, 75))	('BRCA1', 'Gene', (79, 84))	('BRCA2', 'Gene', (88, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA2', 'Gene', '675', (88, 93))	('breast and breast-ovarian cancer', 'Disease', 'MESH:D001943', (17, 49))
36330	25848941	Mutations are rare in population-based, unselected breast cancer cases.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))
36332	25848941	Some phenotypic characteristics influence the probability of carrying a mutation in BRCA1 or BRCA2.	('influence', 'Reg', (32, 41))	('BRCA2', 'Gene', '675', (93, 98))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA1', 'Gene', (84, 89))	('mutation', 'Var', (72, 80))	('BRCA2', 'Gene', (93, 98))
36333	25848941	For example, up to 15% of unselected women with triple-negative breast cancer have a BRCA1 mutation, while there does not seem to be an association with BRCA2.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('mutation', 'Var', (91, 99))	('women', 'Species', '9606', (37, 42))	('BRCA1', 'Gene', (85, 90))	('BRCA2', 'Gene', (153, 158))	('BRCA2', 'Gene', '675', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('BRCA1', 'Gene', '672', (85, 90))	('breast cancer', 'Disease', (64, 77))
36335	25848941	The CIMBA Consortium analyzed the pathology of invasive breast cancers in 6,893 BRCA1/2 mutation carriers, and found that only 2.2% of tumors associated with BRCA1 were ILC.	('invasive breast cancers', 'Disease', 'MESH:D001943', (47, 70))	('mutation', 'Var', (88, 96))	('carriers', 'Reg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('breast cancers', 'Phenotype', 'HP:0003002', (56, 70))	('BRCA1', 'Gene', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('BRCA1', 'Gene', '672', (80, 85))	('BRCA1/2', 'Gene', (80, 87))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('BRCA1', 'Gene', (80, 85))	('BRCA1/2', 'Gene', '672;675', (80, 87))	('invasive breast cancers', 'Disease', (47, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('BRCA1', 'Gene', '672', (158, 163))
36336	25848941	In contrast, the proportion of ILCs in BRCA2 mutation carriers was 8.4%, closer to the characteristics of breast cancers from the general population.	('ILCs', 'Disease', (31, 35))	('breast cancers', 'Disease', 'MESH:D001943', (106, 120))	('breast cancers', 'Disease', (106, 120))	('BRCA2', 'Gene', (39, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('mutation', 'Var', (45, 53))	('BRCA2', 'Gene', '675', (39, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
36338	25848941	It is caused by mutations in the tumour-suppressor gene TP53.	('tumour', 'Disease', (33, 39))	('TP53', 'Gene', '7157', (56, 60))	('mutations', 'Var', (16, 25))	('TP53', 'Gene', (56, 60))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('caused by', 'Reg', (6, 15))	('tumour', 'Disease', 'MESH:D009369', (33, 39))
36342	25848941	Little is known regarding the histological characteristics of breast cancers associated with germline TP53 mutations, but the two studies that have examined the issue have only shown tumors of the ductal type - and none of the lobular type - out of a total of 48 cancers in mutation carriers.	('TP53', 'Gene', (102, 106))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('tumors', 'Disease', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('cancers', 'Disease', (263, 270))	('TP53', 'Gene', '7157', (102, 106))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('associated', 'Reg', (77, 87))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))	('mutations', 'Var', (107, 116))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))
36345	25848941	ILCs are therefore very much underrepresented in carriers of BRCA1 and TP53 mutations, while their frequency in BRCA2 mutation carriers is more similar to that in the general population.	('BRCA1', 'Gene', (61, 66))	('mutations', 'Var', (76, 85))	('BRCA2', 'Gene', (112, 117))	('TP53', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (71, 75))	('BRCA1', 'Gene', '672', (61, 66))	('ILCs', 'Disease', (0, 4))	('BRCA2', 'Gene', '675', (112, 117))
36355	25848941	Therefore, an individual with an inherited, germline mutation in CDH1 is at increased risk of ILC as a single somatic event is sufficient to generate tumorigenesis.	('ILC', 'Disease', (94, 97))	('CDH1', 'Gene', (65, 69))	('CDH1', 'Gene', '999', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('germline mutation', 'Var', (44, 61))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
36357	25848941	Like in ILC, E-cadherin inactivation is an early event in diffuse gastric cancer development and, as expected in this context, the histopathological characteristics of diffuse gastric cancer show similarities with ILC, with neoplastic cells permeating the mucosa and wall as scattered individual signet-ring cells or small clusters in an infiltrative growth pattern.	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('inactivation', 'Var', (24, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ILC', 'Disease', (214, 217))	('growth pattern', 'biological_process', 'GO:0007150', ('351', '365'))	('growth pattern', 'biological_process', 'GO:0040007', ('351', '365'))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', (176, 190))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
36361	25848941	Subsequent studies of families with CDH1 mutations led to similar conclusions: in four families with a total of 22 breast cancers, all invasive tumors for which a pathological report was available were lobular.	('mutations', 'Var', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('invasive tumors', 'Disease', (135, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (115, 129))	('invasive tumors', 'Disease', 'MESH:D009369', (135, 150))	('CDH1', 'Gene', (36, 40))	('breast cancers', 'Disease', 'MESH:D001943', (115, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('breast cancers', 'Disease', (115, 129))	('CDH1', 'Gene', '999', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
36362	25848941	There is increasing evidence that a personal history of early-onset bilateral ILC or family history of multiple ILC at a young age, in the absence of diffuse gastric cancer in the family, can be associated with CDH1 germline mutations.	('associated', 'Reg', (195, 205))	('CDH1', 'Gene', (211, 215))	('gastric cancer', 'Disease', 'MESH:D013274', (158, 172))	('gastric cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('germline mutations', 'Var', (216, 234))	('CDH1', 'Gene', '999', (211, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (158, 172))	('early-onset bilateral ILC', 'Disease', (56, 81))
36364	25848941	We reported three female cases who presented with bilateral ILC below age 50 years and turned out to carry mutations in CDH1.	('CDH1', 'Gene', '999', (120, 124))	('mutations', 'Var', (107, 116))	('ILC', 'Disease', (60, 63))	('carry', 'Reg', (101, 106))	('CDH1', 'Gene', (120, 124))
36365	25848941	In the only systematic study of women with bilateral lobular breast neoplasia before age 60 years (ILC and/or lobular carcinoma in situ), Petridis and colleagues found mutations in 4 out of 50 (8%) women.	('neoplasia', 'Phenotype', 'HP:0002664', (68, 77))	('women', 'Species', '9606', (32, 37))	('breast neoplasia', 'Phenotype', 'HP:0100013', (61, 77))	('women', 'Species', '9606', (198, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('bilateral lobular breast neoplasia', 'Disease', (43, 77))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (110, 127))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (110, 135))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (118, 135))	('lobular carcinoma', 'Disease', 'MESH:D018275', (110, 127))	('lobular carcinoma', 'Disease', (110, 127))	('bilateral lobular breast neoplasia', 'Disease', 'MESH:D009369', (43, 77))	('mutations', 'Var', (168, 177))
36366	25848941	Schrader and colleagues had previously looked into the issue with discrepant findings, as they only found mutations or potentially causal variants in 4 out of 318 (1%) women with ILC either before age 45 years or regardless of age if there was a family history of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('variants', 'Var', (138, 146))	('breast cancer', 'Disease', (264, 277))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('mutations', 'Var', (106, 115))	('ILC', 'Disease', (179, 182))	('women', 'Species', '9606', (168, 173))
36371	25848941	Surveillance with upper endoscopy is a poor alternative to prophylactic surgery, except in very specific situations (for example, young athletes wishing to delay surgery for professional reasons, and elderly or frail patients), as this screening modality frequently misses foci of diffuse carcinoma in mutation carriers even when accompanied by multiple random biopsies.	('carcinoma', 'Disease', 'MESH:D002277', (289, 298))	('misses', 'NegReg', (266, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('carcinoma', 'Disease', (289, 298))	('patients', 'Species', '9606', (217, 225))	('mutation', 'Var', (302, 310))
36372	25848941	Large, multicenter studies on the prevalence of CDH1 mutations in patients and families with multiple cases of ILC are needed.	('CDH1', 'Gene', '999', (48, 52))	('patients', 'Species', '9606', (66, 74))	('CDH1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))
36373	25848941	The high risk of ILC in females carrying a CDH1 mutation justifies personalized, intensive surveillance.	('mutation', 'Var', (48, 56))	('CDH1', 'Gene', (43, 47))	('ILC', 'Disease', (17, 20))	('CDH1', 'Gene', '999', (43, 47))
36375	25848941	As ILC risk is close to the overall breast cancer risk seen in carriers of BRCA1/BRCA2 mutations, it seems reasonable to offer the same type of surveillance as a routine procedure, and start screening at age 30 years with annual MRI and mammogram.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('BRCA1', 'Gene', (75, 80))	('breast cancer', 'Disease', (36, 49))	('BRCA2', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('BRCA1', 'Gene', '672', (75, 80))	('BRCA2', 'Gene', '675', (81, 86))	('carriers', 'Reg', (63, 71))	('mutations', 'Var', (87, 96))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
36376	25848941	Updated international recommendations on the management of CDH1 mutation carriers that will address the issue are expected soon.	('CDH1', 'Gene', '999', (59, 63))	('mutation', 'Var', (64, 72))	('CDH1', 'Gene', (59, 63))
36474	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))
36481	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))
36500	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))
36519	32289273	An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('epigenetic changes', 'Var', (110, 128))	('tumor', 'Disease', 'MESH:D009369', (149, 154))
36536	32289273	In this review, we summarize mechanisms associated with and/or causal to resistance to estrogen suppression, or inactivation of ER by other means (SERMs/SERDs).	('SERDs', 'Chemical', '-', (153, 158))	('inactivation', 'Var', (112, 124))	('estrogen', 'Protein', (87, 95))
36541	32289273	For example, high EGFR or HER2 expression has been shown to dampen the therapeutic efficacy of tamoxifen in ER+ breast cancers.	('breast cancers', 'Disease', (112, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('ER+', 'Gene', '2069', (108, 111))	('EGFR', 'Gene', '1956', (18, 22))	('tamoxifen', 'Chemical', 'MESH:D013629', (95, 104))	('high', 'Var', (13, 17))	('therapeutic efficacy of tamoxifen', 'MPA', (71, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('EGFR', 'Gene', (18, 22))	('HER2', 'Gene', (26, 30))	('ER+', 'Gene', (108, 111))	('breast cancers', 'Phenotype', 'HP:0003002', (112, 126))	('dampen', 'NegReg', (60, 66))	('HER2', 'Gene', '2064', (26, 30))	('expression', 'Var', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancers', 'Disease', 'MESH:D001943', (112, 126))
36551	32289273	In some cases, there are functional data to causally link these alterations with drug resistance (i.e., HER2, NF1, FGFR, ESR1) (Figure 3), whereas in other cases such causality is less clear.	('NF1', 'Gene', (110, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('drug resistance', 'biological_process', 'GO:0042493', ('81', '96'))	('NF1', 'Gene', '4763', (110, 113))	('drug resistance', 'MPA', (81, 96))	('ESR1', 'Gene', (121, 125))	('alterations', 'Var', (64, 75))	('HER2', 'Gene', (104, 108))	('drug resistance', 'biological_process', 'GO:0009315', ('81', '96'))	('drug resistance', 'Phenotype', 'HP:0020174', (81, 96))	('HER2', 'Gene', '2064', (104, 108))	('ESR1', 'Gene', '2099', (121, 125))
36553	32289273	For many cancer therapies, mutations in the drug target itself are often the preferential mechanism by which the tumor escapes drug inhibition.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', (9, 15))	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
36554	32289273	Point mutations in ESR1, the gene encoding ERalpha were first reported over two decades ago.	('ERalpha', 'Gene', '2099', (43, 50))	('ERalpha', 'Gene', (43, 50))	('ESR1', 'Gene', '2099', (19, 23))	('ESR1', 'Gene', (19, 23))	('Point mutations', 'Var', (0, 15))
36555	32289273	However, it was only recently appreciated that acquired mutations in the ligand-binding domain (LBD) of ESR1 are frequent drivers of resistance in ER+ MBC.	('mutations', 'Var', (56, 65))	('ER+', 'Gene', (147, 150))	('ESR1', 'Gene', (104, 108))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('ligand', 'molecular_function', 'GO:0005488', ('73', '79'))	('MBC', 'Disease', 'MESH:D001943', (151, 154))	('ESR1', 'Gene', '2099', (104, 108))	('ER+', 'Gene', '2069', (147, 150))	('MBC', 'Disease', (151, 154))
36556	32289273	These mutations are found in ~20% of recurrent ER+ breast cancers, usually acquired following long-term treatment with AIs or tamoxifen.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ER+', 'Gene', (47, 50))	('breast cancers', 'Phenotype', 'HP:0003002', (51, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('tamoxifen', 'Chemical', 'MESH:D013629', (126, 135))	('breast cancers', 'Disease', 'MESH:D001943', (51, 65))	('breast cancers', 'Disease', (51, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('ER+', 'Gene', '2069', (47, 50))	('mutations', 'Var', (6, 15))
36557	32289273	The prevalence of ESR1 mutations in plasma ctDNA in similar populations is even higher.	('mutations', 'Var', (23, 32))	('ESR1', 'Gene', (18, 22))	('ESR1', 'Gene', '2099', (18, 22))
36558	32289273	These LBD point mutations (most commonly at Y537 and D538) allow hormone-independent ER transcriptional activity, leading to resistance to AIs and decreased sensitivity to tamoxifen and fulvestrant.	('ER transcriptional activity', 'MPA', (85, 112))	('decreased', 'NegReg', (147, 156))	('fulvestrant', 'Chemical', 'MESH:D000077267', (186, 197))	('tamoxifen', 'Chemical', 'MESH:D013629', (172, 181))	('resistance to AIs', 'MPA', (125, 142))	('Y537', 'Var', (44, 48))	('D538', 'Var', (53, 57))
36560	32289273	showed that the Y537S and D538G mutants also show allele-specific differences in their cistromes and transcriptomes that enhance transcription of metastasis-associated genes.	('transcription', 'MPA', (129, 142))	('D538G', 'Mutation', 'p.D538G', (26, 31))	('metastasis-associated genes', 'Gene', (146, 173))	('Y537S', 'Var', (16, 21))	('enhance', 'PosReg', (121, 128))	('Y537S', 'Mutation', 'rs1164665914', (16, 21))	('D538G', 'Var', (26, 31))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))
36561	32289273	This could be reversed by combining fulvestrant with a CDK7 inhibitor, suggesting a potential therapeutic strategy for tumors with these ESR1 mutations.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('mutations', 'Var', (142, 151))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('CDK7', 'Gene', '1022', (55, 59))	('ESR1', 'Gene', '2099', (137, 141))	('fulvestrant', 'Chemical', 'MESH:D000077267', (36, 47))	('CDK', 'molecular_function', 'GO:0004693', ('55', '58'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('CDK7', 'Gene', (55, 59))	('ESR1', 'Gene', (137, 141))
36562	32289273	Similarly, the Y537S and D538G mutants displayed enhanced interactions with coactivators such as steroid receptor coactivator (SRC) family members, which could be potential targets in tumors with these ESR1 mutations.	('ESR1', 'Gene', (202, 206))	('SRC', 'Gene', '10011', (127, 130))	('D538G', 'Var', (25, 30))	('steroid receptor coactivator', 'Gene', (97, 125))	('enhanced', 'PosReg', (49, 57))	('interactions', 'Interaction', (58, 70))	('D538G', 'Mutation', 'p.D538G', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Y537S', 'Var', (15, 20))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('SRC', 'Gene', (127, 130))	('ESR1', 'Gene', '2099', (202, 206))	('Y537S', 'Mutation', 'rs1164665914', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('steroid receptor coactivator', 'Gene', '10011', (97, 125))
36563	32289273	While the LBD mutations reduce the potency of fulvestrant, next-generation oral SERMs or SERDs that target both WT and mutant ER are in clinical development (Table 2).	('SERDs', 'Chemical', '-', (89, 94))	('potency of fulvestrant', 'MPA', (35, 57))	('reduce', 'NegReg', (24, 30))	('fulvestrant', 'Chemical', 'MESH:D000077267', (46, 57))	('mutations', 'Var', (14, 23))
36565	32289273	Similarly, the oral SERD AZD9496 reduced on-treatment ESR1-mutant ctDNA levels and GDC-0810 (now discontinued) reduced 18F-fluoroestradiol (FES) uptake by positron emission tomography (PET) in patients with ESR1 mutations.	('FES', 'Chemical', '-', (140, 143))	('patients', 'Species', '9606', (193, 201))	('ESR1', 'Gene', '2099', (207, 211))	('18F-fluoroestradiol', 'Chemical', '-', (119, 138))	('ESR1', 'Gene', '2099', (54, 58))	('uptake', 'biological_process', 'GO:0098739', ('145', '151'))	('reduced', 'NegReg', (111, 118))	('ESR1', 'Gene', (207, 211))	('GDC-0810', 'Chemical', 'MESH:C000606997', (83, 91))	('reduced', 'NegReg', (33, 40))	('mutations', 'Var', (212, 221))	('uptake', 'biological_process', 'GO:0098657', ('145', '151'))	('ESR1', 'Gene', (54, 58))	('AZD9496', 'Chemical', 'MESH:C000604573', (25, 32))	('ctDNA levels', 'MPA', (66, 78))	('SERD', 'Chemical', '-', (20, 24))
36566	32289273	The selective estrogen receptor covalent antagonist (SERCA) H3B-6545 covalently binds the Cys530 residue of both WT and mutant ERalpha, enforcing an irreversible antagonist conformation.	('ERalpha', 'Gene', (127, 134))	('estrogen receptor', 'Gene', (14, 31))	('estrogen receptor', 'Gene', '2099', (14, 31))	('ERalpha', 'Gene', '2099', (127, 134))	('binds', 'Interaction', (80, 85))	('Cys530', 'Chemical', '-', (90, 96))	('Cys530', 'Var', (90, 96))	('mutant', 'Var', (120, 126))
36567	32289273	For example, the PROTAC ARV-471 degrades the Y537S and D538G mutants and inhibits tumor growth in a patient-derived xenograft (PDX) harboring ESR1Y537S.	('degrades', 'NegReg', (32, 40))	('Y537S', 'Mutation', 'rs1164665914', (45, 50))	('Y537S', 'Var', (45, 50))	('D538G', 'Var', (55, 60))	('Y537S', 'Mutation', 'rs1164665914', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('inhibits', 'NegReg', (73, 81))	('D538G', 'Mutation', 'p.D538G', (55, 60))	('patient', 'Species', '9606', (100, 107))	('ESR1Y537S', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('AR', 'Gene', '367', (24, 26))
36568	32289273	We speculate that use of agents that target both mutant and WT ER earlier in the course of breast cancer treatment may prevent the acquisition of LBD mutations.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('mutant', 'Var', (49, 55))	('mutations', 'Var', (150, 159))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
36569	32289273	ESR1 amplifications and gene fusions have been found in ER+ breast cancers, albeit at much lower frequencies than point mutations.	('breast cancers', 'Disease', 'MESH:D001943', (60, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('amplifications', 'Var', (5, 19))	('breast cancers', 'Disease', (60, 74))	('ESR1', 'Gene', (0, 4))	('ER+', 'Gene', '2069', (56, 59))	('found', 'Reg', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('ER+', 'Gene', (56, 59))	('ESR1', 'Gene', '2099', (0, 4))	('breast cancers', 'Phenotype', 'HP:0003002', (60, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
36570	32289273	Whether ESR1 amplification is associated with resistance to endocrine therapy remains unclear.	('associated', 'Reg', (30, 40))	('amplification', 'Var', (13, 26))	('ESR1', 'Gene', (8, 12))	('ESR1', 'Gene', '2099', (8, 12))
36572	32289273	Most ESR1 gene fusions retain the N-terminal DNA binding domain of the ER fused to diverse C-terminal partner genes, thereby excluding the ER LBD.	('ESR1', 'Gene', '2099', (5, 9))	('fusions', 'Var', (15, 22))	('binding', 'Interaction', (49, 56))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('DNA binding', 'molecular_function', 'GO:0003677', ('45', '56'))	('ESR1', 'Gene', (5, 9))	('N-terminal DNA', 'MPA', (34, 48))	('excluding', 'NegReg', (125, 134))
36575	32289273	reported CYP19A1 amplifications in 21.5% of AI-treated, relapsed patients, but <2% in primary tumors.	('CYP19A1', 'Gene', '1588', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CYP19A1', 'Gene', (9, 16))	('amplifications', 'Var', (17, 31))	('tumors', 'Disease', (94, 100))	('patients', 'Species', '9606', (65, 73))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
36576	32289273	CYP19A1 amplification increases aromatase activity and leads to recruitment of ER to target genes in the absence of exogenous estrogen, thus inducing resistance to estrogen suppression with nonsteroidal AIs.	('aromatase activity', 'molecular_function', 'GO:0070330', ('32', '50'))	('activity', 'MPA', (42, 50))	('amplification', 'Var', (8, 21))	('resistance', 'MPA', (150, 160))	('aromatase', 'Gene', (32, 41))	('steroid', 'Chemical', 'MESH:D013256', (193, 200))	('inducing', 'Reg', (141, 149))	('recruitment', 'MPA', (64, 75))	('estrogen suppression with nonsteroidal AIs', 'MPA', (164, 206))	('increases', 'PosReg', (22, 31))	('aromatase', 'Gene', '1588', (32, 41))	('CYP19A1', 'Gene', '1588', (0, 7))	('CYP19A1', 'Gene', (0, 7))
36579	32289273	HER2 (ERBB2) amplification has long been known to reduce sensitivity to anti-estrogen treatment, primarily through activation of alternate survival pathways (ie, PI3K-AKT and MAPK pathways) (Figure 2).	('AKT', 'Gene', (167, 170))	('activation', 'PosReg', (115, 125))	('reduce', 'NegReg', (50, 56))	('ERBB2', 'Gene', '2064', (6, 11))	('ERBB2', 'Gene', (6, 11))	('sensitivity to anti-estrogen treatment', 'MPA', (57, 95))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('amplification', 'Var', (13, 26))	('HER2', 'Gene', (0, 4))	('AKT', 'Gene', '207', (167, 170))	('MAPK', 'molecular_function', 'GO:0004707', ('175', '179'))	('HER2', 'Gene', '2064', (0, 4))
36581	32289273	More recently, HER2-activating mutations have been implicated in both intrinsic and acquired resistance to endocrine therapies, and are found in ~5% of endocrine-resistant MBCs.	('MBC', 'Disease', (172, 175))	('mutations', 'Var', (31, 40))	('HER2', 'Gene', (15, 19))	('MBC', 'Disease', 'MESH:D001943', (172, 175))	('HER2', 'Gene', '2064', (15, 19))	('found', 'Reg', (136, 141))	('implicated', 'Reg', (51, 61))
36582	32289273	ER+ breast cancer cells and xenografts expressing activating HER2 mutants were resistant to estrogen deprivation and fulvestrant, and also responded poorly to the HER2 tyrosine kinase inhibitor neratinib.	('mutants', 'Var', (66, 73))	('HER2', 'Gene', (163, 167))	('neratinib', 'Chemical', 'MESH:C487932', (194, 203))	('fulvestrant', 'Chemical', 'MESH:D000077267', (117, 128))	('poorly', 'NegReg', (149, 155))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('responded', 'MPA', (139, 148))	('HER2', 'Gene', '2064', (163, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('ER+', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', (4, 17))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('177', '193'))	('HER2', 'Gene', (61, 65))	('HER2', 'Gene', '2064', (61, 65))	('activating', 'PosReg', (50, 60))	('ER+', 'Gene', '2069', (0, 3))
36583	32289273	However, combined blockade of HER2 and the ER were synergistic in vitro and in vivo, and the combination of neratinib with fulvestrant has shown promise in ER+ MBCs harboring HER2 mutations.	('MBC', 'Disease', 'MESH:D001943', (160, 163))	('mutations', 'Var', (180, 189))	('HER2', 'Gene', '2064', (175, 179))	('ER+', 'Gene', '2069', (156, 159))	('HER2', 'Gene', (30, 34))	('MBC', 'Disease', (160, 163))	('HER2', 'Gene', (175, 179))	('neratinib', 'Chemical', 'MESH:C487932', (108, 117))	('HER2', 'Gene', '2064', (30, 34))	('ER+', 'Gene', (156, 159))	('fulvestrant', 'Chemical', 'MESH:D000077267', (123, 134))
36585	32289273	Ectopic expression of EGFR promoted fulvestrant resistance, which could be reversed by combining fulvestrant with an EGFR or ERK inhibitor.	('ERK', 'Gene', '5594', (125, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('22', '26'))	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('EGFR', 'Gene', '1956', (117, 121))	('ERK', 'molecular_function', 'GO:0004707', ('125', '128'))	('EGFR', 'Gene', (117, 121))	('ERK', 'Gene', (125, 128))	('Ectopic expression', 'Var', (0, 18))	('promoted', 'PosReg', (27, 35))	('fulvestrant resistance', 'MPA', (36, 58))	('fulvestrant', 'Chemical', 'MESH:D000077267', (97, 108))	('fulvestrant', 'Chemical', 'MESH:D000077267', (36, 47))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
36586	32289273	Amplification of the locus containing FGFR1 is found in ~15% of ER+ MBCs and is associated with de novo endocrine resistance.	('Amplification', 'Var', (0, 13))	('endocrine resistance', 'MPA', (104, 124))	('ER+', 'Gene', (64, 67))	('MBC', 'Disease', 'MESH:D001943', (68, 71))	('FGFR1', 'Gene', (38, 43))	('associated with', 'Reg', (80, 95))	('FGFR1', 'Gene', '2260', (38, 43))	('FGFR', 'molecular_function', 'GO:0005007', ('38', '42'))	('ER+', 'Gene', '2069', (64, 67))	('MBC', 'Disease', (68, 71))
36588	32289273	Clinical studies combining FGFR inhibitors and fulvestrant (and also palbociclib) in ER+ MBCs are ongoing (NCT03238196, NCT04024436).	('NCT04024436', 'Var', (120, 131))	('ER+', 'Gene', (85, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('27', '31'))	('MBC', 'Disease', 'MESH:D001943', (89, 92))	('palbociclib', 'Chemical', 'MESH:C500026', (69, 80))	('FGFR', 'Gene', (27, 31))	('ER+', 'Gene', '2069', (85, 88))	('MBC', 'Disease', (89, 92))	('NCT03238196', 'Var', (107, 118))	('fulvestrant', 'Chemical', 'MESH:D000077267', (47, 58))
36589	32289273	FGFR4 overexpression and hotspot mutations are associated with endocrine-resistant lobular MBC; the combination of endocrine therapy with an FGFR4-selective inhibitor such as fisogatinib is an attractive strategy in these patients.	('MBC', 'Disease', 'MESH:D001943', (91, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))	('FGFR4', 'Gene', '2264', (141, 146))	('FGFR4', 'Gene', (141, 146))	('patients', 'Species', '9606', (222, 230))	('mutations', 'Var', (33, 42))	('fisogatinib', 'Chemical', '-', (175, 186))	('overexpression', 'PosReg', (6, 20))	('MBC', 'Disease', (91, 94))	('FGFR4', 'Gene', '2264', (0, 5))	('FGFR4', 'Gene', (0, 5))	('associated', 'Reg', (47, 57))
36590	32289273	Components of the PI3K pathway (including PIK3CA, PTEN, and AKT1) are frequently mutated in ER+ breast cancers.	('ER+', 'Gene', '2069', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ER+', 'Gene', (92, 95))	('breast cancers', 'Phenotype', 'HP:0003002', (96, 110))	('PIK3CA', 'Gene', (42, 48))	('breast cancers', 'Disease', 'MESH:D001943', (96, 110))	('PTEN', 'Gene', (50, 54))	('breast cancers', 'Disease', (96, 110))	('PTEN', 'Gene', '5728', (50, 54))	('mutated', 'Var', (81, 88))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('PIK3CA', 'Gene', '5290', (42, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('AKT1', 'Gene', '207', (60, 64))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('AKT1', 'Gene', (60, 64))	('PI3K pathway', 'Pathway', (18, 30))
36591	32289273	Clinically, however, PIK3CA mutations are generally associated with a good prognosis in patients with early-stage ER+ tumors and PIK3CA mutation rates are no different between primary and endocrine-resistant metastatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('PIK3CA', 'Gene', (129, 135))	('ER+', 'Gene', '2069', (114, 117))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('PIK3CA', 'Gene', (21, 27))	('PIK3CA', 'Gene', '5290', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('ER+', 'Gene', (114, 117))	('PIK3CA', 'Gene', '5290', (21, 27))	('tumors', 'Disease', (118, 124))	('mutations', 'Var', (28, 37))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
36592	32289273	Nonetheless, in patients with ER+ MBC, the addition of PI3K pathway antagonists has improved outcome of patients, particularly those with tumors harboring activating PIK3CA mutations.	('PIK3CA', 'Gene', '5290', (166, 172))	('outcome', 'MPA', (93, 100))	('patients', 'Species', '9606', (16, 24))	('activating', 'PosReg', (155, 165))	('mutations', 'Var', (173, 182))	('MBC', 'Disease', 'MESH:D001943', (34, 37))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('improved', 'PosReg', (84, 92))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('ER+', 'Gene', '2069', (30, 33))	('PIK3CA', 'Gene', (166, 172))	('MBC', 'Disease', (34, 37))	('patients', 'Species', '9606', (104, 112))	('ER+', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
36593	32289273	For example, alpelisib, a specific inhibitor of the PIK3CA product PI3Kalpha, was recently approved in combination with fulvestrant in ER+ MBCs harboring PIK3CA mutations.	('MBC', 'Disease', 'MESH:D001943', (139, 142))	('PIK3CA', 'Gene', (154, 160))	('PIK3CA', 'Gene', '5290', (52, 58))	('PIK3CA', 'Gene', (52, 58))	('PIK3CA', 'Gene', '5290', (154, 160))	('MBC', 'Disease', (139, 142))	('alpelisib', 'Chemical', 'MESH:C585539', (13, 22))	('ER+', 'Gene', '2069', (135, 138))	('mutations', 'Var', (161, 170))	('PI3Kalpha', 'Gene', '5290', (67, 76))	('PI3Kalpha', 'Gene', (67, 76))	('ER+', 'Gene', (135, 138))	('fulvestrant', 'Chemical', 'MESH:D000077267', (120, 131))
36596	32289273	This combination may be particularly effective in ER+ breast cancers with AKT1 mutations.	('breast cancers', 'Disease', (54, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('ER+', 'Gene', '2069', (50, 53))	('breast cancers', 'Disease', 'MESH:D001943', (54, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('AKT1', 'Gene', '207', (74, 78))	('AKT1', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))	('ER+', 'Gene', (50, 53))
36597	32289273	AKT1 and PTEN mutations are more frequent in advanced/metastatic ER+ breast cancers.	('ER+', 'Gene', '2069', (65, 68))	('AKT1', 'Gene', '207', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('AKT1', 'Gene', (0, 4))	('PTEN', 'Gene', (9, 13))	('frequent', 'Reg', (33, 41))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('PTEN', 'Gene', '5728', (9, 13))	('ER+', 'Gene', (65, 68))	('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))	('mutations', 'Var', (14, 23))
36598	32289273	Acquired hotspot mutations in PIK3CA have been reported following progression on either fulvestrant alone or in combination with CDK4/6 inhibitors (CDK4/6i).	('CDK4/6', 'Gene', (148, 154))	('PIK3CA', 'Gene', (30, 36))	('CDK4/6', 'Gene', '1019;1021', (129, 135))	('CDK', 'molecular_function', 'GO:0004693', ('148', '151'))	('CDK4/6i', 'Gene', (148, 155))	('PIK3CA', 'Gene', '5290', (30, 36))	('CDK4/6', 'Gene', (129, 135))	('CDK', 'molecular_function', 'GO:0004693', ('129', '132'))	('fulvestrant', 'Chemical', 'MESH:D000077267', (88, 99))	('CDK4/6', 'Gene', '1019;1021', (148, 154))	('CDK4/6i', 'Gene', '1019', (148, 155))	('mutations', 'Var', (17, 26))	('hotspot', 'PosReg', (9, 16))
36601	32289273	Components of the MAPK pathway, including NF1, KRAS/NRAS/HRAS, BRAF, and MAP2K1 are frequently mutated in many cancer types, yet rarely mutated in primary breast cancers.	('NRAS', 'Gene', (52, 56))	('MAP2K1', 'Gene', '5604', (73, 79))	('cancer', 'Disease', (162, 168))	('MAP2K1', 'Gene', (73, 79))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('BRAF', 'Gene', '673', (63, 67))	('cancer', 'Disease', (111, 117))	('BRAF', 'Gene', (63, 67))	('MAPK pathway', 'Pathway', (18, 30))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('MAP2K', 'molecular_function', 'GO:0004708', ('73', '78'))	('NRAS', 'Gene', '4893', (52, 56))	('HRAS', 'Gene', '3265', (57, 61))	('KRAS', 'Gene', '3845', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('HRAS', 'Gene', (57, 61))	('NF1', 'Gene', '4763', (42, 45))	('mutated', 'Var', (95, 102))	('KRAS', 'Gene', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('NF1', 'Gene', (42, 45))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
36602	32289273	However, mutations in these genes, in particular NF1, are more frequent in MBC (Table 1).	('MBC', 'Disease', 'MESH:D001943', (75, 78))	('mutations', 'Var', (9, 18))	('MBC', 'Disease', (75, 78))	('frequent', 'Reg', (63, 71))	('NF1', 'Gene', (49, 52))	('NF1', 'Gene', '4763', (49, 52))
36604	32289273	Thus, loss of NF1 results in constitutive RAS activity.	('NF1', 'Gene', '4763', (14, 17))	('loss', 'Var', (6, 10))	('constitutive RAS activity', 'MPA', (29, 54))	('NF1', 'Gene', (14, 17))	('results in', 'Reg', (18, 28))
36605	32289273	Loss-of-function NF1 alterations are associated with both intrinsic and acquired resistance to endocrine therapy.	('Loss-of-function', 'NegReg', (0, 16))	('acquired resistance to endocrine therapy', 'MPA', (72, 112))	('NF1', 'Gene', (17, 20))	('NF1', 'Gene', '4763', (17, 20))	('alterations', 'Var', (21, 32))	('intrinsic', 'MPA', (58, 67))
36606	32289273	CRISPR-medicated knockout of NF1 in MCF7 cells induced MEK/ERK phosphorylation and promoted resistance to fulvestrant, which was reversed by the addition of an ERK inhibitor.	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('ERK', 'Gene', (59, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('ERK', 'Gene', '5594', (160, 163))	('NF1', 'Gene', (29, 32))	('MEK', 'Gene', (55, 58))	('MCF7', 'CellLine', 'CVCL:0031', (36, 40))	('resistance to fulvestrant', 'MPA', (92, 117))	('ERK', 'Gene', (160, 163))	('induced', 'Reg', (47, 54))	('knockout', 'Var', (17, 25))	('MEK', 'Gene', '5609', (55, 58))	('NF1', 'Gene', '4763', (29, 32))	('ERK', 'molecular_function', 'GO:0004707', ('59', '62'))	('promoted', 'PosReg', (83, 91))	('ERK', 'Gene', '5594', (59, 62))	('fulvestrant', 'Chemical', 'MESH:D000077267', (106, 117))
36607	32289273	Depletion of NF1 in ER+ breast cancer cells also promoted ER-independent cyclin D1 expression.	('cyclin D1', 'Gene', (73, 82))	('ER+', 'Gene', '2069', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('NF1', 'Gene', (13, 16))	('ER+', 'Gene', (20, 23))	('breast cancer', 'Disease', (24, 37))	('Depletion', 'Var', (0, 9))	('cyclin', 'molecular_function', 'GO:0016538', ('73', '79'))	('NF1', 'Gene', '4763', (13, 16))	('promoted', 'PosReg', (49, 57))	('expression', 'MPA', (83, 93))	('cyclin D1', 'Gene', '595', (73, 82))
36609	32289273	also reported acquired hotspot alterations in KRAS, BRAF, and MAP2K1 (the gene encoding MEK1) in post-treatment biopsies compared to matched pre-treatment tumors.	('alterations', 'Var', (31, 42))	('MEK1', 'Gene', '5604', (88, 92))	('hotspot', 'PosReg', (23, 30))	('MEK1', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('KRAS', 'Gene', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('KRAS', 'Gene', '3845', (46, 50))	('tumors', 'Disease', (155, 161))	('MAP2K1', 'Gene', '5604', (62, 68))	('BRAF', 'Gene', '673', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('MEK1', 'molecular_function', 'GO:0004708', ('88', '92'))	('MAP2K', 'molecular_function', 'GO:0004708', ('62', '67'))	('BRAF', 'Gene', (52, 56))	('MAP2K1', 'Gene', (62, 68))	('pre', 'molecular_function', 'GO:0003904', ('141', '144'))
36610	32289273	Furthermore, circulating tumor DNA (ctDNA) analysis of AI-resistant MBC revealed KRAS, HRAS, or NRAS mutations in >15% of patients, although mutations were often subclonal.	('KRAS', 'Gene', '3845', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('HRAS', 'Gene', '3265', (87, 91))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', (25, 30))	('HRAS', 'Gene', (87, 91))	('MBC', 'Disease', 'MESH:D001943', (68, 71))	('patients', 'Species', '9606', (122, 130))	('KRAS', 'Gene', (81, 85))	('NRAS', 'Gene', (96, 100))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('MBC', 'Disease', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('NRAS', 'Gene', '4893', (96, 100))
36612	32289273	Finally, inhibitors of the MAPK pathway (BRAF, MEK, and ERK inhibitors) may overcome endocrine resistance mediated by BRAF and MAP2K1 alterations.	('MAP2K1', 'Gene', (127, 133))	('MEK', 'Gene', (47, 50))	('BRAF', 'Gene', '673', (118, 122))	('MEK', 'Gene', '5609', (47, 50))	('ERK', 'Gene', '5594', (56, 59))	('BRAF', 'Gene', (118, 122))	('ERK', 'Gene', (56, 59))	('overcome', 'PosReg', (76, 84))	('BRAF', 'Gene', '673', (41, 45))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('alterations', 'Var', (134, 145))	('BRAF', 'Gene', (41, 45))	('MAP2K1', 'Gene', '5604', (127, 133))	('ERK', 'molecular_function', 'GO:0004707', ('56', '59'))	('MAP2K', 'molecular_function', 'GO:0004708', ('127', '132'))	('MAPK pathway', 'Pathway', (27, 39))	('endocrine resistance', 'MPA', (85, 105))
36617	32289273	CTCF is a transcriptional repressor of Myc, suggesting CTCF loss-of-function mutations may lead to Myc upregulation.	('Myc', 'Gene', (39, 42))	('upregulation', 'PosReg', (103, 115))	('CTCF', 'Gene', (0, 4))	('Myc', 'Gene', (99, 102))	('CTCF', 'Gene', (55, 59))	('CTCF', 'Gene', '10664', (0, 4))	('mutations', 'Var', (77, 86))	('CTCF', 'Gene', '10664', (55, 59))	('Myc', 'Gene', '4609', (39, 42))	('loss-of-function', 'NegReg', (60, 76))	('Myc', 'Gene', '4609', (99, 102))
36621	32289273	Thus, tumors with FOXA1 mutations may still rely on ER protein expression and hence remain sensitive to SERDs.	('FOXA1', 'Gene', '3169', (18, 23))	('FOXA1', 'Gene', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('SERDs', 'Chemical', '-', (104, 109))	('rely', 'Reg', (44, 48))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('mutations', 'Var', (24, 33))	('ER protein', 'Protein', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
36622	32289273	However, promoter hotspot mutations in FOXA1 that increased FOXA1 expression were associated with reduced sensitivity to fulvestrant.	('FOXA1', 'Gene', '3169', (39, 44))	('fulvestrant', 'Chemical', 'MESH:D000077267', (121, 132))	('FOXA1', 'Gene', '3169', (60, 65))	('sensitivity to fulvestrant', 'MPA', (106, 132))	('increased', 'PosReg', (50, 59))	('expression', 'MPA', (66, 76))	('mutations', 'Var', (26, 35))	('FOXA1', 'Gene', (39, 44))	('reduced', 'NegReg', (98, 105))	('FOXA1', 'Gene', (60, 65))
36623	32289273	Loss-of-function mutations or deletions in the SWI/SNF nucleosome remodeling components ARID1A and ARID2 were also acquired following treatment with endocrine therapy.	('Loss-of-function', 'NegReg', (0, 16))	('nucleosome', 'cellular_component', 'GO:0000786', ('55', '65'))	('deletions', 'Var', (30, 39))	('ARID2', 'Gene', '196528', (99, 104))	('mutations', 'Var', (17, 26))	('ARID2', 'Gene', (99, 104))	('ARID1A', 'Gene', '8289', (88, 94))	('SWI/SNF', 'Gene', (47, 54))	('ARID1A', 'Gene', (88, 94))
36624	32289273	recently reported that ARID1A knockout promoted resistance to fulvestrant in ER+ breast cancer cells via impaired SWI/SNF recruitment to chromatin at luminal transcription factor loci, resulting in a luminal-to-basal transition and a loss of dependency on ER.	('ARID1A', 'Gene', '8289', (23, 29))	('breast cancer', 'Disease', (81, 94))	('chromatin', 'cellular_component', 'GO:0000785', ('137', '146'))	('knockout', 'Var', (30, 38))	('dependency', 'MPA', (242, 252))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('luminal-to-basal transition', 'MPA', (200, 227))	('SWI/SNF', 'Protein', (114, 121))	('promoted', 'PosReg', (39, 47))	('impaired', 'NegReg', (105, 113))	('ER+', 'Gene', (77, 80))	('resistance to fulvestrant', 'MPA', (48, 73))	('fulvestrant', 'Chemical', 'MESH:D000077267', (62, 73))	('ER+', 'Gene', '2069', (77, 80))	('luminal', 'Chemical', 'MESH:D010634', (200, 207))	('luminal', 'Chemical', 'MESH:D010634', (150, 157))	('transcription factor', 'molecular_function', 'GO:0000981', ('158', '178'))	('recruitment', 'MPA', (122, 133))	('ARID1A', 'Gene', (23, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
36627	32289273	This suggests that the lack of response to ER antagonists induced by ARID1A loss-of-function mutations could be potentially overcome by BET inhibitors.	('mutations', 'Var', (93, 102))	('ARID1A', 'Gene', '8289', (69, 75))	('loss-of-function', 'NegReg', (76, 92))	('BET', 'Gene', '92737', (136, 139))	('ARID1A', 'Gene', (69, 75))	('BET', 'Gene', (136, 139))
36628	32289273	High mutational load is associated with poor prognosis in ER+ breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ER+', 'Gene', (58, 61))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('High mutational load', 'Var', (0, 20))	('breast cancer', 'Disease', (62, 75))	('ER+', 'Gene', '2069', (58, 61))
36629	32289273	found that loss-of-function mutations and/or low expression of the mismatch repair (MMR) MutL genes (MLH1/3, PMS1/2) were associated with endocrine resistance by abolishing CHK2-mediated inhibition of CDK4.	('CDK4', 'Gene', '1019', (201, 205))	('CDK4', 'Gene', (201, 205))	('CHK2', 'Gene', (173, 177))	('CDK', 'molecular_function', 'GO:0004693', ('201', '204'))	('mismatch repair', 'biological_process', 'GO:0006298', ('67', '82'))	('PMS1/2', 'Gene', '5378;5395', (109, 115))	('CHK2', 'Gene', '11200', (173, 177))	('endocrine resistance', 'MPA', (138, 158))	('MMR', 'Gene', (84, 87))	('expression', 'MPA', (49, 59))	('abolishing', 'NegReg', (162, 172))	('low', 'NegReg', (45, 48))	('PMS1/2', 'Gene', (109, 115))	('loss-of-function', 'NegReg', (11, 27))	('MLH1/3', 'Gene', (101, 107))	('MMR', 'biological_process', 'GO:0006298', ('84', '87'))	('mutations', 'Var', (28, 37))	('MLH1/3', 'Gene', '4292;27030', (101, 107))
36632	32289273	In concert with genomic evolution, epigenetic mechanisms shape tumor architecture by expanding the repertoire of tumor cell populations harboring distinct molecular profiles.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (113, 118))	('expanding', 'PosReg', (85, 94))	('epigenetic mechanisms', 'Var', (35, 56))	('shape', 'Reg', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
36633	32289273	Structural variations and missense mutations in genes encoding enzymes that govern epigenetic regulation have been frequently implicated in breast cancer pathogenesis and resistance to endocrine therapies.	('missense mutations', 'Var', (26, 44))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('implicated', 'Reg', (126, 136))	('Structural variations', 'Var', (0, 21))	('pathogenesis', 'biological_process', 'GO:0009405', ('154', '166'))
36634	32289273	An enrichment of somatic mutations in chromatin remodelers such as histone methyltransferases (KMT2B, KMT2D, KMT2E) and histone demethylases (KDM4A, KDM5B, KDM5C, KDM6A) have been noted particularly in the luminal subtype of breast cancer.	('KDM5B', 'Gene', (149, 154))	('chromatin', 'cellular_component', 'GO:0000785', ('38', '47'))	('KMT2E', 'Gene', (109, 114))	('KDM5C', 'Gene', '8242', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('KMT2B', 'Gene', '9757', (95, 100))	('mutations', 'Var', (25, 34))	('KMT2D', 'Gene', (102, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('KDM5B', 'Gene', '10765', (149, 154))	('KDM6A', 'Gene', '7403', (163, 168))	('KDM5C', 'Gene', (156, 161))	('KMT2E', 'Gene', '55904', (109, 114))	('KMT2B', 'Gene', (95, 100))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Disease', (225, 238))	('luminal', 'Chemical', 'MESH:D010634', (206, 213))	('KDM6A', 'Gene', (163, 168))	('KDM4A', 'Gene', '9682', (142, 147))	('KMT2D', 'Gene', '8085', (102, 107))	('KDM4A', 'Gene', (142, 147))
36637	32289273	Notably, patients with ER+ tumors with a high KDM5B activity score had a shorter disease-specific survival in response to endocrine treatment, compared to those with low KDM5B activity.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ER+', 'Gene', (23, 26))	('patients', 'Species', '9606', (9, 17))	('KDM5B', 'Gene', (170, 175))	('disease-specific survival', 'CPA', (81, 106))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('high', 'Var', (41, 45))	('response to endocrine treatment', 'MPA', (110, 141))	('shorter', 'NegReg', (73, 80))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('ER+', 'Gene', '2069', (23, 26))	('KDM5B', 'Gene', '10765', (46, 51))	('KDM5B', 'Gene', '10765', (170, 175))	('KDM5B', 'Gene', (46, 51))
36641	32289273	Deletion or loss-of-function mutations in H3K4 methyltransferase KMT2C occur frequently in ER+ breast cancers and such alterations have also been associated with diminished response to AIs.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancers', 'Disease', 'MESH:D001943', (95, 109))	('breast cancers', 'Disease', (95, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('breast cancers', 'Phenotype', 'HP:0003002', (95, 109))	('response to AIs', 'MPA', (173, 188))	('mutations', 'Var', (29, 38))	('ER+', 'Gene', '2069', (91, 94))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('H3K4 methyltransferase', 'Enzyme', (42, 64))	('loss-of-function', 'NegReg', (12, 28))	('diminished', 'NegReg', (162, 172))	('KMT2C', 'Gene', '58508', (65, 70))	('KMT2C', 'Gene', (65, 70))	('ER+', 'Gene', (91, 94))	('Deletion', 'Var', (0, 8))
36643	32289273	Direct antagonists of ER may therefore represent an optimal therapeutic option for the treatment of ER+ breast cancers with loss-of-function KMT2C alterations.	('KMT2C', 'Gene', '58508', (141, 146))	('KMT2C', 'Gene', (141, 146))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ER+', 'Gene', '2069', (100, 103))	('ER+', 'Gene', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancers', 'Phenotype', 'HP:0003002', (104, 118))	('loss-of-function', 'NegReg', (124, 140))	('breast cancers', 'Disease', 'MESH:D001943', (104, 118))	('breast cancers', 'Disease', (104, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('alterations', 'Var', (147, 158))
36652	32289273	Amplification/overexpression of the FOXA1 gene in ER+ tumors is associated with inferior relapse-free survival in response to tamoxifen.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('FOXA1', 'Gene', '3169', (36, 41))	('Amplification/overexpression', 'Var', (0, 28))	('tamoxifen', 'Chemical', 'MESH:D013629', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Amplification/overexpression', 'PosReg', (0, 28))	('ER+', 'Gene', '2069', (50, 53))	('relapse-free survival', 'CPA', (89, 110))	('inferior', 'NegReg', (80, 88))	('FOXA1', 'Gene', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))	('ER+', 'Gene', (50, 53))
36657	32289273	Johmura and colleagues demonstrated that in ER+ breast cancers, loss of F-box protein 22 (FBOX22) expression stabilizes KDM4B, facilitating SRC recruitment and ER transcriptional activity, even in the presence of SERMs.	('KDM4B', 'Gene', (120, 125))	('F-box protein 22', 'Gene', (72, 88))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('FBOX22', 'Gene', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('SRC', 'Gene', '10011', (140, 143))	('FBOX22', 'Gene', '26263', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('ER transcriptional activity', 'MPA', (160, 187))	('breast cancers', 'Disease', 'MESH:D001943', (48, 62))	('KDM4B', 'Gene', '23030', (120, 125))	('breast cancers', 'Disease', (48, 62))	('stabilizes', 'PosReg', (109, 119))	('facilitating', 'PosReg', (127, 139))	('ER+', 'Gene', (44, 47))	('F-box protein 22', 'Gene', '26263', (72, 88))	('breast cancers', 'Phenotype', 'HP:0003002', (48, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('ER+', 'Gene', '2069', (44, 47))	('SRC', 'Gene', (140, 143))	('loss', 'Var', (64, 68))
36662	32289273	identified C-terminal Src kinase (CSK) as one of the top tumor suppressors whose deletion restored cell growth in the absence of estrogen.	('Src', 'Gene', '10011', (22, 25))	('CSK', 'Gene', (34, 37))	('cell growth', 'MPA', (99, 110))	('deletion', 'Var', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('restored', 'PosReg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Src', 'Gene', (22, 25))	('tumor', 'Disease', (57, 62))	('cell growth', 'biological_process', 'GO:0016049', ('99', '110'))
36667	32289273	ESR1 fusions (described above) upregulate the expression of EMT-related genes to support metastatic progression.	('metastatic progression', 'CPA', (89, 111))	('ESR1', 'Gene', (0, 4))	('fusions', 'Var', (5, 12))	('support', 'PosReg', (81, 88))	('EMT-related genes', 'Gene', (60, 77))	('ESR1', 'Gene', '2099', (0, 4))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('expression', 'MPA', (46, 56))	('upregulate', 'PosReg', (31, 41))
36673	32289273	Several of the oncogenic alterations outlined above, including ESR1 mutations, Notch signaling, AIB1 overexpression, and tumor microenvironmental factors have been shown to promote breast cancer stem-like cell expansion.	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('cell expansion', 'biological_process', 'GO:0016049', ('205', '219'))	('Notch', 'Gene', '4854;4855', (79, 84))	('overexpression', 'PosReg', (101, 115))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('breast cancer', 'Disease', (181, 194))	('tumor', 'Disease', (121, 126))	('promote', 'PosReg', (173, 180))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('alterations', 'Var', (25, 36))	('AIB1', 'Gene', '8202', (96, 100))	('Notch', 'Gene', (79, 84))	('ESR1', 'Gene', '2099', (63, 67))	('AIB1', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ESR1', 'Gene', (63, 67))	('mutations', 'Var', (68, 77))
36677	32289273	Pharmacological or genomic disruption of Notch 4 activity reversed tamoxifen and fulvestrant resistance and CSC activity, suggesting a causal relationship between a stem cell-like phenotype and endocrine resistance.	('tamoxifen', 'Chemical', 'MESH:D013629', (67, 76))	('CSC activity', 'MPA', (108, 120))	('tamoxifen', 'MPA', (67, 76))	('fulvestrant resistance', 'MPA', (81, 103))	('disruption', 'Var', (27, 37))	('reversed', 'NegReg', (58, 66))	('Notch 4', 'Gene', '4855', (41, 48))	('fulvestrant', 'Chemical', 'MESH:D000077267', (81, 92))	('Notch 4', 'Gene', (41, 48))
36681	32289273	For example, the aggressive nature of ESR1 LBD mutations was attributed to estrogen-independent metabolic rewiring.	('ESR1', 'Gene', '2099', (38, 42))	('mutations', 'Var', (47, 56))	('ESR1', 'Gene', (38, 42))
36690	32289273	Tumors with high miR-155 levels are therefore likely to adapt rapidly and progress on aromatase inhibitors, but could be responsive to SERDs.	('aromatase', 'Gene', (86, 95))	('high', 'Var', (12, 16))	('aromatase', 'Gene', '1588', (86, 95))	('miR-155', 'Gene', (17, 24))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('progress', 'PosReg', (74, 82))	('SERDs', 'Chemical', '-', (135, 140))	('miR-155', 'Gene', '406947', (17, 24))	('adapt', 'MPA', (56, 61))
36698	32289273	In this study, mutations in ERBB2 and AKT1 were associated with increased risk of early relapse.	('AKT1', 'Gene', '207', (38, 42))	('associated', 'Reg', (48, 58))	('AKT1', 'Gene', (38, 42))	('mutations', 'Var', (15, 24))	('ERBB2', 'Gene', '2064', (28, 33))	('ERBB2', 'Gene', (28, 33))	('early', 'Disease', (82, 87))
36699	32289273	reported that loss-of-function NF1 alterations were enriched in endocrine-resistant metastatic ILC.	('alterations', 'Var', (35, 46))	('endocrine-resistant metastatic ILC', 'Disease', (64, 98))	('loss-of-function', 'NegReg', (14, 30))	('NF1', 'Gene', (31, 34))	('NF1', 'Gene', '4763', (31, 34))
36731	32289273	Of note, many of the mechanisms of resistance listed above have also been implicated in endocrine-resistant endometrial cancers, including activation of the PI3K and cell cycle pathways, epigenetic deregulation, and the immune microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('epigenetic deregulation', 'Var', (187, 210))	('endocrine-resistant endometrial cancers', 'Disease', (88, 127))	('activation', 'PosReg', (139, 149))	('cell cycle pathways', 'Pathway', (166, 185))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('endocrine-resistant endometrial cancers', 'Disease', 'MESH:D016889', (88, 127))	('endometrial cancer', 'Phenotype', 'HP:0012114', (108, 126))	('cell cycle', 'biological_process', 'GO:0007049', ('166', '176'))	('PI3K', 'molecular_function', 'GO:0016303', ('157', '161'))
36733	32289273	For example, genomic aberrations in AR and deregulation of AR cofactors and AR-mediated transcription represent major mechanisms of resistance.	('AR', 'Gene', '367', (76, 78))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('AR', 'Gene', '367', (36, 38))	('deregulation', 'MPA', (43, 55))	('genomic aberrations', 'Var', (13, 32))	('AR', 'Gene', '367', (59, 61))
36734	32289273	Lineage plasticity can also promote antiandrogen resistance and AR-independent growth in a similar fashion to the luminal-to-basal transition mediated by ARID1A inactivation in endocrine-resistant breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('ARID1A', 'Gene', '8289', (154, 160))	('inactivation', 'Var', (161, 173))	('ARID1A', 'Gene', (154, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('endocrine-resistant breast cancers', 'Disease', (177, 211))	('luminal', 'Chemical', 'MESH:D010634', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('AR', 'Gene', '367', (154, 156))	('promote', 'PosReg', (28, 35))	('endocrine-resistant breast cancers', 'Disease', 'MESH:D001943', (177, 211))	('AR', 'Gene', '367', (64, 66))	('breast cancers', 'Phenotype', 'HP:0003002', (197, 211))	('antiandrogen resistance', 'CPA', (36, 59))
36736	32289273	These include 1) secondary mutations in the drug target that block drug-mediated target inhibition (ie, ESR1, EGFR, ALK, NTRK, ERBB2, etc), 2) target-independent activation of downstream or bypass signaling pathways (ie, RTK, PI3K, and MAPK pathway deregulation), and 3) microenvironmental components that affect drug sensitivity.	('mutations', 'Var', (27, 36))	('EGFR', 'Gene', '1956', (110, 114))	('downstream', 'Pathway', (176, 186))	('PI3K', 'molecular_function', 'GO:0016303', ('226', '230'))	('MAPK', 'molecular_function', 'GO:0004707', ('236', '240'))	('block', 'NegReg', (61, 66))	('ALK', 'Gene', '238', (116, 119))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('ERBB2', 'Gene', (127, 132))	('ALK', 'Gene', (116, 119))	('ESR1', 'Gene', '2099', (104, 108))	('bypass signaling pathways', 'Pathway', (190, 215))	('EGFR', 'Gene', (110, 114))	('ESR1', 'Gene', (104, 108))	('ERBB2', 'Gene', '2064', (127, 132))	('PI3K', 'Pathway', (226, 230))	('drug sensitivity', 'Phenotype', 'HP:0020174', (313, 329))	('drug-mediated target inhibition', 'MPA', (67, 98))	('MAPK pathway', 'Pathway', (236, 248))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('activation', 'PosReg', (162, 172))
36744	32289273	Some of the somatic alterations described above have also been shown to promote resistance to CDK4/6i, including FGFR1 amplification, PTEN alterations, and ERBB2 mutations.	('resistance', 'MPA', (80, 90))	('alterations', 'Var', (20, 31))	('ERBB2', 'Gene', '2064', (156, 161))	('mutations', 'Var', (162, 171))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('ERBB2', 'Gene', (156, 161))	('CDK', 'molecular_function', 'GO:0004693', ('94', '97'))	('FGFR1', 'Gene', (113, 118))	('alterations', 'Var', (139, 150))	('promote', 'PosReg', (72, 79))	('FGFR1', 'Gene', '2260', (113, 118))	('amplification', 'Var', (119, 132))	('CDK4/6i', 'Gene', '1019', (94, 101))	('PTEN', 'Gene', (134, 138))	('CDK4/6i', 'Gene', (94, 101))	('PTEN', 'Gene', '5728', (134, 138))
36745	32289273	In contrast, RB1 and FAT1 alterations appear to be exclusively associated with resistance to CDK4/6 inhibitors and less to antiestrogens alone.	('CDK', 'molecular_function', 'GO:0004693', ('93', '96'))	('CDK4/6', 'Gene', (93, 99))	('resistance to', 'MPA', (79, 92))	('RB1', 'Gene', '5925', (13, 16))	('associated', 'Reg', (63, 73))	('alterations', 'Var', (26, 37))	('FAT1', 'Gene', '2195', (21, 25))	('CDK4/6', 'Gene', '1019;1021', (93, 99))	('RB1', 'Gene', (13, 16))	('FAT1', 'Gene', (21, 25))
36748	32289273	Intra-tumor heterogeneity of resistance alterations represents a major challenge in treating endocrine-resistant MBC and other drug-resistant cancers.	('MBC', 'Disease', 'MESH:D001943', (113, 116))	('drug-resistant cancers', 'Disease', 'MESH:D009369', (127, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('alterations', 'Var', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('MBC', 'Disease', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('drug-resistant cancers', 'Disease', (127, 149))	('tumor', 'Disease', (6, 11))
36755	31984517	African-American race and heterogeneously or extremely dense mammographic density were associated with multifocal cancers on MRI.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('multifocal cancers', 'Disease', 'MESH:D009369', (103, 121))	('multifocal cancers', 'Disease', (103, 121))	('heterogeneously', 'Var', (26, 41))	('multifocal cancer', 'Phenotype', 'HP:0006625', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('associated with', 'Reg', (87, 102))
36758	31984517	African-American race, heterogeneously or extremely dense mammographic density, invasive lobular carcinoma, and PR-positivity were associated with additional biopsy-proven cancers based on MRI.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('invasive lobular carcinoma', 'Disease', (80, 106))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (80, 106))	('associated', 'Reg', (131, 141))	('PR', 'Gene', '5241', (112, 114))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (89, 106))	('heterogeneously', 'Var', (23, 38))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))
36784	31984517	For descriptive purposes in this text, abnormalities on MRI that were not yet biopsied are subsequently referred to as "lesions," whereas those which were biopsy-proven to be malignant are referred to as "cancers."	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancers', 'Disease', (205, 212))	('abnormalities', 'Var', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
36830	31984517	Our results also demonstrated that heterogeneously or extremely dense breasts were associated with biopsy-proven multifocal breast cancer.	('heterogeneously', 'Var', (35, 50))	('multifocal breast cancer', 'Disease', (113, 137))	('multifocal breast cancer', 'Disease', 'MESH:D001943', (113, 137))	('multifocal breast cancer', 'Phenotype', 'HP:0006625', (113, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('associated', 'Reg', (83, 93))
36836	31984517	This is consistent with a study looking at MRI size and histological and molecular subtype, which found that correlation between primary tumor size on MRI and size as determined on surgical pathology was better for luminal A and triple-negative molecular subtypes than for luminal B and HER 2 molecular subtypes.	('HER 2', 'Gene', (287, 292))	('tumor', 'Disease', (137, 142))	('luminal', 'Var', (215, 222))	('HER 2', 'Gene', '2064', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('luminal', 'Chemical', 'MESH:D010634', (215, 222))	('triple-negative', 'Var', (229, 244))	('luminal', 'Chemical', 'MESH:D010634', (273, 280))
36847	30555634	By comparing normal breast tissue to carcinoma in situ and invasive ductal carcinoma subtypes, we here show that the phosphorylation status of PIP5K1C at serine residue 448 (S448) can be predictive for breast cancer progression to an aggressive phenotype, while PIP5K1C expression levels are not indicative for this event.	('PIP5K1C', 'Gene', (262, 269))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('invasive ductal carcinoma subtypes', 'Disease', 'MESH:D018270', (59, 93))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (37, 54))	('carcinoma in situ', 'Disease', 'MESH:D002278', (37, 54))	('serine', 'Chemical', 'MESH:D012694', (154, 160))	('phosphorylation', 'MPA', (117, 132))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (68, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('PIP5K1C', 'Gene', '23396', (143, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('PIP5K', 'molecular_function', 'GO:0016308', ('143', '148'))	('PIP5K1C', 'Gene', '23396', (262, 269))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Disease', (202, 215))	('carcinoma in situ', 'Disease', (37, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('invasive ductal carcinoma subtypes', 'Disease', (59, 93))	('S448', 'Var', (174, 178))	('PIP5K1C', 'Gene', (143, 150))	('PIP5K', 'molecular_function', 'GO:0016308', ('262', '267'))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
36848	30555634	PIP5K1C phosphorylation at S448 is downregulated in invasive ductal carcinoma, and similarly, the expression levels of PKD1, the kinase that phosphorylates PIP5K1C at this site, are decreased.	('PKD1', 'Gene', (119, 123))	('invasive ductal carcinoma', 'Disease', (52, 77))	('PIP5K1C', 'Gene', '23396', (156, 163))	('decreased', 'NegReg', (182, 191))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (61, 77))	('PIP5K', 'molecular_function', 'GO:0016308', ('156', '161'))	('PKD1', 'Gene', '5587', (119, 123))	('phosphorylation', 'biological_process', 'GO:0016310', ('8', '23'))	('PIP5K1C', 'Gene', (156, 163))	('PIP5K1C', 'Gene', '23396', (0, 7))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (52, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('phosphorylation', 'MPA', (8, 23))	('downregulated', 'NegReg', (35, 48))	('PIP5K', 'molecular_function', 'GO:0016308', ('0', '5'))	('expression levels', 'MPA', (98, 115))	('PIP5K1C', 'Gene', (0, 7))	('at S448', 'Var', (24, 31))
36854	30555634	In glioblastoma multiforme, copy number amplifications in chromosome 19 have been described leading to increased expression of PIP5K1C, AKT2 and PIK3R2.	('expression', 'MPA', (113, 123))	('increased', 'PosReg', (103, 112))	('AKT2', 'Gene', '208', (136, 140))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (3, 26))	('PIK3R2', 'Gene', (145, 151))	('PIK3R2', 'Gene', '5296', (145, 151))	('PIP5K1C', 'Gene', '23396', (127, 134))	('glioblastoma multiforme', 'Disease', (3, 26))	('AKT2', 'Gene', (136, 140))	('PIP5K', 'molecular_function', 'GO:0016308', ('127', '132'))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('copy number amplifications', 'Var', (28, 54))	('PIP5K1C', 'Gene', (127, 134))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
36858	30555634	Depletion of PIP5K1C leads to cytoskeletal changes and severe attachment defects in cells.	('attachment defects', 'Disease', (62, 80))	('PIP5K', 'molecular_function', 'GO:0016308', ('13', '18'))	('cytoskeletal changes', 'CPA', (30, 50))	('Depletion', 'Var', (0, 9))	('PIP5K1C', 'Gene', '23396', (13, 20))	('PIP5K1C', 'Gene', (13, 20))	('attachment defects', 'Disease', 'MESH:D019962', (62, 80))
36860	30555634	PIP5K1C localization to FA is negatively-regulated by p35/Cdk5-mediated phosphorylation at S650; and PIP5K1C degradation is regulated by phosphorylation through p70S6K1 at threonine 553 and serine 555, while its lipid kinase activity is inhibited after phosphorylation through protein kinase D (PKD) at serine 448.	('PIP5K1C', 'Gene', '23396', (101, 108))	('regulated', 'Reg', (124, 133))	('protein kinase D', 'Gene', (277, 293))	('lipid kinase activity', 'molecular_function', 'GO:0001727', ('212', '233'))	('protein', 'cellular_component', 'GO:0003675', ('277', '284'))	('localization', 'biological_process', 'GO:0051179', ('8', '20'))	('degradation', 'MPA', (109, 120))	('p70S6K1', 'Var', (161, 168))	('p35', 'cellular_component', 'GO:0070745', ('54', '57'))	('PIP5K1C', 'Gene', (101, 108))	('phosphorylation', 'biological_process', 'GO:0016310', ('253', '268'))	('PKD', 'Gene', (295, 298))	('threonine', 'Chemical', 'MESH:D013912', (172, 181))	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('p35', 'cellular_component', 'GO:0043514', ('54', '57'))	('degradation', 'biological_process', 'GO:0009056', ('109', '120'))	('PIP5K1C', 'Gene', '23396', (0, 7))	('serine', 'Chemical', 'MESH:D012694', (303, 309))	('serine 555', 'Var', (190, 200))	('PIP5K', 'molecular_function', 'GO:0016308', ('0', '5'))	('serine', 'Chemical', 'MESH:D012694', (190, 196))	('negatively-regulated', 'NegReg', (30, 50))	('PIP5K', 'molecular_function', 'GO:0016308', ('101', '106'))	('lipid', 'Chemical', 'MESH:D008055', (212, 217))	('PKD', 'Gene', '5587', (295, 298))	('protein kinase D', 'Gene', '5587', (277, 293))	('p35', 'Gene', '3592', (54, 57))	('localization', 'MPA', (8, 20))	('Cdk', 'molecular_function', 'GO:0004693', ('58', '61'))	('p35', 'Gene', (54, 57))	('Cdk5', 'Gene', '1020', (58, 62))	('Cdk5', 'Gene', (58, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('137', '152'))	('PIP5K1C', 'Gene', (0, 7))
36869	30555634	Alterations in PIP5K1C expression or activity have been linked to increased cell migration and invasion.	('invasion', 'CPA', (95, 103))	('increased', 'PosReg', (66, 75))	('PIP5K', 'molecular_function', 'GO:0016308', ('15', '20'))	('PIP5K1C', 'Gene', '23396', (15, 22))	('Alterations', 'Var', (0, 11))	('cell migration', 'CPA', (76, 90))	('PIP5K1C', 'Gene', (15, 22))	('activity', 'MPA', (37, 45))	('cell migration', 'biological_process', 'GO:0016477', ('76', '90'))	('expression', 'MPA', (23, 33))
36870	30555634	We used cBioPortal (http://www.cbioportal.org/public-portal/index.do) to analyze three different available datasets, including 2509 breast cancer (BC) samples, 1105 invasive breast carcinoma (IBC, BIC) samples, or 216 metastatic breast cancers (MBC) for gene alterations such as amplification, deletion or mutational events in PIP5K1A, PIP5K1B and PIP5K1C genes.	('breast cancers', 'Disease', (229, 243))	('deletion', 'Var', (294, 302))	('PIP5K1C', 'Gene', (348, 355))	('invasive breast carcinoma', 'Disease', (165, 190))	('BC', 'Phenotype', 'HP:0003002', (147, 149))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('breast cancers', 'Phenotype', 'HP:0003002', (229, 243))	('BC', 'Phenotype', 'HP:0003002', (193, 195))	('PIP5K', 'molecular_function', 'GO:0016308', ('348', '353'))	('BIC', 'Chemical', '-', (197, 200))	('PIP5K1A', 'Gene', '8394', (327, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('BC', 'Phenotype', 'HP:0003002', (246, 248))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('MBC', 'Disease', (245, 248))	('breast carcinoma', 'Phenotype', 'HP:0003002', (174, 190))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('PIP5K', 'molecular_function', 'GO:0016308', ('336', '341'))	('breast cancer', 'Disease', (132, 145))	('PIP5K1C', 'Gene', '23396', (348, 355))	('amplification', 'Var', (279, 292))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (165, 190))	('PIP5K1B', 'Gene', (336, 343))	('mutational events', 'Var', (306, 323))	('MBC', 'Disease', 'MESH:D001943', (245, 248))	('PIP5K1A', 'Gene', (327, 334))	('PIP5K1B', 'Gene', '8395', (336, 343))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PIP5K', 'molecular_function', 'GO:0016308', ('327', '332'))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))	('breast cancers', 'Disease', 'MESH:D001943', (229, 243))
36895	30555634	As a negative control we also determined the phosphorylation status at S650 (Supplementary Figure 1B), which in contrast to S448 is negative-regulatory and is not within a PKD phosphorylation motif.	('PKD', 'Gene', (172, 175))	('S650', 'Var', (71, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('176', '191'))	('PKD', 'Gene', '5587', (172, 175))	('phosphorylation', 'MPA', (45, 60))	('negative-regulatory', 'NegReg', (132, 151))	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))
36897	30555634	To test this we determined the phosphorylation status of PIP5K1C at S448 and S650 (negative control) after expression of constitutively-active versions of PKD1, PKD2 and PKD3 in MCF-7 cells.	('PKD2', 'Gene', (161, 165))	('S650', 'Var', (77, 81))	('MCF-7', 'CellLine', 'CVCL:0031', (178, 183))	('PIP5K', 'molecular_function', 'GO:0016308', ('57', '62'))	('S448', 'Var', (68, 72))	('PKD1', 'Gene', '5587', (155, 159))	('PIP5K1C', 'Gene', '23396', (57, 64))	('PKD1', 'Gene', (155, 159))	('PKD3', 'Gene', '5312', (170, 174))	('phosphorylation', 'MPA', (31, 46))	('PIP5K1C', 'Gene', (57, 64))	('PKD2', 'Gene', '5311', (161, 165))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))	('PKD3', 'Gene', (170, 174))
36898	30555634	Our data indicate that PKD1 in breast cancer cells indeed is the main regulator of PIP5K1C phosphorylation at S448 (Figure 3C), but not at S650 (control, Supplementary Figure 1C).	('PKD1', 'Gene', (23, 27))	('phosphorylation', 'MPA', (91, 106))	('PIP5K1C', 'Gene', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('at S448', 'Var', (107, 114))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('breast cancer', 'Disease', (31, 44))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('PIP5K', 'molecular_function', 'GO:0016308', ('83', '88'))	('PKD1', 'Gene', '5587', (23, 27))	('PIP5K1C', 'Gene', '23396', (83, 90))
36899	30555634	PKD1 expression previously has been shown to be downregulated in invasive breast carcinoma through epigenetic silencing of its PRKD1 gene promoter.	('PKD1', 'Gene', '5587', (0, 4))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (65, 90))	('PKD1', 'Gene', (0, 4))	('downregulated', 'NegReg', (48, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('breast carcinoma', 'Phenotype', 'HP:0003002', (74, 90))	('invasive breast carcinoma', 'Disease', (65, 90))	('epigenetic silencing', 'Var', (99, 119))	('PRKD1', 'Gene', '5587', (127, 132))	('PRKD1', 'Gene', (127, 132))
36903	30555634	MDA-MB-231 cells are highly invasive and do not express PKD1 due to epigenetic downregulation of its promoter.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (0, 10))	('PKD1', 'Gene', '5587', (56, 60))	('promoter', 'MPA', (101, 109))	('PKD1', 'Gene', (56, 60))	('epigenetic', 'Var', (68, 78))	('downregulation', 'NegReg', (79, 93))
36908	30555634	On the other hand, introduction of a kinase-dead version of PKD1 (PKD1.KD) did not alter the PIP5K1C phosphorylation status at S448 in tumors.	('PKD1.', 'Gene', (66, 71))	('PIP5K1C', 'Gene', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('PIP5K', 'molecular_function', 'GO:0016308', ('93', '98'))	('PKD1', 'Gene', '5587', (66, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('101', '116'))	('PKD1.', 'Gene', '5587;5310', (66, 71))	('PKD1', 'Gene', (66, 70))	('S448', 'Var', (127, 131))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('PKD1', 'Gene', '5587', (60, 64))	('PIP5K1C', 'Gene', '23396', (93, 100))	('PKD1', 'Gene', (60, 64))	('phosphorylation', 'MPA', (101, 116))
36913	30555634	Moreover, presence of PKD1 correlated with PIP5K1C phosphorylation at S448, whereas the overall levels of PIP5K1C expression were comparable to normal controls (Figure 6A).	('S448', 'Var', (70, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('PIP5K', 'molecular_function', 'GO:0016308', ('106', '111'))	('PIP5K1C', 'Gene', '23396', (43, 50))	('phosphorylation', 'MPA', (51, 66))	('PIP5K1C', 'Gene', (43, 50))	('PIP5K1C', 'Gene', '23396', (106, 113))	('PIP5K1C', 'Gene', (106, 113))	('PIP5K', 'molecular_function', 'GO:0016308', ('43', '48'))	('PKD1', 'Gene', '5587', (22, 26))	('PKD1', 'Gene', (22, 26))
36915	30555634	By normal standards, this association between the two variables (PKD1 and pS448 expression) is considered statistically significant.	('PKD1', 'Gene', '5587', (65, 69))	('pS448 expression', 'Var', (74, 90))	('PKD1', 'Gene', (65, 69))
36917	30555634	Taken together, our data suggests that the phosphorylation status of PIP5K1C at serine 448 can be predictive for invasive ductal carcinoma of the breast.	('PIP5K1C', 'Gene', (69, 76))	('phosphorylation', 'MPA', (43, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('invasive ductal carcinoma of the breast', 'Disease', 'MESH:D018270', (113, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('PIP5K', 'molecular_function', 'GO:0016308', ('69', '74'))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (129, 152))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (122, 138))	('serine 448', 'Var', (80, 90))	('serine', 'Chemical', 'MESH:D012694', (80, 86))	('invasive ductal carcinoma of the breast', 'Disease', (113, 152))	('PIP5K1C', 'Gene', '23396', (69, 76))
36918	30555634	Alterations in activity of phosphoinositide kinases and associated changes in phosphoinositide signaling are important events driving breast cancer formation and progression.	('phosphoinositide', 'Chemical', 'MESH:D010716', (27, 43))	('changes', 'Reg', (67, 74))	('breast cancer', 'Disease', (134, 147))	('phosphoinositide signaling', 'MPA', (78, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Alterations', 'Var', (0, 11))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('activity', 'MPA', (15, 23))	('phosphoinositide kinases', 'Enzyme', (27, 51))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('phosphoinositide', 'Chemical', 'MESH:D010716', (78, 94))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
36920	30555634	The majority of PI4,5P2 in cells is produced by PIP5K1 lipid kinases, which phosphorylate PI4P as a substrate.	('lipid kinases', 'Enzyme', (55, 68))	('PIP5K1', 'Var', (48, 54))	('lipid', 'Chemical', 'MESH:D008055', (55, 60))	('PI4,5P2', 'Gene', '5267', (16, 23))	('PIP5K', 'molecular_function', 'GO:0016308', ('48', '53'))
36923	30555634	In addition to this, oncogenic, activating mutations in the catalytic subunit of PI3K, the kinase that demands PI4,5P2 as a substrate, have been detected in numerous breast cancer subtypes 25-40%.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('PI3K', 'Gene', (81, 85))	('numerous breast cancer', 'Disease', (157, 179))	('detected', 'Reg', (145, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('mutations', 'Var', (43, 52))	('PI4,5P2', 'Gene', '5267', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('numerous breast cancer', 'Disease', 'MESH:D001943', (157, 179))	('activating', 'PosReg', (32, 42))
36926	30555634	This is in congruence with published findings showing that a large percentage of breast cancers have amplification of chromosome 1q genes, including PIP5K1A.	('PIP5K1A', 'Gene', (149, 156))	('breast cancers', 'Disease', 'MESH:D001943', (81, 95))	('amplification', 'Var', (101, 114))	('breast cancers', 'Disease', (81, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('PIP5K', 'molecular_function', 'GO:0016308', ('149', '154'))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('PIP5K1A', 'Gene', '8394', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (81, 95))	('chromosome 1q genes', 'Gene', (118, 137))
36931	30555634	Using a previously characterized phospho-specific antibody directed against this site, we here show that phosphorylation of PIP5K1C at S448 can be indicative for invasive breast cancer (Figure 2).	('antibody', 'cellular_component', 'GO:0019815', ('50', '58'))	('phosphorylation', 'MPA', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('antibody', 'cellular_component', 'GO:0019814', ('50', '58'))	('PIP5K1C', 'Gene', (124, 131))	('antibody', 'molecular_function', 'GO:0003823', ('50', '58'))	('invasive breast cancer', 'Disease', 'MESH:D001943', (162, 184))	('at S448', 'Var', (132, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('invasive breast cancer', 'Disease', (162, 184))	('antibody', 'cellular_component', 'GO:0042571', ('50', '58'))	('PIP5K', 'molecular_function', 'GO:0016308', ('124', '129'))	('PIP5K1C', 'Gene', '23396', (124, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
36937	30555634	Consequently, the transition from a less aggressive to a metastatic phenotype is characterized by PRKD1 (PKD1) gene promoter methylation and downregulation, and an upregulation PKD2 and PKD3.	('upregulation', 'PosReg', (164, 176))	('methylation', 'biological_process', 'GO:0032259', ('125', '136'))	('PKD3', 'Gene', (186, 190))	('PRKD1', 'Gene', '5587', (98, 103))	('PKD3', 'Gene', '5312', (186, 190))	('PKD2', 'Gene', '5311', (177, 181))	('metastatic', 'CPA', (57, 67))	('downregulation', 'NegReg', (141, 155))	('PRKD1', 'Gene', (98, 103))	('less aggressive', 'CPA', (36, 51))	('PKD1', 'Gene', '5587', (105, 109))	('PKD2', 'Gene', (177, 181))	('PKD1', 'Gene', (105, 109))	('methylation', 'Var', (125, 136))
36965	30555634	The animal experiment in Figure 5 was performed under protocols (A15207 and A14810) approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC), and data on tumor growth has been published elsewhere.	('Mayo', 'Species', '162683', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('A14810', 'Var', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('A15207', 'Var', (65, 71))
36980	26643573	Among 19 LCIS and ILC synchronous pairs, 14 (74%) had at least one identical mutation in common, including identical PIK3CA and CDH1 mutations.	('CDH1', 'Gene', (128, 132))	('CDH1', 'Gene', '999', (128, 132))	('PIK3CA', 'Gene', (117, 123))	('ILC', 'Gene', '10850', (18, 21))	('ILC', 'Gene', (18, 21))	('PIK3CA', 'Gene', '5290', (117, 123))	('mutations', 'Var', (133, 142))
36983	26643573	The presence of identical mutations between LCIS-LCIS and LCIS-ILC pairs demonstrates that LCIS is a clonal neoplastic lesion, and provides additional evidence that at least some LCIS are non-obligate precursors of ILC.	('LCIS', 'Disease', (91, 95))	('neoplastic lesion', 'Disease', 'MESH:D051437', (108, 125))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (108, 125))	('ILC', 'Gene', '10850', (63, 66))	('mutations', 'Var', (26, 35))	('neoplastic lesion', 'Disease', (108, 125))	('ILC', 'Gene', (63, 66))	('LCIS-LCIS', 'Gene', (44, 53))	('ILC', 'Gene', '10850', (215, 218))	('ILC', 'Gene', (215, 218))
36986	26643573	Molecular studies based on the pattern of gene copy number alterations and CDH1 mutations provide supporting evidence that LCIS likely constitutes a non-obligate precursor of invasive lobular carcinoma (ILC).	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (175, 201))	('CDH1', 'Gene', '999', (75, 79))	('mutations', 'Var', (80, 89))	('ILC', 'Gene', '10850', (203, 206))	('ILC', 'Gene', (203, 206))	('invasive lobular carcinoma', 'Disease', (175, 201))	('CDH1', 'Gene', (75, 79))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (184, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
36988	26643573	Historical studies have also demonstrated the presence of the same truncating mutations in the E-cadherin gene CDH1 and loss of heterozygosity (LOH) of the wild-type allele in a small number of synchronous LCIS and ILC cases.	('truncating mutations', 'Var', (67, 87))	('E-cadherin', 'Gene', (95, 105))	('LCIS', 'Disease', (206, 210))	('CDH1', 'Gene', (111, 115))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('E-cadherin', 'Gene', '999', (95, 105))	('CDH1', 'Gene', '999', (111, 115))	('loss', 'NegReg', (120, 124))	('ILC', 'Gene', '10850', (215, 218))	('ILC', 'Gene', (215, 218))
36989	26643573	An analysis of 36 ILCs included in the first genomic characterization of breast cancers by The Cancer Genome Atlas (TCGA) revealed that ILCs harbor a repertoire of somatic mutations similar to that of luminal cancers, but have a higher frequency of CDH1 and ERBB2 somatic mutations.	('ILC', 'Gene', '10850', (136, 139))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (95, 114))	('luminal cancers', 'Disease', 'MESH:D009369', (201, 216))	('ILC', 'Gene', (18, 21))	('higher', 'PosReg', (229, 235))	('Cancer Genome Atlas', 'Disease', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ILC', 'Gene', (136, 139))	('CDH1', 'Gene', '999', (249, 253))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ERBB2', 'Gene', (258, 263))	('breast cancers', 'Disease', 'MESH:D001943', (73, 87))	('breast cancers', 'Disease', (73, 87))	('CDH1', 'Gene', (249, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('luminal cancers', 'Disease', (201, 216))	('mutations', 'Var', (172, 181))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('ILC', 'Gene', '10850', (18, 21))	('ERBB2', 'Gene', '2064', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
37001	26643573	Potential functional effect of each missense SNV was investigated using a combination of MutationTaster and CHASM, and mutations identified as neutral/passengers by both computational prediction algorithms were considered passenger mutations, as previously described.	('CHASM', 'Gene', (108, 113))	('mutations', 'Var', (119, 128))	('CHASM', 'Gene', '219537', (108, 113))
37002	26643573	Genes affected by non-passenger mutations were further annotated using FATHMM and according to their presence in three cancer gene datasets: Cancer Gene Census, 127 genes by Kandoth et al.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('mutations', 'Var', (32, 41))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
37003	26643573	Samples with hotspot PIK3CA mutations and residual DNA were subjected to Sequenom MassARRAY (Sequenom) for validation of the PIK3CA mutations as previously described.	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('PIK3CA', 'Gene', (21, 27))	('PIK3CA', 'Gene', (125, 131))	('PIK3CA', 'Gene', '5290', (21, 27))	('PIK3CA', 'Gene', '5290', (125, 131))	('mutations', 'Var', (28, 37))
37004	26643573	Residual DNA from samples with CDH1 mutations were subjected to Sanger sequencing with primer sets (5'-CTGGGGTCCTCCCCAAT-3' (forward), 5'-GGTGTGGGAGTGCAATTTCT-3' (reverse)) as previously described.	('CDH1', 'Gene', '999', (31, 35))	('CDH1', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))
37012	26643573	Genes recurrently affected by non-synonymous mutations in LCIS included CDH1, PIK3CA and CBFB with mutation frequencies of 56%, 41% and 12%, respectively (Figure 1, Supplementary Table S2).	('PIK3CA', 'Gene', (78, 84))	('CBFB', 'Gene', (89, 93))	('CDH1', 'Gene', (72, 76))	('PIK3CA', 'Gene', '5290', (78, 84))	('LCIS', 'Gene', (58, 62))	('affected', 'Reg', (18, 26))	('CDH1', 'Gene', '999', (72, 76))	('non-synonymous mutations', 'Var', (30, 54))	('CBFB', 'Gene', '865', (89, 93))
37013	26643573	CDH1 gene mutations included 10 non-synonymous SNVs (10 splice-site) and 9 indels (8 frameshift, 1 splice-site) distributed among the multiple domains of the gene (Supplementary Figure S1); all CDH1 mutations were considered likely non-passenger events (Supplementary Table S3).	('CDH1', 'Gene', '999', (0, 4))	('CDH1', 'Gene', (194, 198))	('mutations', 'Var', (199, 208))	('mutations', 'Var', (10, 19))	('CDH1', 'Gene', '999', (194, 198))	('CDH1', 'Gene', (0, 4))
37014	26643573	LOH of 16q with CDH1 mutation was observed in 18/19 samples (Supplementary Table S3).	('CDH1', 'Gene', '999', (16, 20))	('CDH1', 'Gene', (16, 20))	('mutation', 'Var', (21, 29))
37015	26643573	PIK3CA gene mutations identified in LCIS included 15 non-synonymous SNVs (all missense) and 1 indel, of which 8 were found in the kinase domain (5 H1047R, 2 H1047L, 1 D1029H) and 5 in the helical domain (2 E542K, 1 E545K, 1 E545G, 1 Q546R); all mutations outside the helical and kinase domains (1 N345K, 1 D350N) and the indel (E110del) also outside the helical and kinase domains were considered to be non-passenger events (Supplementary Table S3); however, the biological impact of the indel identified remains to be determined.	('E110del', 'Mutation', 'p.110delE', (328, 335))	('E545K', 'Mutation', 'rs104886003', (215, 220))	('1 N345K', 'Var', (295, 302))	('H1047L', 'Mutation', 'rs121913279', (157, 163))	('E542K', 'Mutation', 'rs121913273', (206, 211))	('N345K', 'Mutation', 'rs121913284', (297, 302))	('E545G', 'Var', (224, 229))	('D1029H', 'Var', (167, 173))	('E545K', 'Var', (215, 220))	('H1047L', 'Var', (157, 163))	('E545G', 'Mutation', 'rs121913274', (224, 229))	('2 E542K', 'Var', (204, 211))	('PIK3CA', 'Gene', '5290', (0, 6))	('Q546R', 'Mutation', 'rs397517201', (233, 238))	('H1047R', 'Mutation', 'rs121913279', (147, 153))	('D350N', 'Mutation', 'rs1064793349', (306, 311))	('D350N', 'Var', (306, 311))	('D1029H', 'Mutation', 'p.D1029H', (167, 173))	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', (0, 6))
37016	26643573	CBFB gene mutations included 3 non-synonymous SNVs (all missense) and 1 indel (splice-site), all considered to be non-passenger (Supplementary Table S3).	('CBFB', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('missense', 'Var', (56, 64))	('CBFB', 'Gene', '865', (0, 4))
37017	26643573	LOH with CBFB mutation was observed in all 4 samples (Supplementary Table S3).	('mutation', 'Var', (14, 22))	('CBFB', 'Gene', '865', (9, 13))	('CBFB', 'Gene', (9, 13))
37018	26643573	Among the 3 patients who underwent prophylactic mastectomy, there were 5 LCIS samples, of which one sample harbored a single mutation in the MAP3K1 (I1440T) gene and one sample displayed a mutation in CDH1 (H632fs), ERBB2 (L755S) and LAMA5 (P1241Q) (Supplementary Tables S3 and S4).	('LAMA5', 'Gene', '3911', (234, 239))	('L755S', 'Var', (223, 228))	('L755S', 'Mutation', 'rs121913470', (223, 228))	('I1440T', 'Var', (149, 155))	('patients', 'Species', '9606', (12, 20))	('MAP3K', 'molecular_function', 'GO:0004709', ('141', '146'))	('ERBB2', 'Gene', (216, 221))	('ERBB2', 'Gene', '2064', (216, 221))	('CDH1', 'Gene', (201, 205))	('CDH1', 'Gene', '999', (201, 205))	('MAP3K1', 'Gene', (141, 147))	('LAMA5', 'Gene', (234, 239))	('H632fs', 'Mutation', 'rs1060501224', (207, 213))	('I1440T', 'Mutation', 'p.I1440T', (149, 155))	('P1241Q', 'Mutation', 'p.P1241Q', (241, 247))	('H632fs', 'Var', (207, 213))	('MAP3K1', 'Gene', '4214', (141, 147))
37020	26643573	PIK3CA mutations (H1047R, H1047L, E542K, D350N) in 8 LCIS samples with available residual DNA were confirmed by Sequenom analysis, and CDH1 mutation (Q23*) in 3 LCIS samples with available residual DNA was confirmed by Sanger sequencing analysis (Supplementary Table S3).	('CDH1', 'Gene', '999', (135, 139))	('E542K', 'Mutation', 'rs121913273', (34, 39))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('Q23*', 'SUBSTITUTION', 'None', (150, 154))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('CDH1', 'Gene', (135, 139))	('PIK3CA', 'Gene', (0, 6))	('H1047R', 'Mutation', 'rs121913279', (18, 24))	('D350N', 'Mutation', 'rs1064793349', (41, 46))	('PIK3CA', 'Gene', '5290', (0, 6))	('Q23*', 'Var', (150, 154))	('H1047L', 'Mutation', 'rs121913279', (26, 32))	('E542K', 'Var', (34, 39))	('H1047L', 'Var', (26, 32))	('D350N', 'Var', (41, 46))	('H1047R', 'Var', (18, 24))
37021	26643573	ILC samples were sequenced to a median target depth of 307x (range 55x-665x), which resulted in the identification of 113 somatic mutations (80 non-synonymous SNVs, 12 indels and 21 silent mutations) involving 71 (26%) of the 273 genes analyzed.	('ILC', 'Gene', '10850', (0, 3))	('indels', 'Var', (168, 174))	('ILC', 'Gene', (0, 3))
37022	26643573	As in LCIS samples, the genes recurrently affected by non-synonymous mutations were CDH1, PIK3CA and CBFB with mutation frequencies of 66%, 52% and 19%, respectively (Figure 1, Supplementary Table S2).	('mutations', 'Var', (69, 78))	('CBFB', 'Gene', '865', (101, 105))	('CBFB', 'Gene', (101, 105))	('PIK3CA', 'Gene', (90, 96))	('CDH1', 'Gene', (84, 88))	('PIK3CA', 'Gene', '5290', (90, 96))	('CDH1', 'Gene', '999', (84, 88))
37023	26643573	CDH1 gene mutations included 8 non-synonymous SNVs (6 nonsense and 2 splice-site) and 6 indels (5 frameshift and 1 splice-site); all CDH1 mutations were considered likely non-passenger events (Supplementary Table S3).	('CDH1', 'Gene', '999', (133, 137))	('CDH1', 'Gene', '999', (0, 4))	('CDH1', 'Gene', (133, 137))	('mutations', 'Var', (10, 19))	('CDH1', 'Gene', (0, 4))	('mutations', 'Var', (138, 147))
37025	26643573	PIK3CA gene mutations included 11 non-synonymous SNVs (all missense) and 1 indel (E109del), with 4 mutations found in the kinase domain (3 H1047R, 1 H1047L) and 4 in the helical domain (1 E542K, 3 E545K).	('E545K', 'Var', (197, 202))	('E542K', 'Mutation', 'rs121913273', (188, 193))	('H1047L', 'Mutation', 'rs121913279', (149, 155))	('H1047R', 'Mutation', 'rs121913279', (139, 145))	('PIK3CA', 'Gene', (0, 6))	('H1047L', 'Var', (149, 155))	('PIK3CA', 'Gene', '5290', (0, 6))	('E542K', 'Var', (188, 193))	('E109del', 'Mutation', 'p.109delE', (82, 89))	('E545K', 'Mutation', 'rs104886003', (197, 202))
37026	26643573	All PIK3CA mutations were considered non-passenger events (Supplementary Table S3).	('mutations', 'Var', (11, 20))	('PIK3CA', 'Gene', (4, 10))	('PIK3CA', 'Gene', '5290', (4, 10))
37027	26643573	CBFB gene mutations included 4 non-synonymous SNVs, all missense and considered to be non-passenger events (Supplementary Table S3).	('CBFB', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('missense', 'Var', (56, 64))	('CBFB', 'Gene', '865', (0, 4))
37028	26643573	PIK3CA mutations (H1047R, H1047L, E545K, E542K, N345K) in 9 ILC samples with available residual DNA were confirmed by Sequenom analysis and CDH1 mutation (Q23*) in 2 ILC samples with available residual DNA was confirmed by Sanger sequencing analysis (Supplementary Table S3).	('E542K', 'Var', (41, 46))	('ILC', 'Gene', '10850', (166, 169))	('N345K', 'Var', (48, 53))	('CDH1', 'Gene', '999', (140, 144))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('PIK3CA', 'Gene', '5290', (0, 6))	('H1047L', 'Mutation', 'rs121913279', (26, 32))	('Q23*', 'SUBSTITUTION', 'None', (155, 159))	('ILC', 'Gene', (166, 169))	('ILC', 'Gene', '10850', (60, 63))	('CDH1', 'Gene', (140, 144))	('N345K', 'Mutation', 'rs121913284', (48, 53))	('E545K', 'Mutation', 'rs104886003', (34, 39))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('H1047L', 'Var', (26, 32))	('H1047R', 'Var', (18, 24))	('Q23*', 'Var', (155, 159))	('ILC', 'Gene', (60, 63))	('E545K', 'Var', (34, 39))	('E542K', 'Mutation', 'rs121913273', (41, 46))	('PIK3CA', 'Gene', (0, 6))	('H1047R', 'Mutation', 'rs121913279', (18, 24))
37030	26643573	30 genes were found to be affected by somatic mutations in both LCIS and ILC, including many genes reported to be recurrently mutated in ER-positive/luminal breast cancers (e.g., CDH1, ERBB3, GATA3, FOXA1, PIK3CA, MAP3K1, RUNX1, TP53, PTEN).	('FOXA1', 'Gene', (199, 204))	('ER', 'Gene', '2099', (185, 187))	('ERBB3', 'Gene', (185, 190))	('affected', 'Reg', (26, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('PTEN', 'Gene', (235, 239))	('GATA3', 'Gene', (192, 197))	('ILC', 'Gene', (73, 76))	('MAP3K', 'molecular_function', 'GO:0004709', ('214', '219'))	('luminal breast cancers', 'Disease', 'MESH:D001943', (149, 171))	('MAP3K1', 'Gene', (214, 220))	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('MAP3K1', 'Gene', '4214', (214, 220))	('mutations', 'Var', (46, 55))	('CDH1', 'Gene', '999', (179, 183))	('TP53', 'Gene', '7157', (229, 233))	('PTEN', 'Gene', '5728', (235, 239))	('PIK3CA', 'Gene', '5290', (206, 212))	('CDH1', 'Gene', (179, 183))	('ERBB3', 'Gene', '2065', (185, 190))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('LCIS', 'Gene', (64, 68))	('luminal breast cancers', 'Disease', (149, 171))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('RUNX1', 'Gene', (222, 227))	('PIK3CA', 'Gene', (206, 212))	('FOXA1', 'Gene', '3169', (199, 204))	('ILC', 'Gene', '10850', (73, 76))	('RUNX1', 'Gene', '861', (222, 227))	('TP53', 'Gene', (229, 233))	('ER', 'Gene', '2099', (137, 139))	('GATA3', 'Gene', '2625', (192, 197))
37034	26643573	Among these 14 pairs, 7 LCIS-ILC pairs shared both identical CDH1 and PIK3CA mutations, 5 LCIS-ILC pairs shared a CDH1 mutation, and 1 LCIS-ILC pair shared a PIK3CA mutation.	('CDH1', 'Gene', '999', (61, 65))	('ILC', 'Gene', (95, 98))	('ILC', 'Gene', (29, 32))	('ILC', 'Gene', '10850', (29, 32))	('PIK3CA', 'Gene', (158, 164))	('ILC', 'Gene', '10850', (140, 143))	('ILC', 'Gene', (140, 143))	('PIK3CA', 'Gene', '5290', (158, 164))	('PIK3CA', 'Gene', (70, 76))	('CDH1', 'Gene', (114, 118))	('mutations', 'Var', (77, 86))	('CDH1', 'Gene', '999', (114, 118))	('CDH1', 'Gene', (61, 65))	('ILC', 'Gene', '10850', (95, 98))	('PIK3CA', 'Gene', '5290', (70, 76))
37039	26643573	In the first case (Case #03), the paired lesions were located in the same quadrant of the breast; however, the ILC harbored a PIK3CA and a PIK3R1 mutation, whereas the LCIS harbored a PTEN mutation (Figure 3).	('mutation', 'Var', (146, 154))	('PIK3CA', 'Gene', (126, 132))	('PTEN', 'Gene', (184, 188))	('PTEN', 'Gene', '5728', (184, 188))	('PIK3R1', 'Gene', '5295', (139, 145))	('PIK3CA', 'Gene', '5290', (126, 132))	('PIK3R1', 'Gene', (139, 145))	('ILC', 'Gene', '10850', (111, 114))	('ILC', 'Gene', (111, 114))
37041	26643573	In the third case (Case #24), we found that the ILC harbored a CDH1 (F730fs) and PIK3CA (H1047R) mutation distinct from those found in the LCIS-2 lesion in a different quadrant (CDH1 Q23*; PIK3CA Q546R).	('Q23*', 'Var', (183, 187))	('CDH1', 'Gene', (63, 67))	('PIK3CA', 'Gene', (81, 87))	('CDH1', 'Gene', (178, 182))	('H1047R', 'Mutation', 'rs121913279', (89, 95))	('PIK3CA', 'Gene', '5290', (81, 87))	('CDH1', 'Gene', '999', (178, 182))	('F730fs', 'Var', (69, 75))	('ILC', 'Gene', '10850', (48, 51))	('PIK3CA', 'Gene', (189, 195))	('F730fs', 'Mutation', 'p.F730fsX', (69, 75))	('CDH1', 'Gene', '999', (63, 67))	('Q23*', 'SUBSTITUTION', 'None', (183, 187))	('H1047R', 'Var', (89, 95))	('ILC', 'Gene', (48, 51))	('PIK3CA', 'Gene', '5290', (189, 195))	('Q546R', 'Mutation', 'rs397517201', (196, 201))
37042	26643573	Furthermore, a CBFB mutation was found to be restricted to the ILC, while GATA3, HMNC1, MAP4K4, and MLL3 mutations were unique to the LCIS-2 lesion (Figure 3).	('MLL3', 'Gene', '58508', (100, 104))	('MAP4K4', 'Gene', (88, 94))	('mutation', 'Var', (20, 28))	('GATA3', 'Gene', (74, 79))	('CBFB', 'Gene', '865', (15, 19))	('ILC', 'Gene', '10850', (63, 66))	('GATA3', 'Gene', '2625', (74, 79))	('ILC', 'Gene', (63, 66))	('MLL3', 'Gene', (100, 104))	('CBFB', 'Gene', (15, 19))	('MAP', 'molecular_function', 'GO:0004239', ('88', '91'))	('MAP4K4', 'Gene', '9448', (88, 94))
37047	26643573	Overall, among all 17 LCIS-ILC or LCIS-LCIS pairs inferred to be clonal based on the number of shared mutations and unsupervised hierarchical clustering, 12 (71%) were located in the same quadrant of the breast, whereas 5 (29%) were found in different quadrants (Fisher's exact test, 71% vs 29%, p=0.038).	('ILC', 'Gene', '10850', (27, 30))	('mutations', 'Var', (102, 111))	('ILC', 'Gene', (27, 30))
37051	26643573	In case #48, however, LCIS-1 and ILC (located in the same upper outer quadrant) shared a common CDH1 mutation, which was not present in LCIS-2, located in the upper inner quadrant of the same breast (Figure 3).	('LCIS-1 and ILC', 'Gene', '10850', (22, 36))	('CDH1', 'Gene', (96, 100))	('mutation', 'Var', (101, 109))	('CDH1', 'Gene', '999', (96, 100))
37052	26643573	In case #24, different foci of LCIS harbored distinct mutations affecting the same genes (Figure 3); whilst LCIS-1 and the ILC, which were located in the right lower outer quadrant, shared the same somatic mutations in CDH1 (F730fs), PIK3CA (H1047R) and CBFB (Q67H); the LCIS-2, which was harvested from the upper inner quadrant of the same breast, harbored mutations in CDH1 (Q23*) and PIK3CA (Q546R) distinct from those found in the LCIS-1 and ILC, providing an example of a convergent phenotype in the development of LCIS.	('CDH1', 'Gene', '999', (371, 375))	('PIK3CA', 'Gene', (387, 393))	('ILC', 'Gene', (446, 449))	('CBFB', 'Gene', '865', (254, 258))	('CDH1', 'Gene', (371, 375))	('Q23*', 'SUBSTITUTION', 'None', (377, 381))	('mutations', 'Var', (358, 367))	('CDH1', 'Gene', '999', (219, 223))	('PIK3CA', 'Gene', (234, 240))	('H1047R', 'Mutation', 'rs121913279', (242, 248))	('F730fs', 'Mutation', 'p.F730fsX', (225, 231))	('Q546R', 'Var', (395, 400))	('ILC', 'Gene', '10850', (123, 126))	('CDH1', 'Gene', (219, 223))	('LCIS-1 and ILC', 'Gene', '10850', (435, 449))	('PIK3CA', 'Gene', '5290', (387, 393))	('Q23*', 'Var', (377, 381))	('ILC', 'Gene', '10850', (446, 449))	('CBFB', 'Gene', (254, 258))	('ILC', 'Gene', (123, 126))	('Q67H', 'Mutation', 'p.Q67H', (260, 264))	('PIK3CA', 'Gene', '5290', (234, 240))	('Q546R', 'Mutation', 'rs397517201', (395, 400))
37054	26643573	Morphologic and cytologic similarities between LCIS and ILC, combined with emerging reports of shared genomic alterations (mainly 1q gain, 16q loss and CDH1 mutations) between LCIS and synchronous ILC have reopened the debate about the precursor potential of LCIS; however, most studies have been limited to a small number of cases and based on formalin-fixed paraffin-embedded samples.	('ILC', 'Gene', (197, 200))	('formalin', 'Chemical', 'MESH:D005557', (345, 353))	('CDH1', 'Gene', (152, 156))	('mutations', 'Var', (157, 166))	('CDH1', 'Gene', '999', (152, 156))	('ILC', 'Gene', '10850', (56, 59))	('ILC', 'Gene', (56, 59))	('ILC', 'Gene', '10850', (197, 200))	('gain', 'PosReg', (133, 137))	('paraffin', 'Chemical', 'MESH:D010232', (360, 368))
37059	26643573	In addition to the unique morphologic and cytologic description of the lobular phenotype, loss of E-cadherin protein expression has long been recognized as a hallmark feature of lobular disease.	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('E-cadherin', 'Gene', (98, 108))	('expression', 'MPA', (117, 127))	('loss', 'Var', (90, 94))	('E-cadherin', 'Gene', '999', (98, 108))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('lobular disease', 'Disease', (178, 193))	('lobular disease', 'Disease', 'MESH:D018275', (178, 193))
37060	26643573	Loss of E-cadherin expression is reported to occur through a combination of mechanisms including CDH1 gene mutation, allelic loss and CDH1 promoter methylation.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('expression', 'MPA', (19, 29))	('CDH1', 'Gene', '999', (134, 138))	('CDH1', 'Gene', (97, 101))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))	('Loss', 'NegReg', (0, 4))	('allelic loss', 'Var', (117, 129))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('CDH1', 'Gene', '999', (97, 101))	('mutation', 'Var', (107, 115))	('CDH1', 'Gene', (134, 138))
37061	26643573	Here we confirm that genomic alterations affecting CDH1 are an early event in lobular neoplasia with CDH1 gene mutations observed in 58% and 64% of LCIS and ILC lesions, respectively (Table 2, Figure 1).	('CDH1', 'Gene', (51, 55))	('mutations', 'Var', (111, 120))	('ILC', 'Gene', '10850', (157, 160))	('lobular neoplasia', 'Disease', (78, 95))	('neoplasia', 'Phenotype', 'HP:0002664', (86, 95))	('ILC', 'Gene', (157, 160))	('CDH1', 'Gene', '999', (51, 55))	('CDH1', 'Gene', (101, 105))	('lobular neoplasia', 'Disease', 'MESH:D009369', (78, 95))	('lobular neoplasia', 'Phenotype', 'HP:0030076', (78, 95))	('LCIS', 'Disease', (148, 152))	('CDH1', 'Gene', '999', (101, 105))	('observed', 'Reg', (121, 129))
37062	26643573	Further, there was no significant difference in the pattern of CDH1 mutations between LCIS and ILC samples.	('CDH1', 'Gene', (63, 67))	('ILC', 'Gene', (95, 98))	('CDH1', 'Gene', '999', (63, 67))	('mutations', 'Var', (68, 77))	('ILC', 'Gene', '10850', (95, 98))
37063	26643573	Previous studies with smaller sample sizes and different methodology have reported a higher frequency of CDH1 mutations in ILC; however, our findings are consistent with that of the most recent publication from The Cancer Genome Atlas Project, where CDH1 mutations were identified in 63% (80/127) of classic invasive lobular carcinomas.	('ILC', 'Gene', '10850', (123, 126))	('CDH1', 'Gene', '999', (250, 254))	('Cancer Genome Atlas', 'Disease', (215, 234))	('Cancer', 'Phenotype', 'HP:0002664', (215, 221))	('mutations', 'Var', (110, 119))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (215, 234))	('ILC', 'Gene', (123, 126))	('CDH1', 'Gene', (105, 109))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (308, 335))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (317, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('CDH1', 'Gene', (250, 254))	('invasive lobular carcinomas', 'Disease', (308, 335))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (317, 335))	('CDH1', 'Gene', '999', (105, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (325, 335))
37064	26643573	Mutations in PIK3CA were the second-most frequent mutations in both LCIS and ILC with a mutation frequency of 39% and 55%, respectively (Table 2, Figure 1), which is also consistent with the frequency of PIK3CA mutations reported in ER-positive breast cancer and ILC specifically.	('ILC', 'Gene', (77, 80))	('PIK3CA', 'Gene', '5290', (204, 210))	('ILC', 'Gene', (263, 266))	('PIK3CA', 'Gene', (13, 19))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('PIK3CA', 'Gene', (204, 210))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('ILC', 'Gene', '10850', (263, 266))	('ILC', 'Gene', '10850', (77, 80))	('breast cancer', 'Disease', (245, 258))	('ER', 'Gene', '2099', (233, 235))
37065	26643573	The CBFB gene, which, like CDH1, is located on chromosome 16, was also recurrently mutated in our sample set of LCIS and ILC with a mutational frequency of 11% and 23%, respectively (Table 2, Figure 1).	('mutated', 'Var', (83, 90))	('CDH1', 'Gene', (27, 31))	('CBFB', 'Gene', (4, 8))	('CDH1', 'Gene', '999', (27, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('ILC', 'Gene', '10850', (121, 124))	('ILC', 'Gene', (121, 124))	('CBFB', 'Gene', '865', (4, 8))
37066	26643573	The comparison of the mutational frequency of PIK3CA mutations in our dataset of ILC with that of luminal A ER-positive invasive carcinomas or the lobular TCGA dataset revealed no significant difference.	('ILC', 'Gene', '10850', (81, 84))	('ILC', 'Gene', (81, 84))	('PIK3CA', 'Gene', '5290', (46, 52))	('invasive carcinomas', 'Disease', (120, 139))	('invasive carcinomas', 'Disease', 'MESH:D009361', (120, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('ER', 'Gene', '2099', (108, 110))	('mutations', 'Var', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('PIK3CA', 'Gene', (46, 52))
37067	26643573	In contrast, mutations in CDH1 and CBFB were more frequent in ILCs in our dataset as compared to the luminal A ER-positive subtype from the TCGA dataset (p<0.0001).	('ILC', 'Gene', '10850', (62, 65))	('CBFB', 'Gene', '865', (35, 39))	('frequent', 'Reg', (50, 58))	('ILC', 'Gene', (62, 65))	('ER', 'Gene', '2099', (111, 113))	('CBFB', 'Gene', (35, 39))	('mutations', 'Var', (13, 22))	('CDH1', 'Gene', (26, 30))	('CDH1', 'Gene', '999', (26, 30))
37068	26643573	The increased prevalence of CDH1 mutations among lobular lesions is not unexpected and was confirmed in the TCGA lobular dataset.	('CDH1', 'Gene', '999', (28, 32))	('CDH1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
37069	26643573	The enrichment in mutations targeting CBFB in ILCs in our dataset, however, warrants further validation.	('mutations', 'Var', (18, 27))	('CBFB', 'Gene', (38, 42))	('ILC', 'Gene', '10850', (46, 49))	('CBFB', 'Gene', '865', (38, 42))	('ILC', 'Gene', (46, 49))
37071	26643573	In this independent cohort, 36.4% (8/22) and 27.3% (6/22) of LCIS samples harbored PIK3CA and CDH1 mutations, respectively, which is similar to the mutation frequencies identified in the current series (PIK3CA, Fisher's exact test, two-tailed, p=0.785; CDH1, Fisher's exact test, two-tailed, p=0.054).	('PIK3CA', 'Gene', (203, 209))	('CDH1', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('PIK3CA', 'Gene', '5290', (203, 209))	('PIK3CA', 'Gene', (83, 89))	('CDH1', 'Gene', '999', (94, 98))	('CDH1', 'Gene', (253, 257))	('PIK3CA', 'Gene', '5290', (83, 89))	('CDH1', 'Gene', '999', (253, 257))
37072	26643573	Different methodologies have been used in the literature to assess clonal relatedness between LCIS and adjacent malignancies including ILC, yet most are based on the analysis of gene copy number alterations in formalin-fixed paraffin-embedded samples, or on the presence of identical CDH1 mutations.	('mutations', 'Var', (289, 298))	('malignancies', 'Disease', (112, 124))	('LCIS', 'Disease', (94, 98))	('paraffin', 'Chemical', 'MESH:D010232', (225, 233))	('CDH1', 'Gene', (284, 288))	('formalin', 'Chemical', 'MESH:D005557', (210, 218))	('ILC', 'Gene', '10850', (135, 138))	('malignancies', 'Disease', 'MESH:D009369', (112, 124))	('CDH1', 'Gene', '999', (284, 288))	('ILC', 'Gene', (135, 138))
37073	26643573	One of the most frequently cited studies reporting the presence of shared mutations in LCIS and ILC included only 2 sets of paired lesions with common point mutations in the CDH1 gene (Vos, 1997 #1}.	('CDH1', 'Gene', (174, 178))	('CDH1', 'Gene', '999', (174, 178))	('ILC', 'Gene', '10850', (96, 99))	('LCIS', 'Disease', (87, 91))	('mutations', 'Var', (74, 83))	('ILC', 'Gene', (96, 99))
37074	26643573	Nonetheless, given that CDH1 mutations in ILC do not occur at hotspots but at different residues within the gene, their specificity makes CDH1 highly informative when assessing clonal relatedness.	('CDH1', 'Gene', (24, 28))	('CDH1', 'Gene', '999', (24, 28))	('CDH1', 'Gene', (138, 142))	('mutations', 'Var', (29, 38))	('CDH1', 'Gene', '999', (138, 142))	('ILC', 'Gene', '10850', (42, 45))	('ILC', 'Gene', (42, 45))
37080	26643573	The presence of identical mutations between LCIS-LCIS and LCIS-ILC pairs demonstrates that LCIS is a clonal neoplastic lesion and provides additional data that LCIS is a non-obligate precursor of ILC.	('LCIS', 'Disease', (91, 95))	('neoplastic lesion', 'Disease', 'MESH:D051437', (108, 125))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (108, 125))	('ILC', 'Gene', '10850', (196, 199))	('ILC', 'Gene', (196, 199))	('ILC', 'Gene', '10850', (63, 66))	('mutations', 'Var', (26, 35))	('neoplastic lesion', 'Disease', (108, 125))	('ILC', 'Gene', (63, 66))	('LCIS-LCIS', 'Gene', (44, 53))
37238	31229512	Frequent amplifications of ESR1, ERBB2 and MDM4 in primary invasive lobular breast carcinoma Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer following invasive ductal carcinoma (IDC).	('MDM4', 'Gene', (43, 47))	('ESR1', 'Gene', '2099', (27, 31))	('ERBB2', 'Gene', '2064', (33, 38))	('invasive lobular breast carcinoma', 'Disease', (59, 92))	('Invasive lobular carcinoma', 'Disease', 'MESH:D018275', (93, 119))	('breast carcinoma', 'Phenotype', 'HP:0003002', (76, 92))	('ESR1', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Invasive lobular carcinoma', 'Disease', (93, 119))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D001943', (59, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (200, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (102, 119))	('invasive ductal carcinoma', 'Disease', (200, 225))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (209, 225))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('MDM4', 'Gene', '4194', (43, 47))	('amplifications', 'Var', (9, 23))	('breast cancer', 'Disease', (176, 189))	('ERBB2', 'Gene', (33, 38))
37239	31229512	We confirmed prior observations of frequent amplification of CCND1 (33%), and MYC (17%) in ILC, but additionally identified a substantial subset of ILCs with ESR1 and ERBB2 (19%) amplifications.	('ILCs', 'Disease', (148, 152))	('ERBB2', 'Gene', (167, 172))	('amplification', 'MPA', (44, 57))	('amplifications', 'Var', (179, 193))	('ESR1', 'Gene', (158, 162))	('ERBB2', 'Gene', '2064', (167, 172))	('MYC', 'Gene', '4609', (78, 81))	('ILC', 'Disease', (91, 94))	('CCND1', 'Gene', (61, 66))	('ESR1', 'Gene', '2099', (158, 162))	('CCND1', 'Gene', '595', (61, 66))	('MYC', 'Gene', (78, 81))
37240	31229512	Of interest, tumors with ESR1 CN gains (14%) and amplification (10%) were more likely to recur compared to those with normal CN.	('amplification', 'Var', (49, 62))	('ESR1', 'Gene', (25, 29))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('gains', 'PosReg', (33, 38))	('ESR1', 'Gene', '2099', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('recur', 'CPA', (89, 94))
37242	31229512	MDM4 knockdown in TP53 wild-type ILC cell lines caused increased apoptosis, decreased proliferation associated with cell cycle arrest, and concomitant activation of TP53 target genes.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('116', '133'))	('arrest', 'Disease', (127, 133))	('MDM4', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (55, 64))	('proliferation', 'CPA', (86, 99))	('decreased', 'NegReg', (76, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('apoptosis', 'CPA', (65, 74))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (116, 133))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('arrest', 'Disease', 'MESH:D006323', (127, 133))	('activation', 'PosReg', (151, 161))
37243	31229512	To conclude, amplification of ESR1 and MDM4 are potential genetic drivers of ILC.	('ESR1', 'Gene', (30, 34))	('drivers', 'Reg', (66, 73))	('ILC', 'Disease', (77, 80))	('amplification', 'Var', (13, 26))	('ESR1', 'Gene', '2099', (30, 34))	('MDM4', 'Gene', (39, 43))
37248	31229512	These studies have uncovered a number of specific differences in the genetic make-up of ILC compared to IDC, including enrichment of PTEN loss, PIK3CA, FOXA1, ERBB2 and ERBB3 mutations, in addition to the well described ILC genetic hallmark of CDH1 loss.	('CDH1', 'Gene', (244, 248))	('CDH1', 'Gene', '999', (244, 248))	('PIK3CA', 'Gene', (144, 150))	('FOXA1', 'Gene', (152, 157))	('ILC', 'Disease', (88, 91))	('PIK3CA', 'Gene', '5290', (144, 150))	('ERBB2', 'Gene', '2064', (159, 164))	('PTEN loss', 'Disease', 'MESH:D006223', (133, 142))	('mutations', 'Var', (175, 184))	('ERBB3', 'Gene', '2065', (169, 174))	('ERBB2', 'Gene', (159, 164))	('ERBB3', 'Gene', (169, 174))	('ILC', 'Disease', (220, 223))	('PTEN loss', 'Disease', (133, 142))	('FOXA1', 'Gene', '3169', (152, 157))
37253	31229512	While some studies report ESR1 amplifications at a relatively high rate of ~20%, associated with either improved or worse outcomes, others have detected a significantly lower ESR1-amplification frequency (<5%), possibly due to differences in methodology, sample cohorts, and threshold definitions.	('ESR1', 'Gene', (175, 179))	('amplifications', 'Var', (31, 45))	('ESR1', 'Gene', '2099', (26, 30))	('ESR1', 'Gene', '2099', (175, 179))	('lower', 'NegReg', (169, 174))	('ESR1', 'Gene', (26, 30))
37254	31229512	Intriguingly, Desmedt et al recently reported ESR1 amplification in up to 25% of ILC samples, a finding that warrants validation in an independent cohort.	('ILC', 'Disease', (81, 84))	('ESR1', 'Gene', (46, 50))	('ESR1', 'Gene', '2099', (46, 50))	('amplification', 'Var', (51, 64))
37256	31229512	Besides confirming frequent ESR1 CN gain and amplifications, we also show a significant association with higher risk of subsequent recurrence.	('gain', 'PosReg', (36, 40))	('ESR1', 'Gene', (28, 32))	('amplifications', 'Var', (45, 59))	('ESR1', 'Gene', '2099', (28, 32))
37260	31229512	DNA and RNA isolations were performed using the QIAamp DNA FFPE kit (cat#56404) and Qiagen RNeasy FFPE kit (cat#73504) respectively, as per manufacturer's instructions.	('cat#56404', 'Var', (69, 78))	('kit', 'Gene', '3815', (64, 67))	('cat', 'molecular_function', 'GO:0004096', ('69', '72'))	('RNA', 'cellular_component', 'GO:0005562', ('8', '11'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('kit', 'Gene', (103, 106))	('kit', 'Gene', '3815', (103, 106))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('kit', 'Gene', (64, 67))	('cat#73504', 'Var', (108, 117))	('cat', 'molecular_function', 'GO:0004096', ('108', '111'))
37280	31229512	shRNA expression was induced by treatment with 200 ng/ml and 160ng/ml DOX in BCK4 and SUM44PE cells, respectively, with replenishment every 3-4 days.	('160ng/ml', 'Var', (61, 69))	('shRNA expression', 'Gene', (0, 16))	('BCK', 'molecular_function', 'GO:0047323', ('77', '80'))	('DOX', 'Chemical', 'MESH:D004318', (70, 73))	('induced', 'Reg', (21, 28))
37288	31229512	25-50 mug per sample was run on 9% or 15% gradient SDS-PAGE gels and transferred to PVDF membranes (Millipore#IPFL00010), and blocked using Odyssey PBS blocking buffer (LiCor#927-40000) and incubated with the following antibodies: TP53 (1:500; sc-6243, Santa Cruz Biotechnology), MDM4 (1:500; A300-287A, Bethyl Laboratories), P21 (1:200; sc-397, Santa Cruz Biotechnology), PUMA (1:500; D30C10, Cell Signaling Technology), BAX (1:500; D2E11, Cell Signaling Technology), Tubulin gamma (1:10,000; ab11317, Abcam), ER (1:1000; 6F11, Leica Biosystems) and secondary antibodies anti-mouse 800CW: LiCor#925-32210, anti-rabbit 800CW: LiCor#925-32211.	('Signaling', 'biological_process', 'GO:0023052', ('399', '408'))	('mouse', 'Species', '10090', (577, 582))	('mug', 'molecular_function', 'GO:0043739', ('6', '9'))	('PBS', 'Chemical', 'MESH:D007854', (148, 151))	('P21', 'Gene', '12575', (326, 329))	('Signaling', 'biological_process', 'GO:0023052', ('446', '455'))	('P21', 'Gene', (326, 329))	('anti-mouse', 'Var', (572, 582))	('ER', 'Gene', '2099', (511, 513))
37290	31229512	Based on average calls from probes covering the promoter region, two non-coding exons, and seven coding exons, we detected ~24% of samples with ESR1 gains (CN 2.7-10; 10 tumors; 14% of samples) or amplifications (CN >=10; 7 tumors; 14% of samples).	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('gains', 'PosReg', (149, 154))	('ESR1', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('ESR1', 'Gene', '2099', (144, 148))	('amplifications', 'Var', (197, 211))	('tumors', 'Disease', (170, 176))
37292	31229512	ER histological scores (H-scores) were available for a subset of 53 samples, which were slightly higher in the group with ESR1 gains and amplifications; though did not reach statistical significance (Figure S1A).	('ER', 'Gene', '2099', (0, 2))	('ESR1', 'Gene', (122, 126))	('higher', 'PosReg', (97, 103))	('amplifications', 'Var', (137, 151))	('gains', 'Var', (127, 132))	('ESR1', 'Gene', '2099', (122, 126))
37294	31229512	To determine whether ESR1 CN alterations were associated with clinical outcome, we compared groups with (n=18) or without recurrence (n=52) (Table 1).	('ESR1', 'Gene', (21, 25))	('ESR1', 'Gene', '2099', (21, 25))	('alterations', 'Var', (29, 40))	('associated', 'Reg', (46, 56))
37297	31229512	Overall, these results demonstrate that primary ILC exhibit frequent ESR1 gains and amplifications, which are significant enriched in samples with subsequent recurrence, suggesting a potential role for ESR1 CN gains/amplifications in endocrine resistance.	('ESR1', 'Gene', (202, 206))	('ESR1', 'Gene', (69, 73))	('ESR1', 'Gene', '2099', (202, 206))	('amplifications', 'Var', (84, 98))	('ESR1', 'Gene', '2099', (69, 73))	('gains', 'Var', (74, 79))
37302	31229512	We observed some associations between amplifications of CCND1, FGF19, FADD, AAMDC, PAK1 and CTTN as was expected given these genes map to the well described 11q13 amplicon.	('AAMDC', 'Gene', '28971', (76, 81))	('amplifications', 'Var', (38, 52))	('FGF19', 'Gene', '9965', (63, 68))	('CCND1', 'Gene', '595', (56, 61))	('FGF19', 'Gene', (63, 68))	('CTTN', 'Gene', (92, 96))	('FADD', 'Gene', '8772', (70, 74))	('PAK1', 'Gene', '5058', (83, 87))	('CTTN', 'Gene', '2017', (92, 96))	('PAK1', 'Gene', (83, 87))	('FADD', 'Gene', (70, 74))	('associations', 'Interaction', (17, 29))	('CCND1', 'Gene', (56, 61))	('AAMDC', 'Gene', (76, 81))
37303	31229512	In summary, the NanoString analysis confirmed prior observations of frequent amplification of 11q13, including CCND1, but also identified a higher than expected rate of ERBB2 amplification as well as novel MDM4 amplifications.	('CCND1', 'Gene', (111, 116))	('ERBB2', 'Gene', (169, 174))	('amplification', 'MPA', (77, 90))	('CCND1', 'Gene', '595', (111, 116))	('amplification', 'Var', (175, 188))	('11q13', 'Gene', (94, 99))	('ERBB2', 'Gene', '2064', (169, 174))
37305	31229512	In line with this, MDM4 amplification and/or overexpression is more frequent in tumors that retain wild type TP53 (wt TP53).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('amplification', 'Var', (24, 37))	('tumors', 'Disease', (80, 86))	('MDM4', 'Gene', (19, 23))	('overexpression', 'PosReg', (45, 59))
37306	31229512	We performed sanger sequencing of TP53 in eight tumors with MDM4 amplification, and determined a wt TP53 status in all sequenced samples, in line with the low TP53 mutation frequency seen in primary TCGA ILC tumors (~7%).	('MDM4 amplification', 'Var', (60, 78))	('ILC tumors', 'Disease', (204, 214))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('ILC tumors', 'Disease', 'MESH:D009369', (204, 214))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
37307	31229512	The IDC cell line MCF-7 harboring a previously described MDM4 amplification was included as a positive control and data were normalized to normal breast tissue.	('amplification', 'Var', (62, 75))	('MCF-7', 'CellLine', 'CVCL:0031', (18, 23))	('MDM4', 'Gene', (57, 61))
37308	31229512	MM134 and MM330 cells harbor TP53 E285K and Y220C mutations, respectively, both of which were reported as loss-of-function changes in the IARC TP53 database (http://p53.iarc.fr/).	('p53', 'Gene', (165, 168))	('p53', 'Gene', '7157', (165, 168))	('Y220C', 'Mutation', 'rs121912666', (44, 49))	('loss-of-function', 'NegReg', (106, 122))	('E285K', 'Var', (34, 39))	('Y220C', 'Var', (44, 49))	('E285K', 'Mutation', 'rs112431538', (34, 39))	('TP53', 'Gene', (29, 33))
37309	31229512	A truncating TP53 frameshift mutation (82_84delinsCA, pE28fsX16) was found in Sum44PE cells, which was also reported in the IARC database.	('pE28fsX16', 'Var', (54, 63))	('TP53', 'Gene', (13, 17))	('82_84delinsCA', 'Var', (39, 52))	('82_84delinsCA', 'Mutation', 'c.82_84delinsCA', (39, 52))
37310	31229512	In addition, we tested the effect of MDM4 KD in the wildtype (wt) TP53 IDC cell line MCF7 and observed a similar growth inhibitory effect (Figure S4F).	('growth', 'MPA', (113, 119))	('MDM4 KD', 'Var', (37, 44))	('MCF7', 'CellLine', 'CVCL:0031', (85, 89))
37311	31229512	In addition to transient experiments, the ability of MDM4 KD to decrease cell proliferation in BCK4 cells was also seen by lentiviral-mediated doxycycline (DOX)-inducible shRNAs (verified by immunoblot in Figure 3B) in both a growth assay (Figure S5A) and a colony formation assay (Figure 3C).	('BCK', 'molecular_function', 'GO:0047323', ('95', '98'))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('decrease', 'NegReg', (64, 72))	('DOX', 'Chemical', 'MESH:D004318', (156, 159))	('cell proliferation', 'CPA', (73, 91))	('doxycycline', 'Chemical', 'MESH:D004318', (143, 154))	('MDM4 KD', 'Var', (53, 60))	('formation', 'biological_process', 'GO:0009058', ('265', '274'))
37312	31229512	Cell cycle analysis revealed a reproducible and significantly increased G0/G1 arrest after MDM4 KD for 4 days (Figure 3D, E).	('arrest', 'Disease', (78, 84))	('increased', 'PosReg', (62, 71))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('MDM4 KD for', 'Var', (91, 102))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))
37313	31229512	In addition to reduced proliferation, we also observed an increase in apoptosis in cells transfected with siMDM4 relative to siCTL, as determined by FACS analysis (Figure 3F).	('siCTL', 'Disease', (125, 130))	('siCTL', 'Disease', 'None', (125, 130))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('reduced', 'NegReg', (15, 22))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('proliferation', 'CPA', (23, 36))	('apoptosis', 'CPA', (70, 79))	('siMDM4', 'Var', (106, 112))
37314	31229512	MDM4 siRNA KD in BCK4 cells did not alter TP53 expression at the protein level but did induce the pro-apoptotic Bcl-2 family members PUMA and BAX, and cell cycle inhibitor p21 at both the RNA and protein levels.	('p21', 'Gene', (172, 175))	('Bcl-2', 'molecular_function', 'GO:0015283', ('112', '117'))	('cell cycle', 'CPA', (151, 161))	('p21', 'Gene', '644914', (172, 175))	('BCK', 'molecular_function', 'GO:0047323', ('17', '20'))	('PUMA', 'Gene', (133, 137))	('Bcl-2', 'Gene', (112, 117))	('BAX', 'Gene', (142, 145))	('Bcl-2', 'Gene', '596', (112, 117))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('induce', 'PosReg', (87, 93))	('RNA', 'cellular_component', 'GO:0005562', ('188', '191'))	('MDM4', 'Var', (0, 4))	('cell cycle', 'biological_process', 'GO:0007049', ('151', '161'))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
37315	31229512	These results are consistent with previous studies of MDM4 KD in TP53wt cell lines from breast cancer and other cancers.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('MDM4 KD', 'Var', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
37316	31229512	In addition, we also knocked down MDM4 using dox-inducible shRNAs in Sum44PE cells (Figure 4B) and observed a similar inhibitory effect in both growth (Figure S5), and colony formation assays (Figure 4C).	('colony formation assays', 'CPA', (168, 191))	('formation', 'biological_process', 'GO:0009058', ('175', '184'))	('dox', 'Chemical', 'MESH:D004317', (45, 48))	('MDM4', 'Gene', (34, 38))	('knocked', 'Var', (21, 28))	('inhibitory', 'NegReg', (118, 128))	('growth', 'CPA', (144, 150))
37317	31229512	Interestingly, this MDM4 KD induced growth inhibition phenotype was cell line-dependent as we did not observe comparable changes in growth rates of the other two TP53mut ILC cell lines, MM330 (Figure S4D) and MM134 (Figure 4A), while seeing effects in the TP53mut IDC cell line T47D (Figure S4H).	('T47D', 'CellLine', 'CVCL:0553', (278, 282))	('growth', 'MPA', (36, 42))	('MDM4 KD', 'Var', (20, 27))
37321	31229512	In our CNA study in ILC, we made a number of novel observations with potential clinical implications, including (1) frequent ESR1 CN gain (14%) or amplification (10%) associated with disease recurrence, (2) frequent ERBB2 amplification (19%), and (3) frequent MDM4 amplifications (17%) and a functional role for MDM4 in ILC.	('ESR1', 'Gene', '2099', (125, 129))	('ILC', 'Disease', (320, 323))	('MDM4', 'Gene', (260, 264))	('associated with', 'Reg', (167, 182))	('disease recurrence', 'Disease', (183, 201))	('ERBB2', 'Gene', (216, 221))	('ERBB2', 'Gene', '2064', (216, 221))	('amplification', 'Var', (222, 235))	('ESR1', 'Gene', (125, 129))	('amplifications', 'Var', (265, 279))	('amplification', 'Var', (147, 160))
37323	31229512	Our CN characterization of ILC revealed frequent ESR1 amplifications in about one quarter of cases (24%), associated with significantly higher mRNA expression.	('ESR1', 'Gene', (49, 53))	('higher', 'PosReg', (136, 142))	('mRNA expression', 'MPA', (143, 158))	('ESR1', 'Gene', '2099', (49, 53))	('amplifications', 'Var', (54, 68))
37324	31229512	Importantly, ESR1 amplifications were significantly enriched in samples from patients with subsequent recurrences.	('patients', 'Species', '9606', (77, 85))	('ESR1', 'Gene', (13, 17))	('amplifications', 'Var', (18, 32))	('ESR1', 'Gene', '2099', (13, 17))
37325	31229512	Our findings are in agreement with the recently reported study detailing ESR1 amplifications in 25% of primary ILC, association with mRNA expression, and enrichment in aggressive ILC tumors by Desmedt et al.	('amplifications', 'Var', (78, 92))	('association', 'Interaction', (116, 127))	('mRNA expression', 'MPA', (133, 148))	('ESR1', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('primary ILC', 'Disease', (103, 114))	('aggressive ILC tumors', 'Disease', 'MESH:D001523', (168, 189))	('ESR1', 'Gene', '2099', (73, 77))	('aggressive ILC tumors', 'Disease', (168, 189))
37326	31229512	In that study, the alterations were significantly enriched in ILC versus IDC, suggesting a unique role for amplified ESR1 in modulating response to estradiol and endocrine therapy in tumors lacking functional E-cadherin.	('ESR1', 'Gene', '2099', (117, 121))	('amplified', 'Var', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('estradiol', 'Chemical', 'MESH:D004958', (148, 157))	('cadherin', 'molecular_function', 'GO:0008014', ('211', '219'))	('modulating', 'Reg', (125, 135))	('ILC versus IDC', 'Disease', 'MESH:D006086', (62, 76))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('E-cadherin', 'Gene', (209, 219))	('response to estradiol', 'biological_process', 'GO:0032355', ('136', '157'))	('ESR1', 'Gene', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('ILC versus IDC', 'Disease', (62, 76))	('E-cadherin', 'Gene', '999', (209, 219))	('tumors', 'Disease', (183, 189))
37329	31229512	Given the growing evidence for increased rates of HER2/HER3 mutations in ILC, the finding of higher rates of ERBB2 amplification is of potential interest.	('ILC', 'Disease', (73, 76))	('HER3', 'Gene', (55, 59))	('HER2', 'Gene', (50, 54))	('ERBB2', 'Gene', '2064', (109, 114))	('HER3', 'Gene', '2065', (55, 59))	('HER2', 'Gene', '2064', (50, 54))	('ERBB2', 'Gene', (109, 114))	('mutations', 'Var', (60, 69))
37331	31229512	An example for complex structural genomic rearrangement in the absence of high level amplification are the recently reported segmental tandem duplications in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('segmental tandem duplications', 'Var', (125, 154))
37332	31229512	In addition to ESR1 and ERBB2, we also observed MDM4 amplifications in 17% of our primary ILC cases.	('primary ILC', 'Disease', (82, 93))	('ESR1', 'Gene', '2099', (15, 19))	('ERBB2', 'Gene', (24, 29))	('MDM4', 'Gene', (48, 52))	('ERBB2', 'Gene', '2064', (24, 29))	('ESR1', 'Gene', (15, 19))	('amplifications', 'Var', (53, 67))
37333	31229512	Previous studies have identified varying rates of MDM4 amplification in breast cancer, with studies using fluorescence in situ hybridization (FISH) suggesting a low frequency (<5%).	('amplification', 'Var', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('MDM4', 'Gene', (50, 54))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
37335	31229512	MDM4 amplification has previously been implicated in breast cancer metastasis from genomic evolution analyses among paired primary and metastatic tumors.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('implicated', 'Reg', (39, 49))	('MDM4', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('tumors', 'Disease', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
37336	31229512	Previously, downregulation of MDM4 mRNA using RNAi in vitro and in vivo was shown to attenuate both we TP53 and mutant TP53 breast cancer cell growth; however, little is known about the role of MDM4 specifically in ILC.	('downregulation', 'NegReg', (12, 26))	('cell growth', 'biological_process', 'GO:0016049', ('138', '149'))	('ILC', 'Disease', (215, 218))	('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))	('mutant', 'Var', (112, 118))	('RNAi', 'biological_process', 'GO:0016246', ('46', '50'))	('TP53', 'Gene', (119, 123))	('attenuate', 'NegReg', (85, 94))
37337	31229512	Conversely, in the ILC cell line Sum44PE, with truncated TP53, MDM4 knockdown led to a reproducible and significant induction of G0/G1 arrest and an increase in apoptotic cell death, further supporting the growing literature that MDM4 has TP53 independent roles.	('apoptotic cell death', 'biological_process', 'GO:0006915', ('161', '181'))	('increase', 'PosReg', (149, 157))	('arrest', 'Disease', 'MESH:D006323', (135, 141))	('MDM4', 'Gene', (63, 67))	('apoptotic cell death', 'CPA', (161, 181))	('arrest', 'Disease', (135, 141))	('truncated', 'Var', (47, 56))	('knockdown', 'Var', (68, 77))	('TP53', 'Gene', (57, 61))
37344	31229512	In conclusion, our CNA study of 70 primary ILC specimens has revealed clinically relevant gains and amplifications in ESR1, that are associated with disease recurrence, frequent ERBB2 amplifications often in the absence of clinical IHC scores, and frequent MDM4 amplifications.	('associated with', 'Reg', (133, 148))	('gains', 'PosReg', (90, 95))	('disease', 'Disease', (149, 156))	('ESR1', 'Gene', '2099', (118, 122))	('ERBB2', 'Gene', '2064', (178, 183))	('amplifications', 'Var', (100, 114))	('ERBB2', 'Gene', (178, 183))	('amplifications', 'Var', (184, 198))	('ESR1', 'Gene', (118, 122))
37346	31229512	(Amp) Amplification (CGH) chromosomal comparative genomic hybridization (CNA) copy number alteration (Del) deletion (DOX) doxycycline (E2) estradiol (ER) estrogen receptor (IDC) invasive ductal carcinoma (ILC) Invasive lobular carcinoma (KD) knock down (RFS) Recurrence free survival (TP53mut) TP53 mutant (TP53wt) TP53 wild type Comprehensive high-resolution copy number alteration study in primary Invasive Lobular Carcinoma (n=70) Frequent ESR1 CN gain (14%) or amplification (10%) associated with disease recurrence Frequent ERBB2 amplification (19%) in primary ILC Frequent MDM4 amplifications (17%) and a functional role for MDM4 in ILC.	('estrogen receptor', 'Gene', '2099', (154, 171))	('ESR1', 'Gene', (443, 447))	('DOX', 'Chemical', 'MESH:D004318', (117, 120))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (219, 236))	('Amp', 'Chemical', 'MESH:D000249', (6, 9))	('ER', 'Gene', '2099', (150, 152))	('primary Invasive Lobular Carcinoma', 'Disease', (392, 426))	('MDM4', 'Gene', (579, 583))	('(E2)', 'Chemical', 'MESH:D004958', (134, 138))	('estradiol', 'Chemical', 'MESH:D004958', (139, 148))	('ERBB2', 'Gene', (529, 534))	('primary Invasive Lobular Carcinoma', 'Disease', 'MESH:D009361', (392, 426))	('doxycycline', 'Chemical', 'MESH:D004318', (122, 133))	('amplification', 'PosReg', (535, 548))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (187, 203))	('Carcinoma', 'Phenotype', 'HP:0030731', (417, 426))	('estrogen receptor', 'Gene', (154, 171))	('ER', 'Gene', '2099', (529, 531))	('amplifications', 'Var', (584, 598))	('invasive ductal carcinoma', 'Disease', 'MESH:D009361', (178, 203))	('gain', 'PosReg', (451, 455))	('ERBB2', 'Gene', '2064', (529, 534))	('primary ILC', 'Disease', (558, 569))	('deletion', 'Var', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('Amp', 'Chemical', 'MESH:D000249', (1, 4))	('invasive ductal carcinoma', 'Disease', (178, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('Invasive lobular carcinoma', 'Disease', 'MESH:D018275', (210, 236))	('mutant', 'Var', (299, 305))	('ESR1', 'Gene', '2099', (443, 447))	('Invasive lobular carcinoma', 'Disease', (210, 236))	('disease recurrence', 'Disease', (501, 519))	('Lobular Carcinoma', 'Phenotype', 'HP:0030076', (409, 426))
37518	30228172	Here we report a comprehensive 2D and 3D phenotypic characterization of four estrogen receptor-positive human ILC cell lines: MDA-MB-134, SUM44, MDA-MB-330 and BCK4.	('estrogen receptor', 'Gene', '2099', (77, 94))	('BCK', 'molecular_function', 'GO:0047323', ('160', '163'))	('BCK', 'Gene', '1152', (160, 163))	('BCK', 'Gene', (160, 163))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (145, 155))	('MDA-MB-134', 'Var', (126, 136))	('human', 'Species', '9606', (104, 109))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (126, 136))	('ILC', 'Disease', 'MESH:D018275', (110, 113))	('estrogen receptor', 'Gene', (77, 94))	('ILC', 'Disease', (110, 113))
37531	30228172	This hallmark E-cadherin loss, found in 95% of all ILC tumors versus in only 7% of IDCs, occurs through truncating mutations and loss-of-heterozygosity.	('IDC', 'Disease', 'MESH:D044584', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('E-cadherin', 'Gene', '999', (14, 24))	('loss-of-heterozygosity', 'NegReg', (129, 151))	('IDC', 'Disease', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ILC', 'Disease', 'MESH:D018275', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (55, 60))	('truncating mutations', 'Var', (104, 124))	('loss', 'NegReg', (25, 29))	('E-cadherin', 'Gene', (14, 24))	('ILC', 'Disease', (51, 54))
37533	30228172	Multi-omics profiling of human tumors has begun to reveal candidate disease drivers such as HER2, HER3, FOXA1 and PIK3CA mutations, PTEN loss and ESR1 amplifications, events more frequently observed in ILC compared to IDC.	('PIK3CA', 'Gene', '5290', (114, 120))	('PTEN', 'Gene', (132, 136))	('mutations', 'Var', (121, 130))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('HER2', 'Gene', (92, 96))	('FOXA1', 'Gene', (104, 109))	('IDC', 'Disease', 'MESH:D044584', (218, 221))	('HER3', 'Gene', (98, 102))	('ESR1', 'Gene', '2099', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PTEN', 'Gene', '5728', (132, 136))	('amplifications', 'Var', (151, 165))	('ESR1', 'Gene', (146, 150))	('human', 'Species', '9606', (25, 30))	('loss', 'NegReg', (137, 141))	('ILC', 'Disease', 'MESH:D018275', (202, 205))	('PIK3CA', 'Gene', (114, 120))	('HER2', 'Gene', '2064', (92, 96))	('IDC', 'Disease', (218, 221))	('ILC', 'Disease', (202, 205))	('HER3', 'Gene', '2065', (98, 102))	('tumor', 'Disease', (31, 36))	('FOXA1', 'Gene', '3169', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
37541	30228172	SUM44PE (SUM44) was purchased from Asterand and BCK4 cells were developed as previously reported.	('BCK', 'Gene', '1152', (48, 51))	('SUM44PE', 'Var', (0, 7))	('BCK', 'Gene', (48, 51))	('BCK', 'molecular_function', 'GO:0047323', ('48', '51'))
37542	30228172	Cell lines were maintained in the following media (Life Technologies) with 10% FBS: MDA-MB-134 and MDA-MB-330 in 1:1 DMEM:L-15, MCF7 and MDA-MB-231 in DMEM, T47D in RPMI, BCK4 in MEM with non-essential amino acids (Life Technologies) and insulin (Sigma-Aldrich).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (137, 147))	('insulin', 'Gene', '3630', (238, 245))	('T47D', 'CellLine', 'CVCL:0553', (157, 161))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (84, 94))	('T47D', 'Var', (157, 161))	('MCF7', 'CellLine', 'CVCL:0031', (128, 132))	('BCK', 'molecular_function', 'GO:0047323', ('171', '174'))	('MDA-MB-134', 'Var', (84, 94))	('MCF7', 'Var', (128, 132))	('insulin', 'molecular_function', 'GO:0016088', ('238', '245'))	('MDA-MB-330', 'Var', (99, 109))	('BCK', 'Gene', '1152', (171, 174))	('BCK', 'Gene', (171, 174))	('MDA-MB-231', 'Var', (137, 147))	('insulin', 'Gene', (238, 245))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (99, 109))
37564	30228172	As expected, E-cadherin was absent from MDA-MB-134, SUM44, which harbor CDH1 truncating mutations, from BCK4 cells, as well as from MDA-MB-231 cells, in which the CDH1 promoter is hypermethylated (Fig.	('absent', 'NegReg', (28, 34))	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('BCK', 'Gene', '1152', (104, 107))	('BCK', 'Gene', (104, 107))	('CDH1', 'Gene', (72, 76))	('mutations', 'Var', (88, 97))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (40, 50))	('CDH1', 'Gene', (163, 167))	('BCK', 'molecular_function', 'GO:0047323', ('104', '107'))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('CDH1', 'Gene', '999', (72, 76))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (132, 142))	('CDH1', 'Gene', '999', (163, 167))
37566	30228172	Interestingly, MDA-MB-330 cells, which harbor a bi-allelic, truncating CTNNA1 mutation, still expressed E-cadherin and beta-catenin in the absence of alpha-catenin.	('beta-catenin', 'Gene', '1499', (119, 131))	('expressed', 'MPA', (94, 103))	('mutation', 'Var', (78, 86))	('CTNNA1', 'Gene', (71, 77))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (15, 25))	('beta-catenin', 'Gene', (119, 131))	('cadherin', 'molecular_function', 'GO:0008014', ('106', '114'))	('CTNNA1', 'Gene', '1495', (71, 77))	('E-cadherin', 'Gene', (104, 114))	('E-cadherin', 'Gene', '999', (104, 114))
37580	30228172	Flow cytometric analysis of stem cell markers similarly did not identify a putative CD24low/CD44high or CD49fhigh/EPCAMlow stem cell population in the ILC cell lines (Supplementary Fig.	('CD44', 'Gene', (92, 96))	('ILC', 'Disease', 'MESH:D018275', (151, 154))	('ILC', 'Disease', (151, 154))	('CD49fhigh/EPCAMlow', 'Var', (104, 122))	('CD44', 'Gene', '960', (92, 96))
37602	30228172	Interestingly, unsupervised clustering of the ILC and IDC cell lines using publicly available transcript profiling data showed that MDA-MB-134 cells clustered separately from the other ILC cell lines, displaying a unique expression pattern of genes encoding both integrins (Supplementary Fig.	('rat', 'Species', '10116', (163, 166))	('ILC', 'Disease', (46, 49))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (132, 142))	('MDA-MB-134', 'Var', (132, 142))	('IDC', 'Disease', (54, 57))	('IDC', 'Disease', 'MESH:D044584', (54, 57))	('ILC', 'Disease', (185, 188))	('ILC', 'Disease', 'MESH:D018275', (185, 188))	('ILC', 'Disease', 'MESH:D018275', (46, 49))
37624	30228172	Almost half of all human ILC tumors harbor activating, hotspot mutations in PIK3CA and 13% have PTEN loss due to inactivating mutations or deletions.	('mutations', 'Var', (63, 72))	('PTEN', 'Gene', '5728', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('loss', 'NegReg', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('inactivating mutations', 'Var', (113, 135))	('PIK3CA', 'Gene', (76, 82))	('human', 'Species', '9606', (19, 24))	('tumor', 'Disease', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('ILC', 'Disease', (25, 28))	('ILC', 'Disease', 'MESH:D018275', (25, 28))	('activating', 'PosReg', (43, 53))	('PIK3CA', 'Gene', '5290', (76, 82))	('PTEN', 'Gene', (96, 100))	('deletions', 'Var', (139, 148))
37625	30228172	These alterations are known to activate downstream Akt signaling, which can induce cell migration and invasion.	('alterations', 'Var', (6, 17))	('Akt', 'Gene', (51, 54))	('activate', 'PosReg', (31, 39))	('rat', 'Species', '10116', (91, 94))	('cell migration', 'CPA', (83, 97))	('invasion', 'CPA', (102, 110))	('induce', 'PosReg', (76, 82))	('Akt', 'Gene', '207', (51, 54))	('rat', 'Species', '10116', (10, 13))	('cell migration', 'biological_process', 'GO:0016477', ('83', '97'))	('Akt signaling', 'biological_process', 'GO:0043491', ('51', '64'))
37626	30228172	While MCF7 and T47D both harbor PIK3CA mutations, human ILC cell lines are wild type for PIK3CA and PTEN.	('PTEN', 'Gene', (100, 104))	('ILC', 'Disease', (56, 59))	('PIK3CA', 'Gene', '5290', (32, 38))	('PTEN', 'Gene', '5728', (100, 104))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('mutations', 'Var', (39, 48))	('T47D', 'CellLine', 'CVCL:0553', (15, 19))	('harbor', 'Reg', (25, 31))	('human', 'Species', '9606', (50, 55))	('MCF7', 'CellLine', 'CVCL:0031', (6, 10))	('ILC', 'Disease', 'MESH:D018275', (56, 59))	('PIK3CA', 'Gene', (32, 38))
37627	30228172	We therefore overexpressed PIK3CA mutants and knocked down PTEN in MDA-MB-134 cells to potentially augment their migration ability.	('migration ability', 'CPA', (113, 130))	('mutants', 'Var', (34, 41))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (67, 77))	('knocked', 'Var', (46, 53))	('PIK3CA', 'Gene', (27, 33))	('rat', 'Species', '10116', (116, 119))	('PIK3CA', 'Gene', '5290', (27, 33))	('PTEN', 'Gene', (59, 63))	('augment', 'PosReg', (99, 106))	('PTEN', 'Gene', '5728', (59, 63))
37628	30228172	Interestingly, compared to the respective controls, only the H1047R but not the E545K mutation activated downstream Akt signaling, along with all four PTEN shRNAs in MDA-MB-134 cells, which was different from the highly active MCF7 cells that harbor the endogenous E545K mutation (Supplementary Fig.	('Akt signaling', 'biological_process', 'GO:0043491', ('116', '129'))	('E545K', 'Mutation', 'p.E545K', (265, 270))	('MCF7', 'CellLine', 'CVCL:0031', (227, 231))	('E545K', 'Mutation', 'p.E545K', (80, 85))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (166, 176))	('activated', 'PosReg', (95, 104))	('H1047R', 'Var', (61, 67))	('Akt', 'Gene', '207', (116, 119))	('H1047R', 'Mutation', 'p.H1047R', (61, 67))	('Akt', 'Gene', (116, 119))	('PTEN', 'Gene', (151, 155))	('PTEN', 'Gene', '5728', (151, 155))
37670	30228172	Such a divergent pattern was especially evident in the ECM adhesion experiments, where MDA-MB-134 generally exhibited a less preference for interacting with matrix proteins.	('matrix proteins', 'Protein', (157, 172))	('MDA-MB-134', 'Var', (87, 97))	('ECM', 'Gene', '22915', (55, 58))	('interacting', 'Interaction', (140, 151))	('ECM', 'Gene', (55, 58))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (87, 97))
37684	30228172	p53 mutations despite only 4-8% of ILCs with altered p53, K-Ras mutation in MDA-MB-134 and HER2 amplification in MDA-MB-330 cells), which makes it challenging to assign experimental outcomes uniquely to ILC.	('p53', 'Gene', (0, 3))	('ILC', 'Disease', (35, 38))	('p53', 'Gene', '7157', (0, 3))	('mutation', 'Var', (64, 72))	('altered', 'Var', (45, 52))	('K-Ras', 'Gene', '3845', (58, 63))	('HER2', 'Gene', (91, 95))	('p53', 'Gene', (53, 56))	('K-Ras', 'Gene', (58, 63))	('p53', 'Gene', '7157', (53, 56))	('ILC', 'Disease', 'MESH:D018275', (203, 206))	('HER2', 'Gene', '2064', (91, 95))	('mutations', 'Var', (4, 13))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (76, 86))	('ILC', 'Disease', 'MESH:D018275', (35, 38))	('ILC', 'Disease', (203, 206))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (113, 123))
37691	30228172	It is commonly fused to oncogenes such as RET in thyroid cancer and the hypo-methylation of its enhancer is associated with increased breast cancer risk.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('thyroid cancer', 'Disease', (49, 63))	('RET', 'Gene', '5979', (42, 45))	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('breast cancer', 'Disease', (134, 147))	('enhancer', 'PosReg', (96, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('thyroid cancer', 'Disease', 'MESH:D013964', (49, 63))	('hypo-methylation', 'Var', (72, 88))	('associated', 'Reg', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('RET', 'Gene', (42, 45))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
37745	33520704	Hallmark features of ILC include; the loss of cell-cell adhesion molecule E-cadherin, resulting in small, discohesive cells proliferating in single-file strands, positivity for both the estrogen (ER) and progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) negativity.	('cell-cell adhesion molecule', 'molecular_function', 'GO:0098632', ('46', '73'))	('negativity', 'Reg', (285, 295))	('epidermal growth factor receptor 2', 'Gene', (242, 276))	('ER', 'Gene', '2069', (279, 281))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('positivity', 'Var', (162, 172))	('ILC', 'Disease', (21, 24))	('PR', 'Gene', '5241', (227, 229))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (74, 84))	('ER', 'Gene', '2069', (196, 198))	('discohesive cells proliferating', 'CPA', (106, 137))	('human', 'Species', '9606', (236, 241))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('242', '265'))	('progesterone receptor', 'Gene', (204, 225))	('progesterone receptor', 'Gene', '5241', (204, 225))	('HER-2', 'Gene', '2064', (278, 283))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('46', '64'))	('epidermal growth factor receptor 2', 'Gene', '2064', (242, 276))	('loss', 'NegReg', (38, 42))	('HER-2', 'Gene', (278, 283))
37763	33520704	Hereditary ILC is rare but cases have been reported to occur as a secondary tumor in patients or families with hereditary diffuse gastric cancer syndrome who harbor a germline mutation of the CDH1 gene.	('CDH1', 'Gene', '999', (192, 196))	('germline mutation', 'Var', (167, 184))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('patients', 'Species', '9606', (85, 93))	('hereditary diffuse gastric cancer syndrome', 'Disease', (111, 153))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('hereditary diffuse gastric cancer syndrome', 'Disease', 'MESH:D013274', (111, 153))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('CDH1', 'Gene', (192, 196))
37785	33520704	Biomarkers associated with poor clinical outcomes are rarely displayed in ILC; however, pleomorphic ILC is an exception to this rule, exhibiting a lack of ER and PR expression, HER2 amplification, p53 expression and higher proliferation rates.	('lack', 'NegReg', (147, 151))	('PR', 'Gene', '5241', (162, 164))	('pleomorphic ILC', 'Disease', (88, 103))	('HER2', 'Gene', (177, 181))	('ER', 'Gene', '2069', (178, 180))	('HER2', 'Gene', '2064', (177, 181))	('p53', 'Gene', (197, 200))	('p53', 'Gene', '7157', (197, 200))	('higher', 'PosReg', (216, 222))	('expression', 'MPA', (201, 211))	('amplification', 'Var', (182, 195))	('ER', 'Gene', '2069', (155, 157))
37787	33520704	E-cadherin is an essential molecule in mediating cell-cell adhesion in order to maintain cell viability; dysregulation results in the distinctive discohesive growth pattern observed in ILC.	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('49', '67'))	('discohesive growth pattern', 'CPA', (146, 172))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('growth pattern', 'biological_process', 'GO:0007150', ('158', '172'))	('results in', 'Reg', (119, 129))	('E-cadherin', 'Gene', (0, 10))	('growth pattern', 'biological_process', 'GO:0040007', ('158', '172'))	('ILC', 'Disease', (185, 188))	('E-cadherin', 'Gene', '999', (0, 10))	('dysregulation', 'Var', (105, 118))
37791	33520704	The hallmark loss of E-cadherin is driven by alterations to the CDH1 gene, located on chromosome 16q22, which codes for E-cadherin.	('alterations', 'Var', (45, 56))	('cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))	('E-cadherin', 'Gene', (120, 130))	('CDH1', 'Gene', (64, 68))	('E-cadherin', 'Gene', '999', (120, 130))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('loss', 'NegReg', (13, 17))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('cadherin', 'molecular_function', 'GO:0008014', ('122', '130'))	('CDH1', 'Gene', '999', (64, 68))
37792	33520704	Despite the strong association between CDH1 mutation or deletion and the hallmark loss of E-cadherin in ILC, mechanisms underlying this alteration are not well studied.	('et', 'Gene', '79157', (59, 61))	('mutation', 'Var', (44, 52))	('E-cadherin', 'Gene', '999', (90, 100))	('et', 'Gene', '79157', (32, 34))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))	('loss', 'NegReg', (82, 86))	('CDH1', 'Gene', (39, 43))	('CDH1', 'Gene', '999', (39, 43))	('E-cadherin', 'Gene', (90, 100))	('ILC', 'Disease', (104, 107))
37793	33520704	The most likely explanation for the inactivation of CDH1 follows the "two-hit hypothesis" model where a first-event somatic mutation is followed by loss of heterozygosity or gene methylation.	('CDH1', 'Gene', (52, 56))	('et', 'Gene', '79157', (180, 182))	('CDH1', 'Gene', '999', (52, 56))	('mutation', 'Var', (124, 132))	('inactivation', 'Var', (36, 48))	('et', 'Gene', '79157', (157, 159))
37794	33520704	Mutations in CDH1 have been identified in other epithelial cancers, most notably in diffuse gastric cancer, which shares similar features with ILC.	('identified', 'Reg', (28, 38))	('CDH1', 'Gene', '999', (13, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('epithelial cancers', 'Disease', 'MESH:D009369', (48, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('ILC', 'Disease', (143, 146))	('CDH1', 'Gene', (13, 17))	('epithelial cancers', 'Disease', (48, 66))
37797	33520704	Overall, this suggests CDH1 inactivation is a key event in the pathogenesis of ILC.	('pathogenesis', 'biological_process', 'GO:0009405', ('63', '75'))	('inactivation', 'Var', (28, 40))	('CDH1', 'Gene', (23, 27))	('CDH1', 'Gene', '999', (23, 27))	('ILC', 'Disease', (79, 82))
37799	33520704	The Cancer Genome Atlas (TCGA) study has also identified a number of ILC-enriched mutations including FOXA1, RUNX1, and TBX3.	('TBX3', 'Gene', '6926', (120, 124))	('FOXA1', 'Gene', '3169', (102, 107))	('TBX3', 'Gene', (120, 124))	('mutations', 'Var', (82, 91))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('RUNX1', 'Gene', (109, 114))	('RUNX1', 'Gene', '861', (109, 114))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('ILC-enriched', 'Gene', (69, 81))	('FOXA1', 'Gene', (102, 107))
37800	33520704	FOXA1 expression is high in BC and mutations are present in approximately 7% of all ILC cases.	('FOXA1', 'Gene', (0, 5))	('ILC', 'Disease', (84, 87))	('expression', 'MPA', (6, 16))	('FOXA1', 'Gene', '3169', (0, 5))	('high', 'Reg', (20, 24))	('mutations', 'Var', (35, 44))
37801	33520704	FOXA1 is as a key transcription modulator of ER activity, therefore mutations can affect ER function as the loss of ER-binding blocks ER-mediated gene expression, altering the response of endocrine targeted therapies such as Tamoxifen.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('response', 'MPA', (176, 184))	('FOXA1', 'Gene', (0, 5))	('Tamoxifen', 'Chemical', 'MESH:D013629', (225, 234))	('loss', 'Var', (108, 112))	('ER', 'Gene', '2069', (134, 136))	('gene expression', 'biological_process', 'GO:0010467', ('146', '161'))	('ER', 'Gene', '2069', (116, 118))	('FOXA1', 'Gene', '3169', (0, 5))	('ER', 'Gene', '2069', (89, 91))	('blocks', 'NegReg', (127, 133))	('altering', 'Reg', (163, 171))	('ER', 'Gene', '2069', (45, 47))	('transcription', 'biological_process', 'GO:0006351', ('18', '31'))	('mutations', 'Var', (68, 77))	('affect', 'Reg', (82, 88))	('et', 'Gene', '79157', (202, 204))
37802	33520704	In a study conducted by Desmedt et al., aimed to characterize the genome of 630 ILC tumors, CDH1 mutations occurred in 65% of tumors.	('mutations', 'Var', (97, 106))	('occurred', 'Reg', (107, 115))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CDH1', 'Gene', (92, 96))	('et', 'Gene', '79157', (32, 34))	('ILC tumors', 'Disease', 'MESH:D009369', (80, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('CDH1', 'Gene', '999', (92, 96))	('ILC tumors', 'Disease', (80, 90))
37803	33520704	However, the phosphatidylinositol 3-kinase (PI3K) pathway showed three key genes with alterations: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN) and AKT1 mutations were present in 50% of cases.	('alterations', 'Reg', (86, 97))	('phosphatase', 'molecular_function', 'GO:0016791', ('180', '191'))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))	('PIK3CA', 'Gene', (171, 177))	('AKT1', 'Gene', (222, 226))	('PIK3CA', 'Gene', '5290', (171, 177))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (13, 42))	('phosphatidylinositol 3-kinase', 'Gene', (13, 42))	('phosphatase and tensin homolog', 'Gene', '5728', (180, 210))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (99, 169))	('PTEN', 'Gene', (212, 216))	('PTEN', 'Gene', '5728', (212, 216))	('AKT1', 'Gene', '207', (222, 226))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('180', '210'))	('mutations', 'Var', (227, 236))
37804	33520704	PIK3CA mutations were associated with low proliferation rates, as defined by Ki-67 and AKT1 tumors were related to a short-term risk of relapse.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('AKT1', 'Gene', '207', (87, 91))	('AKT1', 'Gene', (87, 91))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('mutations', 'Var', (7, 16))
37805	33520704	While loss or inactivation of PTEN can result in a more aggressive phenotype ( Figure 4 ).	('loss', 'NegReg', (6, 10))	('aggressive phenotype', 'MPA', (56, 76))	('result in', 'Reg', (39, 48))	('inactivation', 'Var', (14, 26))	('PTEN', 'Gene', (30, 34))	('PTEN', 'Gene', '5728', (30, 34))
37806	33520704	ILC is overwhelmingly characterized by HER2 negativity, displaying a low rate of ERBB2 amplification.	('ERBB2', 'Gene', (81, 86))	('negativity', 'Var', (44, 54))	('ERBB2', 'Gene', '2064', (81, 86))	('HER2', 'Gene', (39, 43))	('HER2', 'Gene', '2064', (39, 43))	('ILC', 'Disease', (0, 3))
37807	33520704	However, ERBB2 mutations or amplifications have been found in up to 8% of ILCs.	('found', 'Reg', (53, 58))	('amplifications', 'Var', (28, 42))	('mutations', 'Var', (15, 24))	('ILCs', 'Disease', (74, 78))	('ERBB2', 'Gene', (9, 14))	('ERBB2', 'Gene', '2064', (9, 14))
37808	33520704	These mutations are most associated with pleomorphic and solid histology and this is thought to account for the aggressive tumor phenotype.	('associated', 'Reg', (25, 35))	('aggressive tumor', 'Disease', (112, 128))	('aggressive tumor', 'Disease', 'MESH:D001523', (112, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mutations', 'Var', (6, 15))
37861	33520704	assessed the impact of MRI on re-excision rates in ILC and concluded that patients who had an MRI prior to surgery had significantly lower rates of re-excision (9%) than those who did not undergo an MRI (27%).	('re-excision', 'MPA', (148, 159))	('MRI', 'Var', (94, 97))	('lower', 'NegReg', (133, 138))	('patients', 'Species', '9606', (74, 82))
37863	33520704	Overall, MRI is particularly advantageous over standard imaging methods due to its increased sensitivity in detecting ILC tumors and improving the detection of ipsilateral and contralateral tumors ( Figure 5 ).	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('ILC tumors', 'Disease', (118, 128))	('et', 'Gene', '79157', (65, 67))	('increased', 'PosReg', (83, 92))	('improving', 'PosReg', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('contralateral tumors', 'Disease', (176, 196))	('et', 'Gene', '79157', (148, 150))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('et', 'Gene', '79157', (109, 111))	('contralateral tumors', 'Disease', 'MESH:C535634', (176, 196))	('ILC tumors', 'Disease', 'MESH:D009369', (118, 128))	('MRI', 'Var', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
37921	33520704	Tumors acquiring mutations in ESR1, ERBB2 and FGFR1 have been found to exhibit a poorer response to targeted ET.	('ESR1', 'Gene', (30, 34))	('ERBB2', 'Gene', (36, 41))	('ERBB2', 'Gene', '2064', (36, 41))	('ET', 'Gene', '79157', (109, 111))	('et', 'Gene', '79157', (104, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ESR1', 'Gene', '2099', (30, 34))	('FGFR1', 'Gene', (46, 51))	('mutations', 'Var', (17, 26))	('FGFR1', 'Gene', '2260', (46, 51))
37949	33520704	Crizotinib targets alterations in the CDH1 gene that cause E-cadherin deficiency and inhibits tyrosine kinase ROS1, which is vital for cell viability, while fulvestrant blocks the ER signaling pathway on BC cells.	('cause', 'Reg', (53, 58))	('CDH1', 'Gene', (38, 42))	('inhibits', 'NegReg', (85, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('61', '69'))	('CDH1', 'Gene', '999', (38, 42))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('ROS1', 'Gene', (110, 114))	('alterations', 'Var', (19, 30))	('ROS1', 'Gene', '6098', (110, 114))	('et', 'Gene', '79157', (15, 17))	('deficiency', 'NegReg', (70, 80))	('E-cadherin', 'Gene', '999', (59, 69))	('E-cadherin', 'Gene', (59, 69))	('blocks', 'NegReg', (169, 175))	('signaling pathway', 'biological_process', 'GO:0007165', ('183', '200'))	('ER', 'Gene', '2069', (180, 182))
37950	33520704	Crizotinib is already licensed in the treatment of non-small cell lung cancer and, if found to be effective in the treatment of ILC, may result in further trials investigating the inhibition of ROS1 as a novel therapeutic strategy for ILC.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (55, 77))	('ILC', 'Disease', (128, 131))	('ROS1', 'Gene', '6098', (194, 198))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('lung cancer', 'Disease', (66, 77))	('ILC', 'Disease', (235, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (51, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('inhibition', 'Var', (180, 190))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('ROS1', 'Gene', (194, 198))
37952	33520704	Amplifications of FGFR1 are the most common reported alterations occurring in around 14% of BCs.	('FGFR1', 'Gene', (18, 23))	('BCs', 'Phenotype', 'HP:0003002', (92, 95))	('Amplifications', 'Var', (0, 14))	('BCs', 'Disease', (92, 95))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('FGFR1', 'Gene', '2260', (18, 23))
37954	33520704	Comparative genomic hybridization identified amplifications of 8p12-p11.2 driven by FGFR1.	('FGFR1', 'Gene', (84, 89))	('p11', 'Gene', (68, 71))	('FGFR1', 'Gene', '2260', (84, 89))	('p11', 'Gene', '8909', (68, 71))	('amplifications', 'Var', (45, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))
37956	33520704	Overall, these data suggest that FGFR1 inhibitors may prove useful as a therapeutic in ILC.	('inhibitors', 'Var', (39, 49))	('ILC', 'Disease', (87, 90))	('FGFR1', 'Gene', '2260', (33, 38))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('FGFR1', 'Gene', (33, 38))
37971	33520704	ILC represents a biologically distinct subset of BC, characterized by hallmark molecular features such as loss of E-cadherin expression, ER positivity, and HER2 negativity.	('E-cadherin', 'Gene', (114, 124))	('HER2', 'Gene', (156, 160))	('E-cadherin', 'Gene', '999', (114, 124))	('HER2', 'Gene', '2064', (156, 160))	('ER', 'Gene', '2069', (137, 139))	('expression', 'MPA', (125, 135))	('ER', 'Gene', '2069', (157, 159))	('et', 'Gene', '79157', (43, 45))	('negativity', 'Var', (161, 171))	('ILC', 'Disease', (0, 3))	('cadherin', 'molecular_function', 'GO:0008014', ('116', '124'))	('loss', 'NegReg', (106, 110))
37979	33520704	It is evident that mutations within the CDH1 gene are common factors in the pathogenesis of ILC alongside mutations within the PI3K pathway.	('CDH1', 'Gene', (40, 44))	('mutations', 'Var', (19, 28))	('ILC', 'Disease', (92, 95))	('PI3K', 'molecular_function', 'GO:0016303', ('127', '131'))	('common factors', 'Reg', (54, 68))	('pathogenesis', 'biological_process', 'GO:0009405', ('76', '88'))	('CDH1', 'Gene', '999', (40, 44))
37984	30641862	High Frequency of ERBB2 Activating Mutations in Invasive Lobular Breast Carcinoma with Pleomorphic Features Background: Characterisation of molecular alterations of pleomorphic lobular carcinoma (PLC), an aggressive subtype of invasive lobular carcinoma (ILC), have not been yet completely accomplished.	('invasive lobular carcinoma', 'Disease', (227, 253))	('Activating', 'PosReg', (24, 34))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (177, 194))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (227, 253))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (236, 253))	('pleomorphic lobular carcinoma', 'Disease', 'MESH:D018275', (165, 194))	('ERBB2', 'Gene', '2064', (18, 23))	('Carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('Lobular Breast Carcinoma', 'Disease', 'MESH:D018275', (57, 81))	('pleomorphic lobular carcinoma', 'Disease', (165, 194))	('Lobular Breast Carcinoma', 'Disease', (57, 81))	('ERBB2', 'Gene', (18, 23))	('Breast Carcinoma', 'Phenotype', 'HP:0003002', (65, 81))	('PLC', 'cellular_component', 'GO:0042824', ('196', '199'))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('Mutations', 'Var', (35, 44))
37989	30641862	ERBB2 mutations preferentially affected the tyrosine-kinase activity domain, being the most frequent the targetable mutation p.L755S (57%).	('kinase activity', 'molecular_function', 'GO:0016301', ('53', '68'))	('ERBB2', 'Gene', '2064', (0, 5))	('tyrosine-kinase activity domain', 'MPA', (44, 75))	('ERBB2', 'Gene', (0, 5))	('affected', 'Reg', (31, 39))	('p.L755S', 'Mutation', 'rs121913470', (125, 132))	('p.L755S', 'Var', (125, 132))	('mutations', 'Var', (6, 15))
37990	30641862	We also observed higher frequency of mutations in ARID1B, KMT2C, MAP3K1, TP53 and ARID1A in PLC than previously reported in classic ILC.	('MAP3K1', 'Gene', '4214', (65, 71))	('TP53', 'Gene', '7157', (73, 77))	('ARID1B', 'Gene', '57492', (50, 56))	('ARID1A', 'Gene', '8289', (82, 88))	('MAP3K', 'molecular_function', 'GO:0004709', ('65', '70'))	('ARID1A', 'Gene', (82, 88))	('TP53', 'Gene', (73, 77))	('PLC', 'cellular_component', 'GO:0042824', ('92', '95'))	('ARID1B', 'Gene', (50, 56))	('mutations', 'Var', (37, 46))	('KMT2C', 'Gene', '58508', (58, 63))	('KMT2C', 'Gene', (58, 63))	('MAP3K1', 'Gene', (65, 71))
37991	30641862	Alterations related to progression from in situ to invasive carcinoma and/or to lymph node metastases included TP53 mutation, amplification of PIK3CA and CCND1 and loss of ARID1A expression.	('CCND1', 'Gene', '595', (154, 159))	('expression', 'MPA', (179, 189))	('ARID1A', 'Gene', '8289', (172, 178))	('TP53', 'Gene', '7157', (111, 115))	('mutation', 'Var', (116, 124))	('ARID1A', 'Gene', (172, 178))	('PIK3CA', 'Gene', (143, 149))	('metastases', 'Disease', (91, 101))	('invasive carcinoma', 'Disease', (51, 69))	('CCND1', 'Gene', (154, 159))	('TP53', 'Gene', (111, 115))	('amplification', 'Var', (126, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('PIK3CA', 'Gene', '5290', (143, 149))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('invasive carcinoma', 'Disease', 'MESH:D009361', (51, 69))	('loss', 'NegReg', (164, 168))
37992	30641862	Conclusions: The high frequency of ERBB2 mutations observed suggests that ERBB2 mutation testing should be considered in all invasive lobular carcinomas with nuclear grade 3.	('mutations', 'Var', (41, 50))	('invasive lobular carcinomas', 'Disease', 'MESH:D018275', (125, 152))	('ERBB2', 'Gene', '2064', (74, 79))	('ERBB2', 'Gene', (74, 79))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (134, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (134, 152))	('ERBB2', 'Gene', (35, 40))	('ERBB2', 'Gene', '2064', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('invasive lobular carcinomas', 'Disease', (125, 152))
37998	30641862	Deleterious mutations in CDH1 are usually accompanied by the loss of 16q, where the gene is located.	('accompanied', 'Reg', (42, 53))	('16q', 'MPA', (69, 72))	('mutations', 'Var', (12, 21))	('CDH1', 'Gene', '999', (25, 29))	('loss', 'NegReg', (61, 65))	('CDH1', 'Gene', (25, 29))
38000	30641862	In addition, the loss of E-cadherin expression is also observed in LCIS, so CDH1 mutations/alterations are expected to be early events in this subtype.	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))	('CDH1', 'Gene', (76, 80))	('mutations/alterations', 'Var', (81, 102))	('CDH1', 'Gene', '999', (76, 80))	('E-cadherin', 'Gene', '999', (25, 35))	('E-cadherin', 'Gene', (25, 35))	('loss', 'NegReg', (17, 21))	('LCIS', 'Disease', (67, 71))	('expression', 'MPA', (36, 46))
38001	30641862	These studies have demonstrated that there are molecular differences between ILC and IDC and that the PI3K pathway is the most frequently altered due to mutations in PIK3CA, PTEN or AKT1.	('PTEN', 'Gene', '5728', (174, 178))	('IDC', 'Gene', '4000', (85, 88))	('AKT1', 'Gene', '207', (182, 186))	('PIK3CA', 'Gene', '5290', (166, 172))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('mutations', 'Var', (153, 162))	('altered', 'Reg', (138, 145))	('IDC', 'Gene', (85, 88))	('ILC', 'Disease', (77, 80))	('AKT1', 'Gene', (182, 186))	('PI3K pathway', 'Pathway', (102, 114))	('PIK3CA', 'Gene', (166, 172))	('PTEN', 'Gene', (174, 178))
38002	30641862	These analyses have confirmed the loss of E-cadherin expression and 16q loss of heterocigosity (LOH) in PLC.	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('loss of', 'NegReg', (72, 79))	('PLC', 'cellular_component', 'GO:0042824', ('104', '107'))	('16q', 'Var', (68, 71))	('E-cadherin', 'Gene', (42, 52))	('E-cadherin', 'Gene', '999', (42, 52))	('expression', 'MPA', (53, 63))	('loss', 'NegReg', (34, 38))
38003	30641862	Additionally, PLC carries molecular alterations typical of high-grade IDC, such as HER2 and TP53 alterations, more frequently than classic ILC.	('alterations', 'Var', (97, 108))	('PLC', 'cellular_component', 'GO:0042824', ('14', '17'))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('HER2', 'Gene', (83, 87))	('IDC', 'Gene', (70, 73))	('HER2', 'Gene', '2064', (83, 87))	('IDC', 'Gene', '4000', (70, 73))
38024	30641862	Although two different polymorphisms (rs3743674 and rs1801552) were constitutively identified in our tumour set, they failed to estimate the LOH status in the region, due to the allele frequencies in the population and the apparently linked status of their alleles.	('rs3743674', 'Mutation', 'rs3743674', (38, 47))	('rs1801552', 'Mutation', 'rs1801552', (52, 61))	('rs3743674', 'Var', (38, 47))	('tumour', 'Disease', (101, 107))	('rs1801552', 'Var', (52, 61))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
38038	30641862	As expected, most samples (24 out of 27, 88.89%) had mutations in CDH1 (see Table 2), the most frequently mutated gene in this series.	('CDH1', 'Gene', (66, 70))	('CDH1', 'Gene', '999', (66, 70))	('mutations', 'Var', (53, 62))
38039	30641862	The distribution of mutations across CDH1 is shown in Figure 3A.	('CDH1', 'Gene', (37, 41))	('mutations', 'Var', (20, 29))	('CDH1', 'Gene', '999', (37, 41))
38041	30641862	According to the wTi we calculated for 24 cases in which the percentage of tumour cells could be estimated (see Supplementary Table S4), we considered that up to 18 out of 21 (85%) cases with mutations in CDH1 could probably also carry LOH in the region.	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('CDH1', 'Gene', (205, 209))	('tumour', 'Disease', (75, 81))	('CDH1', 'Gene', '999', (205, 209))	('mutations', 'Var', (192, 201))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
38045	30641862	Most mutations in PIK3CA were found in hotspot positions: p.H1047R (58%), located in the phosphoinositide-3-kinase domain; and p.E545K (17%) and p.E542K (8.5%), both located in the protein kinase-C homology domain.	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('p.E545K', 'Var', (127, 134))	('p.E542K', 'Var', (145, 152))	('p.E545K', 'Mutation', 'rs104886003', (127, 134))	('p.H1047R', 'Var', (58, 66))	('PIK3CA', 'Gene', (18, 24))	('p.E542K', 'Mutation', 'rs121913273', (145, 152))	('p.H1047R', 'Mutation', 'rs121913279', (58, 66))	('PIK3CA', 'Gene', '5290', (18, 24))
38047	30641862	Similarly, we found a predominant hotspot mutation in ERBB2 (p.L755S, 57%) and other 2 mutations (p.E717K and p.L869R) also affecting the tyrosine-kinase activity domain.	('ERBB2', 'Gene', '2064', (54, 59))	('p.E717K', 'Var', (98, 105))	('tyrosine-kinase activity domain', 'MPA', (138, 169))	('p.L755S', 'Var', (61, 68))	('ERBB2', 'Gene', (54, 59))	('p.L869R', 'Var', (110, 117))	('p.L869R', 'Mutation', 'rs1131692237', (110, 117))	('p.E717K', 'Mutation', 'p.E717K', (98, 105))	('affecting', 'Reg', (124, 133))	('kinase activity', 'molecular_function', 'GO:0016301', ('147', '162'))	('p.L755S', 'Mutation', 'rs121913470', (61, 68))
38049	30641862	Mutations in other genes involved in the PI3K/AKT pathway included mutations in MAP3K1 (present in 5 cases, 19%) and AKT1 (present in 2 cases, 8%).	('AKT', 'Gene', '207', (117, 120))	('AKT', 'Gene', '207', (46, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('AKT1', 'Gene', '207', (117, 121))	('AKT', 'Gene', (117, 120))	('mutations', 'Var', (67, 76))	('AKT', 'Gene', (46, 49))	('AKT1', 'Gene', (117, 121))	('MAP3K1', 'Gene', (80, 86))	('MAP3K', 'molecular_function', 'GO:0004709', ('80', '85'))	('MAP3K1', 'Gene', '4214', (80, 86))
38050	30641862	Mutations in PIK3CA, ERBB2 and AKT1 (present in a total of 16 cases) tend to be mutually exclusive (only cases PLC9 and PLC19 carried mutations in both PIK3CA and ERBB2).	('PIK3CA', 'Gene', '5290', (152, 158))	('PIK3CA', 'Gene', (13, 19))	('AKT1', 'Gene', '207', (31, 35))	('PLC', 'cellular_component', 'GO:0042824', ('111', '114'))	('ERBB2', 'Gene', '2064', (21, 26))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', '5290', (13, 19))	('AKT1', 'Gene', (31, 35))	('ERBB2', 'Gene', (21, 26))	('mutations', 'Var', (134, 143))	('PIK3CA', 'Gene', (152, 158))	('PLC', 'cellular_component', 'GO:0042824', ('120', '123'))	('ERBB2', 'Gene', (163, 168))	('carried', 'Reg', (126, 133))	('ERBB2', 'Gene', '2064', (163, 168))
38051	30641862	In contrast, all MAP3K1 mutations occurred in cases with mutations in PIK3CA or ERBB2.	('MAP3K', 'molecular_function', 'GO:0004709', ('17', '22'))	('MAP3K1', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (70, 76))	('ERBB2', 'Gene', '2064', (80, 85))	('PIK3CA', 'Gene', (70, 76))	('mutations', 'Var', (57, 66))	('MAP3K1', 'Gene', '4214', (17, 23))	('mutations', 'Var', (24, 33))	('occurred', 'Reg', (34, 42))	('ERBB2', 'Gene', (80, 85))
38052	30641862	Mutations in TP53 occurred in 5 cases (18.52%).	('TP53', 'Gene', '7157', (13, 17))	('Mutations', 'Var', (0, 9))	('occurred', 'Reg', (18, 26))	('TP53', 'Gene', (13, 17))
38053	30641862	Interestingly, whereas 2 cases had mutations producing truncated proteins (c.550_551delGA and p.R342*), the remaining 3 cases displayed missense mutations (p.R175H, p.Y220C and p.E286K) affecting the DNA binding domain.	('p.Y220C', 'Var', (165, 172))	('p.R175H', 'Var', (156, 163))	('p.R342*', 'Var', (94, 101))	('c.550_551delGA', 'Var', (75, 89))	('p.R342*', 'Mutation', 'p.R342*', (94, 101))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('p.E286K', 'Var', (177, 184))	('p.R175H', 'Mutation', 'rs28934578', (156, 163))	('c.550_551delGA', 'Mutation', 'c.550_551delGA', (75, 89))	('DNA binding', 'molecular_function', 'GO:0003677', ('200', '211'))	('p.E286K', 'Mutation', 'rs786201059', (177, 184))	('p.Y220C', 'Mutation', 'rs121912666', (165, 172))
38054	30641862	Mutations in the chromatin remodelling genes ARID1B and ARID1A were found in 6 (22%) and 4 (15%) tumours, respectively.	('ARID1B', 'Gene', (45, 51))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('17', '38'))	('tumours', 'Disease', (97, 104))	('chromatin', 'cellular_component', 'GO:0000785', ('17', '26'))	('ARID1A', 'Gene', '8289', (56, 62))	('found', 'Reg', (68, 73))	('Mutations', 'Var', (0, 9))	('ARID1A', 'Gene', (56, 62))	('ARID1B', 'Gene', '57492', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
38055	30641862	Mutations in the gene encoding the histone H3 lysine 4 methyltransferase KMT2C were found in 5 cases (19%).	('found', 'Reg', (84, 89))	('Mutations', 'Var', (0, 9))	('KMT2C', 'Gene', '58508', (73, 78))	('KMT2C', 'Gene', (73, 78))
38057	30641862	The extreme overrepresentation of BRCA2 variants and ERRB2 variant rs141116145 (p.A356D) is noteworthy, since two different cases present the variant allele while the expected number of carriers in our set was 0.05 according to Hardy-Weinberg equilibrium (see Supplementary Table S5).	('overrepresentation', 'PosReg', (12, 30))	('variant rs141116145', 'Var', (59, 78))	('variant', 'Var', (142, 149))	('BRCA2', 'Gene', '675', (34, 39))	('p.A356D', 'Mutation', 'rs141116145', (80, 87))	('ERRB2', 'Gene', (53, 58))	('rs141116145', 'Mutation', 'rs141116145', (67, 78))	('rs141116145', 'Var', (67, 78))	('BRCA2', 'Gene', (34, 39))	('variants', 'Var', (40, 48))
38058	30641862	Interestingly, PLC13 carried the pathogenic mutation c.3860delA in BRCA2 (confirmed as a germline mutation) and had a family record in which her mother had an ovary carcinoma and her daughter debuted with breast carcinoma at the age of 30.	('breast carcinoma', 'Phenotype', 'HP:0003002', (205, 221))	('c.3860delA', 'Var', (53, 63))	('c.3860delA', 'Mutation', 'rs80359406', (53, 63))	('pathogenic', 'Reg', (33, 43))	('BRCA2', 'Gene', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('PLC', 'cellular_component', 'GO:0042824', ('15', '18'))	('ovary carcinoma', 'Disease', 'MESH:D010051', (159, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('breast carcinoma', 'Disease', 'MESH:D001943', (205, 221))	('breast carcinoma', 'Disease', (205, 221))	('BRCA2', 'Gene', '675', (67, 72))	('ovary carcinoma', 'Disease', (159, 174))	('ovary carcinoma', 'Phenotype', 'HP:0025318', (159, 174))
38061	30641862	In 3 out of the 4 cases we identified mutations in CDH1 that affected canonical splicing sites (c.531+1G > C, c.687+1G > T and c.2164+1G > C), according to in-silico assays (data not shown).	('CDH1', 'Gene', (51, 55))	('c.531+1G > C', 'Var', (96, 108))	('affected', 'Reg', (61, 69))	('CDH1', 'Gene', '999', (51, 55))	('c.2164+1G > C', 'Var', (127, 140))	('c.2164+1G > C', 'Mutation', 'c.2164+1G>C', (127, 140))	('c.687+1G > T', 'Mutation', 'c.687+1G>T', (110, 122))	('canonical splicing sites', 'MPA', (70, 94))	('splicing', 'biological_process', 'GO:0045292', ('80', '88'))	('c.687+1G > T', 'Var', (110, 122))	('c.531+1G > C', 'Mutation', 'c.531+1G>C', (96, 108))
38063	30641862	On the other hand, we found other three cases (PLC10, PLC16 and PLC27) portraying mutations that affected canonical splicing sites (c.1565+1G > A, c.163+2T > G and c.1936+1G > C), which presented negative expression of E-cadherin.	('c.1936+1G > C', 'Var', (164, 177))	('c.1565+1G > A', 'Var', (132, 145))	('c.1936+1G > C', 'Mutation', 'c.1936+1G>C', (164, 177))	('PLC', 'cellular_component', 'GO:0042824', ('47', '50'))	('cadherin', 'molecular_function', 'GO:0008014', ('221', '229'))	('c.1565+1G > A', 'Mutation', 'rs587780113', (132, 145))	('PLC', 'cellular_component', 'GO:0042824', ('64', '67'))	('E-cadherin', 'Gene', (219, 229))	('E-cadherin', 'Gene', '999', (219, 229))	('c.163+2T > G', 'Mutation', 'c.163+2T>G', (147, 159))	('c.163+2T > G', 'Var', (147, 159))	('splicing', 'biological_process', 'GO:0045292', ('116', '124'))	('PLC', 'cellular_component', 'GO:0042824', ('54', '57'))
38064	30641862	In spite of a high frequency of ARID1B and ARID1A mutations in this series, only one tumour showed absence of expression of ARID1A.	('ARID1B', 'Gene', '57492', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('mutations', 'Var', (50, 59))	('tumour', 'Disease', (85, 91))	('ARID1A', 'Gene', '8289', (124, 130))	('ARID1B', 'Gene', (32, 38))	('ARID1A', 'Gene', (124, 130))	('ARID1A', 'Gene', '8289', (43, 49))	('ARID1A', 'Gene', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
38065	30641862	Similarly to CDH1, LOH status of the ARID1A region was estimated in the four cases presenting mutations in this gene and we concluded that LOH could probably occur in only two cases (see Supplementary Table S4).	('CDH1', 'Gene', '999', (13, 17))	('mutations', 'Var', (94, 103))	('ARID1A', 'Gene', '8289', (37, 43))	('ARID1A', 'Gene', (37, 43))	('CDH1', 'Gene', (13, 17))
38066	30641862	Interestingly, lack of ARID1A expression was confirmed only in the metastatic component of PLC24 (see Figure 4), validating the LOH status of the ARID1A region in this sample and confirming the pathogenic role of the nonsense p.S634* mutation.	('p.S634*', 'Var', (226, 233))	('pathogenic', 'Reg', (194, 204))	('ARID1A', 'Gene', '8289', (23, 29))	('ARID1A', 'Gene', (23, 29))	('p.S634*', 'Mutation', 'p.S634*', (226, 233))	('PLC', 'cellular_component', 'GO:0042824', ('91', '94'))	('ARID1A', 'Gene', '8289', (146, 152))	('ARID1A', 'Gene', (146, 152))
38067	30641862	It is important to highlight that mutations in ERBB2 and TP53 did not produced abnormal patterns of IHC features.	('ERBB2', 'Gene', (47, 52))	('ERBB2', 'Gene', '2064', (47, 52))	('IHC features', 'Disease', (100, 112))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (34, 43))
38069	30641862	Molecular similarities among components highlighted TP53 mutations and amplifications of PIK3CA and CCND1 as progression hallmarks.	('CCND1', 'Gene', (100, 105))	('amplifications', 'Var', (71, 85))	('TP53', 'Gene', '7157', (52, 56))	('PIK3CA', 'Gene', (89, 95))	('CCND1', 'Gene', '595', (100, 105))	('PIK3CA', 'Gene', '5290', (89, 95))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))
38070	30641862	It is interesting to note that we were able to detect ERBB2 mutations in the in-situ component of two cases of PLC that carried this alteration in the invasive component too.	('ERBB2', 'Gene', '2064', (54, 59))	('ERBB2', 'Gene', (54, 59))	('PLC', 'cellular_component', 'GO:0042824', ('111', '114'))	('detect', 'Reg', (47, 53))	('mutations', 'Var', (60, 69))
38076	30641862	All intrinsic subtypes of breast cancer were represented in this series, although most tumours were classified as luminal A with grade 2, probably due to our selection criteria (high nuclear grade and loss or aberrant expression of E-cadherine, independently of the mitotic rate).	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('tumours', 'Disease', (87, 94))	('loss', 'NegReg', (201, 205))	('aberrant', 'Var', (209, 217))	('E-cadherine', 'Chemical', '-', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('E-cadherine', 'Protein', (232, 243))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('expression', 'MPA', (218, 228))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('tumours', 'Disease', 'MESH:D009369', (87, 94))
38077	30641862	Thus, although CDH1 was the most frequently mutated gene in different series of ILC, the frequency of tumours carrying mutations in CDH1 was about 88% in our series whereas frequencies varied from 43% to 65% in the other studies.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('CDH1', 'Gene', (132, 136))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Disease', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('CDH1', 'Gene', '999', (132, 136))	('CDH1', 'Gene', (15, 19))	('CDH1', 'Gene', '999', (15, 19))	('mutations', 'Var', (119, 128))
38080	30641862	series had negative E-cadherin staining, the percentage of cases that carried CDH1 mutations was 59%.	('mutations', 'Var', (83, 92))	('E-cadherin', 'Gene', (20, 30))	('E-cadherin', 'Gene', '999', (20, 30))	('CDH1', 'Gene', (78, 82))	('CDH1', 'Gene', '999', (78, 82))	('cadherin', 'molecular_function', 'GO:0008014', ('22', '30'))
38082	30641862	Previous studies suggested that in these cases the loss of E-cadherin expression could be due to a combination of CDH1 LOH and promoter hypermethylation.	('cadherin', 'molecular_function', 'GO:0008014', ('61', '69'))	('LOH', 'NegReg', (119, 122))	('CDH1', 'Gene', (114, 118))	('expression', 'MPA', (70, 80))	('CDH1', 'Gene', '999', (114, 118))	('promoter hypermethylation', 'Var', (127, 152))	('loss', 'NegReg', (51, 55))	('E-cadherin', 'Gene', (59, 69))	('E-cadherin', 'Gene', '999', (59, 69))
38083	30641862	In our series, although we did not studied CDH1 promoter hypermethylation, we estimated the presence of LOH in 16q22 in 85% of the tumours, which is in agreement with previous studies.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumours', 'Disease', (131, 138))	('LOH', 'Var', (104, 107))	('16q22', 'Gene', (111, 116))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('CDH1', 'Gene', (43, 47))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('CDH1', 'Gene', '999', (43, 47))
38084	30641862	One interesting finding in our study is the observation of 4 cases (15%) with morphological characteristic of PLC, an abnormal pattern of E-cadherin expression and the presence of CDH1 mutations.	('PLC', 'Disease', (110, 113))	('presence', 'Reg', (168, 176))	('cadherin', 'molecular_function', 'GO:0008014', ('140', '148'))	('CDH1', 'Gene', (180, 184))	('CDH1', 'Gene', '999', (180, 184))	('expression', 'MPA', (149, 159))	('mutations', 'Var', (185, 194))	('PLC', 'cellular_component', 'GO:0042824', ('110', '113'))	('E-cadherin', 'Gene', (138, 148))	('E-cadherin', 'Gene', '999', (138, 148))
38086	30641862	Our study suggested that certain types of CDH1 mutations, especially splice site mutations located in specific domains, are more prone to be related to aberrant E-cadherin expression.	('CDH1', 'Gene', (42, 46))	('CDH1', 'Gene', '999', (42, 46))	('mutations', 'Var', (47, 56))	('expression', 'MPA', (172, 182))	('E-cadherin', 'Gene', (161, 171))	('E-cadherin', 'Gene', '999', (161, 171))	('cadherin', 'molecular_function', 'GO:0008014', ('163', '171'))	('related', 'Reg', (141, 148))
38087	30641862	An important finding in our study, with potential therapeutic implications, is the high frequency (26%) of ERBB2 mutations observed in PLC.	('mutations', 'Var', (113, 122))	('PLC', 'cellular_component', 'GO:0042824', ('135', '138'))	('ERBB2', 'Gene', (107, 112))	('ERBB2', 'Gene', '2064', (107, 112))
38088	30641862	Previous NGS studies reported a frequency of ERBB2 mutations in about 5% of unselected ILC.	('ERBB2', 'Gene', '2064', (45, 50))	('ERBB2', 'Gene', (45, 50))	('ILC', 'Disease', (87, 90))	('mutations', 'Var', (51, 60))
38089	30641862	reported a correlation between ERBB2 mutations and histological grade, in accordance with our results.	('mutations', 'Var', (37, 46))	('ERBB2', 'Gene', '2064', (31, 36))	('correlation', 'Reg', (11, 22))	('ERBB2', 'Gene', (31, 36))	('histological grade', 'CPA', (51, 69))
38090	30641862	observed a frequency of 20.8% of ERBB2 mutations in PLC compared to only a 2% in classic ILC.	('ERBB2', 'Gene', '2064', (33, 38))	('PLC', 'Disease', (52, 55))	('mutations', 'Var', (39, 48))	('PLC', 'cellular_component', 'GO:0042824', ('52', '55'))	('ERBB2', 'Gene', (33, 38))
38091	30641862	in their recent NGS study of 16 ILC observed that ERBB2 was mutated in 17% of the samples.	('mutated', 'Var', (60, 67))	('ERBB2', 'Gene', (50, 55))	('ERBB2', 'Gene', '2064', (50, 55))
38092	30641862	Our results confirmed the important role of ERBB2 gain-of-function mutations in high-grade invasive lobular breast carcinoma, in agreement with previous observations.	('gain-of-function', 'PosReg', (50, 66))	('breast carcinoma', 'Phenotype', 'HP:0003002', (108, 124))	('ERBB2', 'Gene', '2064', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('ERBB2', 'Gene', (44, 49))	('mutations', 'Var', (67, 76))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (91, 124))	('invasive lobular breast carcinoma', 'Disease', (91, 124))
38093	30641862	Of note, ERBB2 activating mutations are considered targetable by anti-ERBB2 drugs and other alternatives could be beneficial for these patients.	('patients', 'Species', '9606', (135, 143))	('mutations', 'Var', (26, 35))	('activating', 'PosReg', (15, 25))	('ERBB2', 'Gene', (70, 75))	('ERBB2', 'Gene', '2064', (70, 75))	('ERBB2', 'Gene', (9, 14))	('ERBB2', 'Gene', '2064', (9, 14))
38094	30641862	A comparative study of the frequency of activating mutations in ERBB2 is shown in Table 3.	('activating', 'PosReg', (40, 50))	('ERBB2', 'Gene', (64, 69))	('mutations', 'Var', (51, 60))	('ERBB2', 'Gene', '2064', (64, 69))
38095	30641862	In agreement with previous studies, we did not observe that ERBB2 mutations were associated with a higher risk of relapse.	('mutations', 'Var', (66, 75))	('ERBB2', 'Gene', (60, 65))	('relapse', 'CPA', (114, 121))	('ERBB2', 'Gene', '2064', (60, 65))
38096	30641862	Alterations in the phosphatidylinositol 3-kinase (PI3K) pathway were present in 13 cases (50%), with mutations in PIK3CA (9 cases, one of them with a combination of gene mutation and amplification), MAP3K1 (5 cases) and AKT1 (2 cases).	('PIK3CA', 'Gene', '5290', (114, 120))	('AKT1', 'Gene', '207', (220, 224))	('mutations', 'Var', (101, 110))	('MAP3K1', 'Gene', (199, 205))	('AKT1', 'Gene', (220, 224))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('MAP3K', 'molecular_function', 'GO:0004709', ('199', '204'))	('PIK3CA', 'Gene', (114, 120))	('MAP3K1', 'Gene', '4214', (199, 205))	('Alterations', 'Reg', (0, 11))
38097	30641862	As expected, mutations in PIK3CA and AKT1 were mutually exclusive but 3 MP3K1 mutations were associated with PIK3CA mutations.	('MP3K1', 'Gene', (72, 77))	('AKT1', 'Gene', (37, 41))	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', '5290', (109, 115))	('PIK3CA', 'Gene', '5290', (26, 32))	('mutations', 'Var', (78, 87))	('associated', 'Reg', (93, 103))	('mutations', 'Var', (116, 125))	('AKT1', 'Gene', '207', (37, 41))	('PIK3CA', 'Gene', (26, 32))
38098	30641862	Whereas the frequency of PIK3CA mutations in the current series is similar to those reported in other ILC NGS studies, the frequency of MAP3K1 mutations seems to be higher (19% vs. 5-6%).	('MAP3K1', 'Gene', (136, 142))	('PIK3CA', 'Gene', (25, 31))	('MAP3K1', 'Gene', '4214', (136, 142))	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', '5290', (25, 31))	('MAP3K', 'molecular_function', 'GO:0004709', ('136', '141'))	('mutations', 'Var', (143, 152))
38099	30641862	reporting that MAP3K1 mutations occurred at a higher frequency in PLC than in ILC.	('MAP3K', 'molecular_function', 'GO:0004709', ('15', '20'))	('MAP3K1', 'Gene', (15, 21))	('MAP3K1', 'Gene', '4214', (15, 21))	('PLC', 'cellular_component', 'GO:0042824', ('66', '69'))	('mutations', 'Var', (22, 31))	('PLC', 'Disease', (66, 69))
38100	30641862	Whereas a unique mutation was found in AKT1 (p.E17K), different known activating mutations were present in PIK3CA (p.E545K, p.E542K and p.H1047R).	('AKT1', 'Gene', (39, 43))	('p.E17K', 'Mutation', 'rs121434592', (45, 51))	('p.H1047R', 'Var', (136, 144))	('p.E17K', 'Var', (45, 51))	('p.E542K', 'Var', (124, 131))	('activating', 'PosReg', (70, 80))	('p.H1047R', 'Mutation', 'rs121913279', (136, 144))	('PIK3CA', 'Gene', (107, 113))	('p.E545K', 'Var', (115, 122))	('p.E542K', 'Mutation', 'rs121913273', (124, 131))	('PIK3CA', 'Gene', '5290', (107, 113))	('p.E545K', 'Mutation', 'rs104886003', (115, 122))	('AKT1', 'Gene', '207', (39, 43))
38101	30641862	Moreover, another different case (PLC-8) showed the two most frequent mutations in PIK3CA, p.E545K and p.H1047R, a phenomenon that seems to be infrequent.	('p.E545K', 'Mutation', 'rs104886003', (91, 98))	('p.H1047R', 'Mutation', 'rs121913279', (103, 111))	('p.H1047R', 'Var', (103, 111))	('PIK3CA', 'Gene', (83, 89))	('p.E545K', 'Var', (91, 98))	('PLC', 'cellular_component', 'GO:0042824', ('34', '37'))	('PIK3CA', 'Gene', '5290', (83, 89))
38102	30641862	Interestingly, the frequency of the variant alleles in the tumour were ~11% for p.E545K and ~26% for p.H1047R, denoting that the former could have been acquired at a later stage in a different chromosome in a specific clone, suggesting clonal diversity.	('p.H1047R', 'Mutation', 'rs121913279', (101, 109))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('chromosome', 'cellular_component', 'GO:0005694', ('193', '203'))	('p.E545K', 'Var', (80, 87))	('p.H1047R', 'Var', (101, 109))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('p.E545K', 'Mutation', 'rs104886003', (80, 87))	('tumour', 'Disease', (59, 65))
38105	30641862	Only one sample with an ARID1A mutation and LOH showed ARID1A loss of expression.	('loss of', 'NegReg', (62, 69))	('ARID1A', 'Gene', '8289', (24, 30))	('ARID1A', 'Gene', (24, 30))	('mutation', 'Var', (31, 39))	('expression', 'MPA', (70, 80))	('ARID1A', 'Gene', '8289', (55, 61))	('ARID1A', 'Gene', (55, 61))
38107	30641862	In the TCGA study on breast cancer, KTMC2/MLL3 was found to be mutated in the 7% of cases, with little differences amongst subtypes (5-8%).	('mutated', 'Var', (63, 70))	('MLL3', 'Gene', '58508', (42, 46))	('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))	('MLL3', 'Gene', (42, 46))
38108	30641862	However, the percentage of cases in which we identified mutation in KMT2C was almost 20%, which can contribute to the aggressiveness and dedifferentiation of PLCs due to stemness properties acquired through the loss of KMT2C activity.	('aggressiveness', 'Phenotype', 'HP:0000718', (118, 132))	('aggressiveness', 'Disease', 'MESH:D001523', (118, 132))	('KMT2C', 'Gene', '58508', (68, 73))	('KMT2C', 'Gene', (68, 73))	('dedifferentiation', 'biological_process', 'GO:0043696', ('137', '154'))	('mutation', 'Var', (56, 64))	('KMT2C', 'Gene', '58508', (219, 224))	('KMT2C', 'Gene', (219, 224))	('aggressiveness', 'Disease', (118, 132))
38109	30641862	We observed that mutations in TP53 and amplification of 11q13 region were differential features between invasive and in-situ components, highlighting the role of these genes in aggressive tumours as previously stated.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('TP53', 'Gene', (30, 34))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('11q13 region', 'Gene', (56, 68))	('amplification', 'Var', (39, 52))	('aggressive tumours', 'Disease', (177, 195))	('aggressive tumours', 'Disease', 'MESH:D001523', (177, 195))	('TP53', 'Gene', '7157', (30, 34))	('mutations', 'Var', (17, 26))
38110	30641862	Germline mutations in BRCA1 and TP53 have been reported to be predominantly associated with invasive ductal carcinomas, while BRCA2 mutations have been related to both ductal and lobular cancers.	('Germline mutations', 'Var', (0, 18))	('TP53', 'Gene', '7157', (32, 36))	('invasive ductal carcinomas', 'Disease', 'MESH:D018270', (92, 118))	('lobular cancers', 'Disease', 'MESH:D013274', (179, 194))	('BRCA2', 'Gene', (126, 131))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (101, 117))	('invasive ductal carcinomas', 'Disease', (92, 118))	('associated', 'Reg', (76, 86))	('lobular cancers', 'Disease', (179, 194))	('TP53', 'Gene', (32, 36))	('BRCA2', 'Gene', '675', (126, 131))	('related', 'Reg', (152, 159))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('mutations', 'Var', (132, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('BRCA1', 'Gene', '672', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('BRCA1', 'Gene', (22, 27))
38112	30641862	We identified one case out of 27 (~4%) portraying a deleterious germline mutation in BRCA2, with familial history of breast and ovarian cancer.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (117, 142))	('germline mutation', 'Var', (64, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('BRCA2', 'Gene', (85, 90))	('BRCA2', 'Gene', '675', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
38113	30641862	Among them, some variants that are considered of "uncertain significance" in familial breast cancer studies testing BRCA1 and BRCA2.	('BRCA1', 'Gene', (116, 121))	('variants', 'Var', (17, 25))	('familial breast cancer', 'Disease', 'MESH:D001943', (77, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('BRCA2', 'Gene', (126, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('BRCA1', 'Gene', '672', (116, 121))	('familial breast cancer', 'Disease', (77, 99))	('BRCA2', 'Gene', '675', (126, 131))
38114	30641862	Other germline variants were located in ESR1, ERBB2, PIK3CA, KMT2C and ZNF217, genes considered of great importance in the development and outcome of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('PIK3CA', 'Gene', '5290', (53, 59))	('ESR1', 'Gene', (40, 44))	('KMT2C', 'Gene', (61, 66))	('breast cancer', 'Disease', (150, 163))	('ESR1', 'Gene', '2099', (40, 44))	('PIK3CA', 'Gene', (53, 59))	('ZNF217', 'Gene', (71, 77))	('KMT2C', 'Gene', '58508', (61, 66))	('ERBB2', 'Gene', '2064', (46, 51))	('ZNF217', 'Gene', '7764', (71, 77))	('variants', 'Var', (15, 23))	('ERBB2', 'Gene', (46, 51))
38115	30641862	These infrequent germline variants could be risk factors for the development of PLC, although further studies are necessary to confirm their role in breast cancer development.	('risk factors', 'Reg', (44, 56))	('PLC', 'Disease', (80, 83))	('PLC', 'cellular_component', 'GO:0042824', ('80', '83'))	('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))	('variants', 'Var', (26, 34))
38116	30641862	In addition to a high percentage of CDH1 mutations, some of which were associated with an aberrant E-cadherin expression pattern, these tumours seem to be characterized by higher frequency of mutations in genes related to aggressive behaviour, such as ERBB2, TP53 and KMT2C.	('tumours', 'Disease', (136, 143))	('CDH1', 'Gene', '999', (36, 40))	('TP53', 'Gene', (259, 263))	('mutations', 'Var', (192, 201))	('associated', 'Reg', (71, 81))	('mutations', 'Var', (41, 50))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('CDH1', 'Gene', (36, 40))	('E-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', '999', (99, 109))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('ERBB2', 'Gene', (252, 257))	('TP53', 'Gene', '7157', (259, 263))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (222, 242))	('expression', 'MPA', (110, 120))	('KMT2C', 'Gene', '58508', (268, 273))	('KMT2C', 'Gene', (268, 273))	('ERBB2', 'Gene', '2064', (252, 257))	('behaviour', 'biological_process', 'GO:0007610', ('233', '242'))
38117	30641862	The high frequency of treatable ERBB2 mutations in this and other previous series suggest that ERBB2 mutation testing should be considered in all ILC with nuclear grade 3.	('ERBB2', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (32, 37))	('ILC', 'Disease', (146, 149))	('ERBB2', 'Gene', '2064', (95, 100))	('ERBB2', 'Gene', (95, 100))	('mutations', 'Var', (38, 47))
38204	11597316	Invasive lobular breast carcinomas, which are typically completely E-cadherin-negative, often show inactivating mutations in combination with loss of heterozygosity of the wild-type CDH1 allele.	('lobular breast carcinomas', 'Disease', 'MESH:D018275', (9, 34))	('CDH1', 'Gene', (182, 186))	('lobular breast carcinomas', 'Disease', (9, 34))	('CDH1', 'Gene', '999', (182, 186))	('cadherin', 'molecular_function', 'GO:0008014', ('69', '77'))	('breast carcinomas', 'Phenotype', 'HP:0003002', (17, 34))	('inactivating mutations', 'Var', (99, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
38205	11597316	Mutations were found at early noninvasive stages, thus associating E-cadherin mutations with loss of cell growth control and defining CDH1 as the tumor suppressor for the lobular breast cancer subtype.	('CDH1', 'Gene', '999', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('lobular breast cancer', 'Disease', (171, 192))	('E-cadherin', 'Gene', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor suppressor', 'biological_process', 'GO:0051726', ('146', '162'))	('lobular breast cancer', 'Disease', 'MESH:D013274', (171, 192))	('tumor', 'Disease', (146, 151))	('mutations', 'Var', (78, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('cadherin', 'molecular_function', 'GO:0008014', ('69', '77'))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (171, 192))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('146', '162'))	('cell growth', 'biological_process', 'GO:0016049', ('101', '112'))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('CDH1', 'Gene', (134, 138))
38228	11597316	The efforts to allelotype breast cancer showed concurrent loss of heterozygosity (LOH) at multiple chromosomal sites, with LOH at 16q being one of the most common events (52.3%) in sporadic breast cancer.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('loss', 'NegReg', (58, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('heterozygosity', 'MPA', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('LOH at 16q', 'Var', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
38231	11597316	Somatically acquired mutations in CDH1 were found in about 56% of lobular breast tumors, generally (>90%) in combination with loss of the wild-type allele, while no mutations were found in ductal primary breast carcinomas.	('lobular breast tumors', 'Disease', 'MESH:D018275', (66, 87))	('mutations', 'Var', (21, 30))	('breast tumors', 'Phenotype', 'HP:0100013', (74, 87))	('breast carcinomas', 'Phenotype', 'HP:0003002', (204, 221))	('CDH1', 'Gene', '999', (34, 38))	('found', 'Reg', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('lobular breast tumors', 'Disease', (66, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('breast carcinomas', 'Disease', 'MESH:D001943', (204, 221))	('breast carcinomas', 'Disease', (204, 221))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('CDH1', 'Gene', (34, 38))
38232	11597316	Other cancer-confined E-cadherin mutations also result in crippled proteins.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (33, 42))	('E-cadherin', 'Protein', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cadherin', 'molecular_function', 'GO:0008014', ('24', '32'))	('proteins', 'Protein', (67, 75))	('crippled', 'MPA', (58, 66))	('cancer', 'Disease', (6, 12))	('result in', 'Reg', (48, 57))
38234	11597316	The finding that loss of E-cadherin immunoreactivity and corresponding mutations are already present in early noninvasive lobular carcinoma in situ (LCIS) lesions is intriguing.	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))	('lobular carcinoma', 'Disease', (122, 139))	('mutations', 'Var', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('LCIS', 'Phenotype', 'HP:0030076', (149, 153))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (122, 147))	('loss', 'NegReg', (17, 21))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (130, 147))	('lobular carcinoma', 'Disease', 'MESH:D018275', (122, 139))	('E-cadherin', 'Protein', (25, 35))
38241	11597316	This might indicate that the lobular component in these particular breast tumors could originate from ductal carcinomas (in situ or infiltrative variants) through E-cadherin inactivation.	('inactivation', 'Var', (174, 186))	('particular breast tumors', 'Disease', 'MESH:D001943', (56, 80))	('E-cadherin', 'Protein', (163, 173))	('cadherin', 'molecular_function', 'GO:0008014', ('165', '173'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('originate', 'Reg', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ductal carcinomas', 'Disease', 'MESH:D044584', (102, 119))	('ductal carcinomas', 'Disease', (102, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('particular breast tumors', 'Disease', (56, 80))	('breast tumors', 'Phenotype', 'HP:0100013', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
38243	11597316	The nuclear forms of beta-catenin accumulate in colorectal cancers due to mutations in the Wnt signaling pathway, including truncating adenomatous polyposis coli mutation and stabilizing beta-catenin mutations.	('Wnt signaling pathway', 'Pathway', (91, 112))	('beta-catenin', 'Protein', (187, 199))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('mutations', 'Var', (200, 209))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (135, 161))	('colorectal cancers', 'Disease', 'MESH:D015179', (48, 66))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (135, 161))	('colorectal cancers', 'Disease', (48, 66))	('adenomatous polyposis coli', 'Disease', (135, 161))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('mutation', 'Var', (162, 170))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('91', '112'))	('truncating', 'Var', (124, 134))	('accumulate', 'PosReg', (34, 44))
38244	11597316	The concomitant loss of alpha-catenin expression and beta-catenin expression in ILCs with mutated CDH1 gene, however, rules out the possible activation of Wnt signaling through accumulating free cytoplasmic or nuclear beta-catenin in these particular breast cancers.	('particular breast cancers', 'Disease', (240, 265))	('CDH1', 'Gene', '999', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('mutated', 'Var', (90, 97))	('expression', 'MPA', (38, 48))	('beta-catenin', 'Protein', (53, 65))	('free cytoplasmic', 'MPA', (190, 206))	('particular breast cancers', 'Disease', 'MESH:D001943', (240, 265))	('expression', 'MPA', (66, 76))	('loss', 'NegReg', (16, 20))	('rules', 'NegReg', (118, 123))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))	('accumulating', 'PosReg', (177, 189))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('CDH1', 'Gene', (98, 102))	('alpha-catenin', 'Protein', (24, 37))	('breast cancers', 'Phenotype', 'HP:0003002', (251, 265))
38246	11597316	In conflict with mutational data from primary tumors is also the report that 20% (3/15) of breast cancer cell lines of ductal origin carry inactivating E-cadherin mutations in combination with LOH.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('primary tumors', 'Disease', (38, 52))	('inactivating', 'NegReg', (139, 151))	('mutations', 'Var', (163, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('primary tumors', 'Disease', 'MESH:D009369', (38, 52))	('E-cadherin', 'Protein', (152, 162))	('cadherin', 'molecular_function', 'GO:0008014', ('154', '162'))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
38247	11597316	The reason for this discrepancy is presently unclear: it could be a reflection of deviating histopathological diagnosis, or it may be owing to tumor heterogeneity in primary ductal carcinomas with a hardly detectable minority of cells of the ILC type with E-cadherin mutations.	('primary ductal carcinomas', 'Disease', (166, 191))	('tumor', 'Disease', (143, 148))	('mutations', 'Var', (267, 276))	('E-cadherin', 'Protein', (256, 266))	('primary ductal carcinomas', 'Disease', 'MESH:D044584', (166, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cadherin', 'molecular_function', 'GO:0008014', ('258', '266'))
38248	11597316	Moreover, the existence of ductal breast cancer cell lines with loss of functional E-cadherin may be the result of in vitro clonal selection due to growth advantage provided by inactivation of the E-cadherin gene.	('loss of functional', 'NegReg', (64, 82))	('E-cadherin', 'Gene', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ductal breast cancer', 'Disease', 'MESH:D001943', (27, 47))	('E-cadherin', 'Gene', (197, 207))	('cadherin', 'molecular_function', 'GO:0008014', ('199', '207'))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('ductal breast cancer', 'Disease', (27, 47))	('inactivation', 'Var', (177, 189))	('cadherin', 'molecular_function', 'GO:0008014', ('85', '93'))
38249	11597316	The often-occurring inactivation of the CDH1 gene in sporadic ILC of the breast as well as the high frequency of multicentric and bilateral ILC or LCIS strongly suggested E-cadherin as a good candidate tumor suppressor gene for a fraction of the hereditary breast cancers.	('cadherin', 'molecular_function', 'GO:0008014', ('173', '181'))	('LCIS', 'Phenotype', 'HP:0030076', (147, 151))	('tumor', 'Disease', (202, 207))	('inactivation', 'Var', (20, 32))	('breast cancers', 'Phenotype', 'HP:0003002', (257, 271))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('202', '218'))	('CDH1', 'Gene', (40, 44))	('hereditary breast cancers', 'Disease', (246, 271))	('hereditary breast cancers', 'Disease', 'MESH:D001943', (246, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('CDH1', 'Gene', '999', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor suppressor', 'biological_process', 'GO:0051726', ('202', '218'))	('ILC of the breast', 'Disease', (62, 79))
38250	11597316	E-cadherin germ-line mutations have been identified in a number of families with inherited predisposition to diffuse gastric carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('identified', 'Reg', (41, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('gastric carcinomas', 'Disease', (117, 135))	('E-cadherin', 'Protein', (0, 10))	('gastric carcinomas', 'Disease', 'MESH:D013274', (117, 135))	('mutations', 'Var', (21, 30))
38252	11597316	Constitutional CDH1 mutations in a single family have so far been associated with the development of metachronous diffuse gastric cancer and breast cancer of the lobular subtype.	('breast cancer of the lobular subtype', 'Disease', (141, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('breast cancer of the lobular subtype', 'Disease', 'MESH:D013274', (141, 177))	('associated with', 'Reg', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('gastric cancer', 'Disease', (122, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('CDH1', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('CDH1', 'Gene', '999', (15, 19))	('mutations', 'Var', (20, 29))
38253	11597316	The reason for the apparent predominance of gastric cancer in these families is so far unknown; it may be the consequence of a differential inactivation efficiency of the second allele by genetic or epigenetic mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('epigenetic', 'Var', (199, 209))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('inactivation', 'NegReg', (140, 152))
38254	11597316	Patients diagnosed with LCIS do consistently show LOH for 16q22.1 and loss of E-cadherin expression, and somatic mutations in the CDH1 gene of LCIS cells were indeed reported.	('CDH1', 'Gene', '999', (130, 134))	('LCIS', 'Phenotype', 'HP:0030076', (143, 147))	('expression', 'MPA', (89, 99))	('loss', 'NegReg', (70, 74))	('LCIS', 'Phenotype', 'HP:0030076', (24, 28))	('16q22.1', 'Var', (58, 65))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (113, 122))	('E-cadherin', 'Protein', (78, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('LOH', 'Var', (50, 53))	('CDH1', 'Gene', (130, 134))
38256	11597316	Hypermethylation of the CDH1 promoter and the overlapping 5' CpG island has been demonstrated to correlate with loss of E-cadherin expression at the transcriptional level for various breast cancer cell lines and primary ductal breast cancers.	('CDH1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('CDH1', 'Gene', '999', (24, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('breast cancers', 'Phenotype', 'HP:0003002', (227, 241))	('Hypermethylation', 'Var', (0, 16))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('expression', 'MPA', (131, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('loss', 'NegReg', (112, 116))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('primary ductal breast cancers', 'Disease', 'MESH:D001943', (212, 241))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('E-cadherin', 'Protein', (120, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('122', '130'))	('breast cancer', 'Disease', (183, 196))	('primary ductal breast cancers', 'Disease', (212, 241))
38257	11597316	Moreover, several infiltrative lobular cancers were recently reported to carry methylated CDH1 promoter sequences.	('lobular cancers', 'Disease', 'MESH:D013274', (31, 46))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('methylated', 'Var', (79, 89))	('CDH1', 'Gene', (90, 94))	('CDH1', 'Gene', '999', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lobular cancers', 'Disease', (31, 46))
38258	11597316	This might serve as a second gene inactivation event, in combination with either LOH or somatic CDH1 mutations, although biallelic methylation was also assumed to occur.	('CDH1', 'Gene', (96, 100))	('CDH1', 'Gene', '999', (96, 100))	('mutations', 'Var', (101, 110))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))
38261	11597316	It is not yet clear, however, whether the direct involvement of hypermethylation as a predominant mechanism in suppressing E-cadherin gene expression can be extrapolated to most breast cancers showing a methylated gene promoter.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancers', 'Disease', 'MESH:D001943', (178, 192))	('breast cancers', 'Disease', (178, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('hypermethylation', 'Var', (64, 80))	('expression', 'MPA', (139, 149))	('E-cadherin', 'Protein', (123, 133))	('gene expression', 'biological_process', 'GO:0010467', ('134', '149'))	('cadherin', 'molecular_function', 'GO:0008014', ('125', '133'))	('suppressing', 'NegReg', (111, 122))	('breast cancers', 'Phenotype', 'HP:0003002', (178, 192))
38265	11597316	It recently became apparent that integrin-linked kinase activates the Snail promoter in colorectal cancer cell lines with adenomatous polyposis coli mutations.	('activates', 'PosReg', (56, 65))	('colorectal cancer', 'Disease', (88, 105))	('adenomatous polyposis coli', 'Disease', (122, 148))	('mutations', 'Var', (149, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('Snail', 'Gene', '6615', (70, 75))	('Snail', 'Gene', (70, 75))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (122, 148))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (122, 148))
38271	11597316	Today, it is doubtless that inactivation of E-cadherin has an important role in the development of part of the sporadic breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('inactivation', 'Var', (28, 40))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (111, 134))	('sporadic breast cancers', 'Disease', (111, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cadherin', 'molecular_function', 'GO:0008014', ('46', '54'))	('E-cadherin', 'Protein', (44, 54))	('breast cancers', 'Phenotype', 'HP:0003002', (120, 134))
38272	11597316	The high incidence of complete and irreversible inactivation of E-cadherin in infiltrative lobular breast cancer evidences the role of E-cadherin as a genuine tumor suppressor in this specific histological subclass of sporadic breast cancers.	('cadherin', 'molecular_function', 'GO:0008014', ('66', '74'))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (218, 241))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancers', 'Phenotype', 'HP:0003002', (227, 241))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('E-cadherin', 'Protein', (64, 74))	('tumor suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('lobular breast cancer', 'Disease', (91, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('sporadic breast cancers', 'Disease', (218, 241))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('lobular breast cancer', 'Disease', 'MESH:D013274', (91, 112))	('cadherin', 'molecular_function', 'GO:0008014', ('137', '145'))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (91, 112))	('inactivation', 'Var', (48, 60))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))
38305	30839958	A total of ~ 780,000 pixels were averaged for the 6 class stromal model with per class distribution as benign epithelium (~36000), malignant epithelium (~130000), dense stroma (340000), loose stroma (59000), desmoplasia (26000) and others (190000).	('59000', 'Var', (200, 205))	('26000', 'Var', (221, 226))	('340000', 'Var', (177, 183))	('desmoplasia', 'Disease', (208, 219))	('~130000', 'Var', (153, 160))	('~36000', 'Var', (122, 128))	('desmoplasia', 'Disease', 'None', (208, 219))
38406	29672601	In fact, the rate of the PD-L1 positivity is very low in the overall breast cancers based on the findings in the current study, whereas CTLA-4 has a much higher rate of over-expression.	('low', 'NegReg', (50, 53))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('breast cancers', 'Phenotype', 'HP:0003002', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('positivity', 'Var', (31, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('breast cancers', 'Disease', 'MESH:D001943', (69, 83))	('breast cancers', 'Disease', (69, 83))	('PD-L1', 'Gene', (25, 30))
38418	29672601	The presence of CTLA-4 and PD-L1 (small subset) as detected by IHC have the potential to be used not only as a prognostic marker in the breast cancers, but as a potential predictive marker for the immunotherapeutic responses.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancers', 'Disease', 'MESH:D001943', (136, 150))	('breast cancers', 'Disease', (136, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('CTLA-4', 'Gene', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('breast cancers', 'Phenotype', 'HP:0003002', (136, 150))	('presence', 'Var', (4, 12))	('PD-L1', 'Gene', (27, 32))
38492	25682191	The molecular features of PLC were more closely related to ILC (gain of 1q and 16p, loss of 16q and 11q), than high grade IDC, although some of the overlap of molecular alterations that were seen in IDC were also seen in PLC (p53 and HER2 positivity, gain of 8q and 17q24-q25, loss of 13q, amplification of 8q24 [c-myc], 12q14, 17q12 [HER2] and 20q13).	('p53', 'Gene', '7157', (226, 229))	('8q24', 'Protein', (307, 311))	('PLC', 'cellular_component', 'GO:0042824', ('221', '224'))	('c-myc', 'Gene', '4609', (313, 318))	('amplification', 'Var', (290, 303))	('PLC', 'cellular_component', 'GO:0042824', ('26', '29'))	('c-myc', 'Gene', (313, 318))	('12q14', 'Var', (321, 326))	('HER2', 'Gene', (234, 238))	('HER2', 'Gene', (335, 339))	('HER2', 'Gene', '2064', (234, 238))	('loss', 'Var', (277, 281))	('p53', 'Gene', (226, 229))	('HER2', 'Gene', '2064', (335, 339))	('ILC', 'Disease', (59, 62))	('gain', 'PosReg', (251, 255))
38494	25682191	They also found amplification of c-myc and HER-2, which may be partially associated with the aggressive nature of these tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('HER-2', 'Gene', '2064', (43, 48))	('HER-2', 'Gene', (43, 48))	('associated', 'Reg', (73, 83))	('amplification', 'Var', (16, 29))	('c-myc', 'Gene', '4609', (33, 38))	('c-myc', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
38499	25682191	Based on genetic pathway studies, amplifications of c-myc and HER2 detected in PLC may partially account for their more aggressive clinical behavior and the poor outcomes reported in the literature.	('HER2', 'Gene', '2064', (62, 66))	('amplifications', 'Var', (34, 48))	('PLC', 'cellular_component', 'GO:0042824', ('79', '82'))	('c-myc', 'Gene', '4609', (52, 57))	('c-myc', 'Gene', (52, 57))	('HER2', 'Gene', (62, 66))
38524	25355547	Contrary to infiltrating ductal breast cancers (IDBCs), which account for the vast majority of all mammary carcinomas, ILBCs are associated with inactivation of the tumor suppressor gene E-cadherin.	('associated', 'Reg', (129, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('E-cadherin', 'Gene', (187, 197))	('E-cadherin', 'Gene', '999', (187, 197))	('carcinomas', 'Disease', (107, 117))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('165', '181'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('ductal breast cancers', 'Disease', (25, 46))	('tumor suppressor', 'biological_process', 'GO:0051726', ('165', '181'))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('inactivation', 'Var', (145, 157))	('tumor', 'Disease', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cadherin', 'molecular_function', 'GO:0008014', ('189', '197'))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('carcinomas', 'Disease', 'MESH:D002277', (107, 117))	('ductal breast cancers', 'Disease', 'MESH:D001943', (25, 46))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('breast cancers', 'Phenotype', 'HP:0003002', (32, 46))	('ILBCs', 'Disease', (119, 124))
38609	26558248	A biopsy showed an undifferentiated neoplasm (Figure 1), which was initially diagnosed as adenocarcinoma by immunohistochemistry positivity for cytokeratin AE1/AE3 and negativity for CD20 and CD3.	('AE3', 'Gene', '6508', (160, 163))	('undifferentiated neoplasm', 'Disease', (19, 44))	('CD20', 'Gene', '54474', (183, 187))	('undifferentiated neoplasm', 'Disease', 'MESH:D008228', (19, 44))	('CD20', 'Gene', (183, 187))	('AE1', 'Gene', '6521', (156, 159))	('neoplasm', 'Phenotype', 'HP:0002664', (36, 44))	('AE1', 'Gene', (156, 159))	('adenocarcinoma', 'Disease', (90, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('AE3', 'Gene', (160, 163))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('CD3', 'Protein', (192, 195))	('positivity', 'Var', (129, 139))
38612	26558248	The material from the upper GI endoscopy was reviewed and submitted to a new immunohistochemical panel showing positivity for cytokeratin 7 and estrogen receptors, and negativity for cytokeratin 20 and CDX-2, which was consistent with metastatic ILC.	('estrogen receptors', 'Protein', (144, 162))	('cytokeratin 20', 'Gene', (183, 197))	('cytokeratin 7', 'Gene', '3855', (126, 139))	('cytokeratin 20', 'Gene', '54474', (183, 197))	('CDX-2', 'Gene', '1045', (202, 207))	('CDX-2', 'Gene', (202, 207))	('positivity', 'Var', (111, 121))	('cytokeratin 7', 'Gene', (126, 139))
38780	32304318	Factors that increase the risk for all types of male breast cancer include older age, family history, genetic risk factors (BRCA2>BRCA1 mutations, Klinefelter syndrome), hormone status (increased circulating estrogen due to obesity, medications or disease states), and radiation exposure.	('BRCA1', 'Gene', (130, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('BRCA2', 'Gene', (124, 129))	('male breast cancer', 'Disease', 'MESH:D018567', (48, 66))	('obesity', 'Phenotype', 'HP:0001513', (224, 231))	('increased', 'PosReg', (186, 195))	('male breast cancer', 'Disease', (48, 66))	('circulating estrogen', 'MPA', (196, 216))	('BRCA2', 'Gene', '675', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (136, 145))	('obesity', 'Disease', 'MESH:D009765', (224, 231))	('BRCA1', 'Gene', '672', (130, 135))	('obesity', 'Disease', (224, 231))
38807	32085753	The objective of the current study was to elucidate the effectiveness of adjuvant chemotherapy in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1b-c/N0-1/M0 ILC.	('hormone receptor', 'Gene', '3164', (98, 114))	('epidermal growth factor receptor 2', 'Gene', '2064', (136, 170))	('HR', 'Gene', '3164', (116, 118))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('136', '159'))	('HER2', 'Gene', '2064', (172, 176))	('hormone receptor', 'Gene', (98, 114))	('ILC', 'Disease', 'MESH:D018275', (203, 206))	('pT1b-c/N0-1/M0', 'Var', (188, 202))	('HER2', 'Gene', (172, 176))	('ILC', 'Disease', (203, 206))	('epidermal growth factor receptor 2', 'Gene', (136, 170))	('human', 'Species', '9606', (130, 135))
38808	32085753	Based on Surveillance, Epidemiology, and End-Results (SEER) database, we identified original 12,334 HR-positive, HER2-negative, pT1b-c/N0-1/M0 ILC patients, who were then divided into adjuvant chemotherapy group and control group.	('ER', 'Gene', '2099', (56, 58))	('HER2', 'Gene', (113, 117))	('ER', 'Gene', '2099', (114, 116))	('HR', 'Gene', '3164', (100, 102))	('pT1b-c/N0-1/M0', 'Var', (128, 142))	('HER2', 'Gene', '2064', (113, 117))	('patients', 'Species', '9606', (147, 155))	('ILC', 'Disease', 'MESH:D018275', (143, 146))	('ILC', 'Disease', (143, 146))
38810	32085753	In a total of 12,334 patients with HR-positive, HER2-negative, pT1b-c/N0-1/M0 ILC, 1785 patients (14.5%) were allocated into adjuvant chemotherapy group and 10,549 (85.5%) into control group.	('HER2', 'Gene', '2064', (48, 52))	('pT1b-c/N0-1/M0', 'Var', (63, 77))	('ILC', 'Disease', 'MESH:D018275', (78, 81))	('patients', 'Species', '9606', (88, 96))	('HR', 'Gene', '3164', (35, 37))	('ILC', 'Disease', (78, 81))	('patients', 'Species', '9606', (21, 29))	('HER2', 'Gene', (48, 52))
38815	32085753	In this study, adjuvant chemotherapy did not improve survival for patients with HR-positive, HER2-negative pT1b-c/N0-1/M0 ILC.	('HER2', 'Gene', '2064', (93, 97))	('pT1b-c/N0-1/M0', 'Var', (107, 121))	('ILC', 'Disease', (122, 125))	('ILC', 'Disease', 'MESH:D018275', (122, 125))	('HR', 'Gene', '3164', (80, 82))	('HER2', 'Gene', (93, 97))	('patients', 'Species', '9606', (66, 74))
38832	32085753	In a dilemma, how should we make a treatment choice for HR-positive, HER2-negative, pT1-2/N0-1/M0 ILC, especially, the pT1b-c/N0-1/M0 ILC?	('pT1-2/N0-1/M0', 'Var', (84, 97))	('ILC', 'Disease', 'MESH:D018275', (98, 101))	('ILC', 'Disease', (98, 101))	('HR', 'Gene', '3164', (56, 58))	('ILC', 'Disease', 'MESH:D018275', (134, 137))	('ILC', 'Disease', (134, 137))	('HER2', 'Gene', (69, 73))	('pT1b-c/N0-1/M0', 'Var', (119, 133))	('HER2', 'Gene', '2064', (69, 73))
38839	32085753	We obtained patients diagnosed with ILC of pT1b-c/N0-1/M0 according to Site Recode classification and AJCC 7th ed.	('ILC', 'Disease', (36, 39))	('patients', 'Species', '9606', (12, 20))	('pT1b-c/N0-1/M0', 'Var', (43, 57))	('ILC', 'Disease', 'MESH:D018275', (36, 39))
38841	32085753	We retrieved 14,844 record of HR-positive, HER2-negative, pT1b-c/N0-1/M0 ILC (Supplementary Table 1).	('HR', 'Gene', '3164', (30, 32))	('ILC', 'Disease', (73, 76))	('HER2', 'Gene', (43, 47))	('HER2', 'Gene', '2064', (43, 47))	('pT1b-c/N0-1/M0', 'Var', (58, 72))	('ILC', 'Disease', 'MESH:D018275', (73, 76))
38846	32085753	After omitting censored data and excluding patients older than 80 years old, an original of 12,334 patients with HR-positive, Her-2-negative, pT1b-c/N0-1/M0 ILC were enrolled in our study (Supplementary Table 2).	('HR', 'Gene', '3164', (113, 115))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (99, 107))	('pT1b-c/N0-1/M0', 'Var', (142, 156))	('ILC', 'Disease', 'MESH:D018275', (157, 160))	('ILC', 'Disease', (157, 160))
38851	32085753	In the original 12,334 patients with HR-positive, Her-2-negative, T1b-c/N0-1/M0 ILC were followed-up for a median of 42 months (range of 1 to 83 months).	('ILC', 'Disease', 'MESH:D018275', (80, 83))	('ILC', 'Disease', (80, 83))	('patients', 'Species', '9606', (23, 31))	('T1b-c/N0-1/M0', 'Var', (66, 79))	('HR', 'Gene', '3164', (37, 39))
38874	32085753	In this study by using SEER database, we firstly compared the cohort characteristics between the included HR-positive, HER2-negative, pT1b-c/N0-1/M0 ILC patients with and without adjuvant chemotherapy, in both original and propensity score matched sample, respectively.	('patients', 'Species', '9606', (153, 161))	('ER', 'Gene', '2099', (25, 27))	('HR', 'Gene', '3164', (106, 108))	('HER2', 'Gene', (119, 123))	('HER2', 'Gene', '2064', (119, 123))	('ER', 'Gene', '2099', (120, 122))	('pT1b-c/N0-1/M0', 'Var', (134, 148))	('ILC', 'Disease', 'MESH:D018275', (149, 152))	('ILC', 'Disease', (149, 152))
38876	32085753	Our data demonstrate that patients with HR-positive, HER2-negative, pT1b-c/N0-1/M0 ILC could not derive survival benefit from the adjuvant chemotherapy shown in Fig.2, Fig.3 and Table 3, neither for OS nor for BCSM.	('OS', 'Chemical', '-', (199, 201))	('ILC', 'Disease', (83, 86))	('HER2', 'Gene', (53, 57))	('patients', 'Species', '9606', (26, 34))	('HER2', 'Gene', '2064', (53, 57))	('pT1b-c/N0-1/M0', 'Var', (68, 82))	('ILC', 'Disease', 'MESH:D018275', (83, 86))	('HR', 'Gene', '3164', (40, 42))
38890	32085753	For instance, mutations in exon 9 of the PIK3CA gene have previously been reported more frequent in ILC than in IDC.	('frequent', 'Reg', (88, 96))	('PIK3CA', 'Gene', (41, 47))	('mutations in exon', 'Var', (14, 31))	('ILC', 'Disease', 'MESH:D018275', (100, 103))	('IDC', 'Disease', (112, 115))	('IDC', 'Disease', 'MESH:D044584', (112, 115))	('PIK3CA', 'Gene', '5290', (41, 47))	('ILC', 'Disease', (100, 103))
38891	32085753	These mutations increase kinase activity, confer increased resistance to paclitaxel and are associated with metastatic capability.	('resistance to paclitaxel', 'MPA', (59, 83))	('metastatic capability', 'CPA', (108, 129))	('increased', 'PosReg', (49, 58))	('paclitaxel', 'Chemical', 'MESH:D017239', (73, 83))	('kinase activity', 'molecular_function', 'GO:0016301', ('25', '40'))	('increase', 'PosReg', (16, 24))	('kinase activity', 'MPA', (25, 40))	('associated', 'Reg', (92, 102))	('mutations', 'Var', (6, 15))
38892	32085753	Intriguingly, loss of E-cadherin of ILC has been also associated with many genetic and molecular alterations including the inactivation of the CDH1 gene at 16q22 by mutation, loss of heterozygosity, or CDH1 promoter methylation, which finally lead to the poor response to cytotoxic chemotherapy.	('ILC', 'Disease', 'MESH:D018275', (36, 39))	('CDH1', 'Gene', '999', (202, 206))	('E-cadherin', 'Gene', (22, 32))	('ILC', 'Disease', (36, 39))	('E-cadherin', 'Gene', '999', (22, 32))	('promoter', 'MPA', (207, 215))	('lead to', 'Reg', (243, 250))	('mutation', 'Var', (165, 173))	('methylation', 'biological_process', 'GO:0032259', ('216', '227'))	('cadherin', 'molecular_function', 'GO:0008014', ('24', '32'))	('CDH1', 'Gene', (143, 147))	('CDH1', 'Gene', '999', (143, 147))	('loss of heterozygosity', 'Var', (175, 197))	('CDH1', 'Gene', (202, 206))	('associated', 'Reg', (54, 64))	('inactivation', 'NegReg', (123, 135))	('loss', 'NegReg', (14, 18))
38902	32085753	Pleomorphic variant (pleomorphic invasive lobular carcinoma, PILC) shares many additional genomic changes with classic ILC such as TP53 stabilization, amplifications of MYC, MDM2, HER2/TOP2A and 20q13.	('HER2', 'Gene', (180, 184))	('TOP2A', 'Gene', (185, 190))	('MYC', 'Gene', (169, 172))	('MDM2', 'Gene', '4193', (174, 178))	('ILC', 'Disease', (119, 122))	('ILC', 'Disease', (62, 65))	('TOP2A', 'Gene', '7153', (185, 190))	('amplifications', 'Var', (151, 165))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (42, 59))	('TP53', 'Gene', (131, 135))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (33, 59))	('MYC', 'Gene', '4609', (169, 172))	('HER2', 'Gene', '2064', (180, 184))	('invasive lobular carcinoma', 'Disease', (33, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('20q13', 'Gene', (195, 200))	('ILC', 'Disease', 'MESH:D018275', (119, 122))	('TP53', 'Gene', '7157', (131, 135))	('MDM2', 'Gene', (174, 178))	('ILC', 'Disease', 'MESH:D018275', (62, 65))	('Pleomorphic variant', 'Var', (0, 19))
39119	22295233	In our series, as expected and hoped, the number of first local failures was similar in women with converted surgery, compared with patients with any change of treatment (Figure 2); however, we notice that the number of distant metastases seems to be higher in cases with modified surgery versus unmodified surgery.	('women', 'Species', '9606', (88, 93))	('metastases', 'Disease', (228, 238))	('higher', 'PosReg', (251, 257))	('metastases', 'Disease', 'MESH:D009362', (228, 238))	('patients', 'Species', '9606', (132, 140))	('modified surgery', 'Var', (272, 288))
39159	22295233	In women with ADH a review of literature suggests a 4- to 5-fold increased risk of invasive breast cancer, compared with a 6- to 10-fold risk ALH/LIN.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('invasive breast cancer', 'Disease', (83, 105))	('ADH', 'Var', (14, 17))	('ADH', 'molecular_function', 'GO:0047636', ('14', '17'))	('women', 'Species', '9606', (3, 8))	('invasive breast cancer', 'Disease', 'MESH:D001943', (83, 105))	('ADH', 'molecular_function', 'GO:0004022', ('14', '17'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
39163	22295233	After a median followup of 36 months, we reported 5/118 (4.2%) versus 15/407 (3.7%) (NS) local recurrences in women with converted surgery, compared with patients with any change of treatment (Figure 2).	('local recurrences', 'CPA', (89, 106))	('converted surgery', 'Var', (121, 138))	('patients', 'Species', '9606', (154, 162))	('women', 'Species', '9606', (110, 115))
39164	22295233	In our series, we observed higher rates of larger cancers > pT1 (39/118, 33.0% versus 92/407, 22.6%) and of nodal involvement (58/118, 49.1 versus 144/407, 35.4; P < .0001) in cases with modified versus unmodified surgery.	('nodal', 'Gene', (108, 113))	('nodal', 'Gene', '4838', (108, 113))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('pT1', 'Gene', '58492', (60, 63))	('cancers', 'Disease', (50, 57))	('larger', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pT1', 'Gene', (60, 63))	('modified', 'Var', (187, 195))
39175	32374727	Besides the known hotspot mutations in ESR1, we observed a metastatic enrichment of previously unreported, lower-prevalence mutations in the ligand-binding domain, implying that these mutations may also be functional.	('binding', 'molecular_function', 'GO:0005488', ('148', '155'))	('ESR1', 'Gene', '2099', (39, 43))	('mutations', 'Var', (26, 35))	('ligand', 'molecular_function', 'GO:0005488', ('141', '147'))	('ESR1', 'Gene', (39, 43))	('mutations in', 'Var', (124, 136))
39177	32374727	Other alterations enriched across all metastases include loss of function of the CDK4 regulator CDKN1B, and mutations in the transcription factor CTCF.	('loss of function', 'NegReg', (57, 73))	('metastases', 'Disease', 'MESH:D009362', (38, 48))	('mutations', 'Var', (108, 117))	('CDKN1B', 'Gene', (96, 102))	('transcription factor', 'molecular_function', 'GO:0000981', ('125', '145'))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('CTCF', 'Gene', (146, 150))	('CDK4', 'Gene', (81, 85))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('CDK4', 'Gene', '1019', (81, 85))	('CTCF', 'Gene', '10664', (146, 150))	('metastases', 'Disease', (38, 48))	('CDKN1B', 'Gene', '1027', (96, 102))
39179	32374727	We observed an enrichment of KRAS, KEAP1, STK11 and EGFR mutations in lung metastases.	('lung metastases', 'Disease', (70, 85))	('KEAP1', 'Gene', '9817', (35, 40))	('EGFR', 'Gene', '1956', (52, 56))	('lung metastases', 'Disease', 'MESH:D009362', (70, 85))	('EGFR', 'Gene', (52, 56))	('KRAS', 'Gene', (29, 33))	('STK11', 'Gene', (42, 47))	('STK11', 'molecular_function', 'GO:0033868', ('42', '47'))	('KEAP1', 'Gene', (35, 40))	('mutations', 'Var', (57, 66))	('STK11', 'Gene', '6794', (42, 47))	('KRAS', 'Gene', '3845', (29, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))
39180	32374727	However, the patterns of other mutations in these tumors indicate that these are misdiagnosed lung primaries rather than breast metastases.	('mutations', 'Var', (31, 40))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('breast metastases', 'Disease', (121, 138))	('breast metastases', 'Disease', 'MESH:D001943', (121, 138))	('lung primaries', 'Disease', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
39184	32374727	The process via which cancer cells disseminate from the primary tumor, colonize distal sites, and adapt to novel tumor microenvironments has not been fully characterized, but recent work implicates a cascade of genetic and epigenetic events that drive active degradation of the extracellular matrix, induce angiogenesis, enhance motility, promote immune evasion, and co-opt the epithelial-mesenchymal transition.	('motility', 'CPA', (329, 337))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('epithelial-mesenchymal transition', 'CPA', (378, 411))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('278', '298'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('immune evasion', 'biological_process', 'GO:0042783', ('347', '361'))	('degradation', 'MPA', (259, 270))	('immune evasion', 'biological_process', 'GO:0051842', ('347', '361'))	('enhance', 'PosReg', (321, 328))	('epigenetic events', 'Var', (223, 240))	('tumor', 'Disease', (113, 118))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('378', '411'))	('promote', 'PosReg', (339, 346))	('cancer', 'Disease', (22, 28))	('induce', 'PosReg', (300, 306))	('immune evasion', 'MPA', (347, 361))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('angiogenesis', 'CPA', (307, 319))	('tumor', 'Disease', (64, 69))	('angiogenesis', 'biological_process', 'GO:0001525', ('307', '319'))	('degradation', 'biological_process', 'GO:0009056', ('259', '270'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
39193	32374727	The most frequently reported alterations include mutations in TP53, PIK3CA, GATA3, MAP3K1, AKT1, and CBFB ; amplification of HER2, MYC, FGFR1 and FGF3/4; deletion of PTEN, RB1 and CDKN2A/B; and oncogenic germline polymorphisms in BRCA1/2.	('HER2', 'Gene', (125, 129))	('CDKN2A/B', 'Gene', '1029;1030', (180, 188))	('FGFR1', 'Gene', (136, 141))	('TP53', 'Gene', (62, 66))	('MYC', 'Gene', (131, 134))	('PTEN', 'Gene', '5728', (166, 170))	('oncogenic germline', 'CPA', (194, 212))	('RB1', 'Gene', (172, 175))	('amplification', 'Var', (108, 121))	('CBFB ', 'Gene', (101, 106))	('PIK3CA', 'Gene', (68, 74))	('mutations', 'Var', (49, 58))	('BRCA1/2', 'Gene', (230, 237))	('AKT1', 'Gene', '207', (91, 95))	('TP53', 'Gene', '7157', (62, 66))	('MYC', 'Gene', '4609', (131, 134))	('HER2', 'Gene', '2064', (125, 129))	('RB1', 'Gene', '5925', (172, 175))	('CDKN2A/B', 'Gene', (180, 188))	('FGFR1', 'Gene', '2260', (136, 141))	('GATA3', 'Gene', '2625', (76, 81))	('AKT1', 'Gene', (91, 95))	('GATA3', 'Gene', (76, 81))	('BRCA1/2', 'Gene', '672;675', (230, 237))	('PTEN', 'Gene', (166, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('136', '140'))	('FGF3/4', 'Gene', (146, 152))	('PIK3CA', 'Gene', '5290', (68, 74))	('MAP3K', 'molecular_function', 'GO:0004709', ('83', '88'))	('MAP3K1', 'Gene', (83, 89))	('deletion', 'Var', (154, 162))	('MAP3K1', 'Gene', '4214', (83, 89))	('FGF3/4', 'Gene', '2248;2249', (146, 152))
39195	32374727	Clinical trials are ongoing for drugs that target patients with BRCA1/2 mutations, AKT1 mutations, PIK3CA mutations, and FGFR amplification, illustrating the utility of genomics to define patient populations and guide drug discovery.	('mutations', 'Var', (72, 81))	('FGF', 'Gene', '2248;2249;9965', (121, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('121', '125'))	('patients', 'Species', '9606', (50, 58))	('patient', 'Species', '9606', (188, 195))	('AKT1', 'Gene', '207', (83, 87))	('PIK3CA', 'Gene', '5290', (99, 105))	('AKT1', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('BRCA1/2', 'Gene', (64, 71))	('mutations', 'Var', (106, 115))	('FGF', 'Gene', (121, 124))	('patient', 'Species', '9606', (50, 57))	('BRCA1/2', 'Gene', '672;675', (64, 71))	('PIK3CA', 'Gene', (99, 105))
39196	32374727	Initial efforts uncovered mutations in the ligand-binding domain of the estrogen receptor (ESR1) in 10-30% of metastatic breast cancer patients, an alteration that is largely absent in primary disease.	('ESR1', 'Gene', (91, 95))	('patients', 'Species', '9606', (135, 143))	('ligand', 'molecular_function', 'GO:0005488', ('43', '49'))	('estrogen receptor', 'Gene', (72, 89))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('estrogen receptor', 'Gene', '2099', (72, 89))	('mutations in', 'Var', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ESR1', 'Gene', '2099', (91, 95))	('breast cancer', 'Disease', (121, 134))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))
39199	32374727	We hypothesized that relative to local disease, the genomic fingerprints of metastatic tumors are enriched for (i) mechanisms of acquired resistance (due to treatment history) and (ii) alterations that induce or accelerate metastasis.	('metastasis', 'CPA', (223, 233))	('alterations', 'Var', (185, 196))	('induce', 'Reg', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('acquired', 'MPA', (129, 137))	('accelerate', 'PosReg', (212, 222))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
39205	32374727	In all cases, predicted probability of ER-positivity, HER2 status, and mutation load per megabase were used as additional covariates.	('mutation', 'Var', (71, 79))	('HER2', 'Gene', (54, 58))	('ER', 'Gene', '2099', (55, 57))	('ER', 'Gene', '2099', (39, 41))	('HER2', 'Gene', '2064', (54, 58))
39211	32374727	Mutations were called homozygous if all copies in the tumor carried the mutant allele, heterozygous if both the reference and the mutant alleles were present, or sub-clonal somatic if the somatic allele frequency was significantly lower than the expected allele frequency.	('mutant', 'Var', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Mutations', 'Var', (0, 9))	('lower', 'NegReg', (231, 236))	('tumor', 'Disease', (54, 59))	('mutant', 'Var', (130, 136))
39229	32374727	ER and HER2 status differed significantly across metastatic sites, with higher rates of ER positivity in liver and bone, lower rates in brain and lung, and with high prevalence of HER2 amplification in brain (p<1e-6 for association between subtype and site; Fig 1D).	('rates', 'MPA', (127, 132))	('ER', 'Gene', '2099', (0, 2))	('ER', 'Gene', '2099', (181, 183))	('HER2', 'Gene', (180, 184))	('HER2', 'Gene', '2064', (180, 184))	('amplification', 'Var', (185, 198))	('ER', 'Gene', '2099', (8, 10))	('lower', 'NegReg', (121, 126))	('HER2', 'Gene', (7, 11))	('ER', 'Gene', '2099', (88, 90))	('positivity', 'Var', (91, 101))	('HER2', 'Gene', '2064', (7, 11))
39236	32374727	The high TP53 mutation rate relative to prior studies and the presence of ESR1 mutations suggest that both the local and metastatic tumors in this dataset are enriched for patients with poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('ESR1', 'Gene', '2099', (74, 78))	('TP53', 'Gene', '7157', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('TP53', 'Gene', (9, 13))	('mutation', 'Var', (14, 22))	('patients', 'Species', '9606', (172, 180))	('tumors', 'Disease', (132, 138))	('ESR1', 'Gene', (74, 78))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('mutations', 'Var', (79, 88))
39237	32374727	Samples had an average of 6.3 mutations (6.7 in metastases vs 5.6 in local disease, p<2e-16), 5.1 copy number alterations (5.3 in metastases vs 4.9 in local disease, p = 0.003), and 0.55 structural rearrangements (0.53 in metastases vs 0.56 in local disease, p = 0.07).	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('copy number alterations', 'Var', (98, 121))	('metastases', 'Disease', (222, 232))	('metastases', 'Disease', 'MESH:D009362', (222, 232))	('metastases', 'Disease', (130, 140))	('mutations', 'Var', (30, 39))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('metastases', 'Disease', (48, 58))
39238	32374727	One-hundred sixteen samples harbored mutations in more than 25 genes, with a significant enrichment of this hypermutated phenotype in metastatic samples relative to local samples (p<1e-5) and in ER+ samples (p<1e-08).	('mutations', 'Var', (37, 46))	('metastatic', 'Disease', (134, 144))	('ER', 'Gene', '2099', (195, 197))
39239	32374727	A diverse set of genomic alterations were observed at high frequency across the 11,616 samples (Fig 1G), including mutations in TP53 (55.9% of samples), PIK3CA (32.4%), CDH1 (11%), GATA3 (10.9%), ESR1 (10.2%), and KMT2D (9.5%); amplifications of MYC (22.8%), CCND1 (17.4%), and HER2 (9.9%); deletions of PTEN (5.7%), CDKN2A/B (5%), and RB1 (2.5%); and structural rearrangements of HER2 (1.5%) and FGFR1 (1.3%).	('PIK3CA', 'Gene', '5290', (153, 159))	('deletions', 'Var', (291, 300))	('RB1', 'Gene', '5925', (336, 339))	('TP53', 'Gene', '7157', (128, 132))	('FGFR', 'molecular_function', 'GO:0005007', ('397', '401'))	('HER2', 'Gene', '2064', (381, 385))	('FGFR1', 'Gene', (397, 402))	('HER2', 'Gene', '2064', (278, 282))	('GATA3', 'Gene', '2625', (181, 186))	('CDKN2A/B', 'Gene', (317, 325))	('KMT2D', 'Gene', (214, 219))	('PTEN', 'Gene', (304, 308))	('MYC', 'Gene', (246, 249))	('GATA3', 'Gene', (181, 186))	('PIK3CA', 'Gene', (153, 159))	('amplifications', 'Var', (228, 242))	('TP53', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (304, 308))	('CCND1', 'Gene', '595', (259, 264))	('structural rearrangements', 'Var', (352, 377))	('HER2', 'Gene', (381, 385))	('HER2', 'Gene', (278, 282))	('CDH1', 'Gene', '999', (169, 173))	('CDKN2A/B', 'Gene', '1029;1030', (317, 325))	('RB1', 'Gene', (336, 339))	('mutations', 'Var', (115, 124))	('FGFR1', 'Gene', '2260', (397, 402))	('MYC', 'Gene', '4609', (246, 249))	('CCND1', 'Gene', (259, 264))	('KMT2D', 'Gene', '8085', (214, 219))	('CDH1', 'Gene', (169, 173))	('ESR1', 'Gene', '2099', (196, 200))	('ESR1', 'Gene', (196, 200))
39240	32374727	BRCA1/2 sequence variants (including deleterious mutations, variants of unknown significance, and deleterious germline variations) were also highly prevalent, at frequencies of 5.6% for BRCA1 and 7.2% for BRCA2.	('prevalent', 'Reg', (148, 157))	('BRCA1', 'Gene', (0, 5))	('variants', 'Var', (17, 25))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('BRCA1', 'Gene', '672', (186, 191))	('BRCA2', 'Gene', (205, 210))	('BRCA1', 'Gene', (186, 191))	('BRCA2', 'Gene', '675', (205, 210))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA1/2', 'Gene', (0, 7))
39241	32374727	These alterations have been consistently associated with breast cancer in prior reports.	('alterations', 'Var', (6, 17))	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('associated', 'Reg', (41, 51))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
39244	32374727	We confirmed the significant enrichment for ESR1 mutations in metastatic tumors (18.3% in metastases vs. 2.2% in local disease, p<3e-80; Fig 2A, S3 Table, S5-S7 Tables).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('metastases', 'Disease', (90, 100))	('mutations', 'Var', (49, 58))	('ESR1', 'Gene', (44, 48))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ESR1', 'Gene', '2099', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('S7', 'Gene', '6264', (158, 160))
39245	32374727	Beyond this principal feature of metastatic breast cancer, we found a previously unreported enrichment for CTCF mutations in metastatic samples (2% in metastases vs. 0.9% in local disease, p<2e-5; Fig 2A).	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('breast cancer', 'Disease', (44, 57))	('CTCF', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (112, 121))	('CTCF', 'Gene', '10664', (107, 111))	('metastases', 'Disease', (151, 161))
39246	32374727	Mutations in CTCF and at CTCF binding sites have previously been associated with multiple forms of cancer, putatively disrupting the epigenetic regulation of proliferation.	('regulation', 'biological_process', 'GO:0065007', ('144', '154'))	('disrupting', 'NegReg', (118, 128))	('CTCF', 'Gene', (25, 29))	('CTCF', 'Gene', '10664', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('CTCF', 'Gene', '10664', (25, 29))	('cancer', 'Disease', (99, 105))	('associated', 'Reg', (65, 75))	('Mutations', 'Var', (0, 9))	('binding', 'molecular_function', 'GO:0005488', ('30', '37'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CTCF', 'Gene', (13, 17))	('epigenetic regulation of proliferation', 'MPA', (133, 171))
39248	32374727	As such, we speculate that CTCF mutations are a metastatic driver in up to 2% of metastatic breast cancers.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('CTCF', 'Gene', (27, 31))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('CTCF', 'Gene', '10664', (27, 31))	('mutations', 'Var', (32, 41))	('breast cancers', 'Phenotype', 'HP:0003002', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancers', 'Disease', 'MESH:D001943', (92, 106))	('breast cancers', 'Disease', (92, 106))
39249	32374727	In addition, we observed a significantly higher rate of CDKN1B (p27kip1) amplification in local tumors (1.3% in metastases vs. 3.6% in local disease, p<2e-5) (Fig 2A).	('CDKN1B', 'Gene', '1027', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('CDKN1B', 'Gene', (56, 62))	('metastases', 'Disease', (112, 122))	('p27kip1', 'Gene', (64, 71))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('higher', 'PosReg', (41, 47))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('p27kip1', 'Gene', '1027', (64, 71))	('amplification', 'Var', (73, 86))
39250	32374727	Strengthening this result, the opposite alterations, CDKN1B deletions (0.2% in metastases vs. 0.1% in local disease, p = 0.09) and mutations (1.9% in metastases vs. 1.1% in local disease, p = 0.05), trend toward significant enrichment in metastatic tumors.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('mutations', 'Var', (131, 140))	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('deletions', 'Var', (60, 69))	('CDKN1B', 'Gene', '1027', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('CDKN1B', 'Gene', (53, 59))	('metastases', 'Disease', (150, 160))	('metastases', 'Disease', (79, 89))	('metastases', 'Disease', 'MESH:D009362', (150, 160))	('tumors', 'Disease', (249, 255))
39251	32374727	CDKN1B controls cell cycle progression at G1 via inhibition of CDK4/6, and high expression of CDKN1B is a positive prognostic biomarker in early-stage disease.	('high expression', 'Var', (75, 90))	('CDKN1B', 'Gene', '1027', (0, 6))	('CDKN1B', 'Gene', (0, 6))	('CDKN1B', 'Gene', '1027', (94, 100))	('cell cycle', 'biological_process', 'GO:0007049', ('16', '26'))	('CDKN1B', 'Gene', (94, 100))	('CDK4/6', 'Gene', '1019;1021', (63, 69))	('CDK', 'molecular_function', 'GO:0004693', ('63', '66'))	('cell cycle progression', 'CPA', (16, 38))	('early-stage disease', 'Disease', (139, 158))	('inhibition', 'NegReg', (49, 59))	('CDK4/6', 'Gene', (63, 69))
39253	32374727	One possible interpretation of our data is that CDKN1B amplification in primary tumors acts to slow the rate of tumor proliferation and metastasis, which would point toward the possible utility of CDK4/6 inhibitors as a means of delaying progression to metastatic disease.	('CDK4/6', 'Gene', '1019;1021', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('amplification', 'Var', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CDKN1B', 'Gene', (48, 54))	('CDK', 'molecular_function', 'GO:0004693', ('197', '200'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('primary tumors', 'Disease', (72, 86))	('CDK4/6', 'Gene', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('slow', 'NegReg', (95, 99))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('primary tumors', 'Disease', 'MESH:D001932', (72, 86))	('tumor', 'Disease', (112, 117))	('rate', 'CPA', (104, 108))	('CDKN1B', 'Gene', '1027', (48, 54))
39258	32374727	Lastly, when only considering variants with known or likely tumorigenic potential, we found a significant enrichment of KRAS and NF1 mutations in metastatic tumors (KRAS:1.9% in metastases vs. 1.1% in local disease, p = 0.0045; NF1-4.7% vs. 3.3%, p = 0.013, S5 Table), which suggests a potential role for the ras/MAPK pathway in metastasis.	('metastatic', 'Disease', (146, 156))	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('NF1', 'Gene', '4763', (228, 231))	('metastases', 'Disease', (178, 188))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (60, 65))	('NF1', 'Gene', (228, 231))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MAPK', 'molecular_function', 'GO:0004707', ('313', '317'))	('mutations', 'Var', (133, 142))	('KRAS', 'Gene', '3845', (120, 124))	('tumors', 'Disease', (157, 163))	('NF1', 'Gene', '4763', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('KRAS', 'Gene', (120, 124))	('tumor', 'Disease', (157, 162))	('KRAS', 'Gene', '3845', (165, 169))	('NF1', 'Gene', (129, 132))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('KRAS', 'Gene', (165, 169))
39259	32374727	Next we provided a comprehensive portrait of the prevalence and diversity of ESR1 mutations in metastatic breast cancer.	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('ESR1', 'Gene', '2099', (77, 81))	('mutations', 'Var', (82, 91))	('ESR1', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
39260	32374727	ESR1 mutations are found in 1,183 tumors, 8.9% of those carry more than one ESR1 mutation, and 922 (78%) are metastases.	('tumors', 'Disease', (34, 40))	('ESR1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('ESR1', 'Gene', '2099', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('mutation', 'Var', (81, 89))	('mutations', 'Var', (5, 14))	('metastases', 'Disease', (109, 119))	('ESR1', 'Gene', (76, 80))	('ESR1', 'Gene', '2099', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
39261	32374727	The ESR1 mutation rate is highest in ER+ liver metastases (44%), followed by pleura (25%), lung (24%) and bone (20%) (Fig 2B).	('mutation', 'Var', (9, 17))	('highest', 'Reg', (26, 33))	('ESR1', 'Gene', (4, 8))	('pleura', 'Disease', (77, 83))	('metastases', 'Disease', (47, 57))	('ER', 'Gene', '2099', (37, 39))	('ESR1', 'Gene', '2099', (4, 8))	('metastases', 'Disease', 'MESH:D009362', (47, 57))
39263	32374727	The most prevalent ESR1 mutations are gain-of-function mutations in the ligand-binding domain, which have been shown to confer constitutive activity in the absence of estrogen (Fig 2C): D538G - 33.2% of all ESR1 mutations; Y537S - 21.4%; E380Q - 8.5%; Y537N - 8.0%; Y537C - 4.3%; L536H -1.9%; and V422del -1.4%.	('Y537S', 'Var', (223, 228))	('Y537C', 'SUBSTITUTION', 'None', (266, 271))	('Y537N', 'SUBSTITUTION', 'None', (252, 257))	('gain-of-function', 'PosReg', (38, 54))	('D538G', 'SUBSTITUTION', 'None', (186, 191))	('mutations', 'Var', (24, 33))	('Y537N', 'Var', (252, 257))	('ESR1', 'Gene', '2099', (19, 23))	('E380Q', 'Var', (238, 243))	('ligand', 'molecular_function', 'GO:0005488', ('72', '78'))	('E380Q', 'SUBSTITUTION', 'None', (238, 243))	('ESR1', 'Gene', (19, 23))	('L536H', 'SUBSTITUTION', 'None', (280, 285))	('Y537C', 'Var', (266, 271))	('ESR1', 'Gene', '2099', (207, 211))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('D538G', 'Var', (186, 191))	('ESR1', 'Gene', (207, 211))	('L536H', 'Var', (280, 285))	('V422del', 'DELETION', 'None', (297, 304))	('V422del', 'Var', (297, 304))	('Y537S', 'SUBSTITUTION', 'None', (223, 228))
39264	32374727	We also see enrichment for rare ESR1 mutations in metastases relative to local disease (p<1e-04 for the set of mutations seen twice; p<1e-05 for the set of mutations seen once) (Fig 2D).	('ESR1', 'Gene', '2099', (32, 36))	('metastases', 'Disease', (50, 60))	('mutations', 'Var', (37, 46))	('ESR1', 'Gene', (32, 36))	('metastases', 'Disease', 'MESH:D009362', (50, 60))
39265	32374727	This effect is confined to the ligand-binding domain of ESR1 (p = 0.004 for the set of mutations seen once in the ligand-binding domain vs. p = 0.9 for the set of mutations seen once outside the ligand-binding domain; p = 0.04 comparing enrichment between the two sets, demonstrating that the difference is not attributable to the larger number of mutations within the ligand-binding domain), suggesting that a long tail of mutations in the ESR1 ligand-binding domain represents additional resistance mechanisms to aromatase inhibition.	('ESR1', 'Gene', '2099', (441, 445))	('ligand', 'molecular_function', 'GO:0005488', ('369', '375'))	('binding', 'molecular_function', 'GO:0005488', ('202', '209'))	('ESR1', 'Gene', (441, 445))	('ligand', 'molecular_function', 'GO:0005488', ('195', '201'))	('ligand', 'molecular_function', 'GO:0005488', ('114', '120'))	('resistance mechanisms', 'MPA', (490, 511))	('aromatase', 'Gene', '1588', (515, 524))	('long tail', 'Phenotype', 'HP:0002831', (411, 420))	('ligand', 'molecular_function', 'GO:0005488', ('446', '452'))	('binding', 'molecular_function', 'GO:0005488', ('376', '383'))	('binding', 'molecular_function', 'GO:0005488', ('38', '45'))	('ESR1', 'Gene', '2099', (56, 60))	('aromatase', 'Gene', (515, 524))	('ligand', 'molecular_function', 'GO:0005488', ('31', '37'))	('mutations', 'Var', (424, 433))	('ESR1', 'Gene', (56, 60))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('binding', 'molecular_function', 'GO:0005488', ('453', '460'))
39266	32374727	The prevalence of these hotspot mutations further varies by site of metastasis (p<7e-7) and the histological subtype of the tumor (p = 0.003) (Fig 2B).	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
39267	32374727	In terms of metastatic site, visceral tissue (liver, pleura, pleural fluid, brain, and lung) has significantly more D538G mutations (20-48% of ESR1 mutations) than all other ESR1 hotspot mutations, including Y537S (p = 0.007).	('Y537S', 'SUBSTITUTION', 'None', (208, 213))	('ESR1', 'Gene', (174, 178))	('pleural fluid', 'Phenotype', 'HP:0002202', (61, 74))	('Y537S', 'Var', (208, 213))	('ESR1', 'Gene', '2099', (143, 147))	('ESR1', 'Gene', '2099', (174, 178))	('D538G', 'Var', (116, 121))	('D538G', 'SUBSTITUTION', 'None', (116, 121))	('ESR1', 'Gene', (143, 147))
39268	32374727	Bone metastases (non-visceral), on the other hand, have significantly more Y537S mutations (29%) relative to D538G (22%).	('D538G', 'SUBSTITUTION', 'None', (109, 114))	('Y537S', 'SUBSTITUTION', 'None', (75, 80))	('Y537S', 'Var', (75, 80))	('metastases', 'Disease', (5, 15))	('D538G', 'Var', (109, 114))	('metastases', 'Disease', 'MESH:D009362', (5, 15))
39269	32374727	Peripheral tissue (chest wall) has increased prevalence of E380Q mutations (31%), and both local breast tumors and lymph node metastases have higher rates of likely passenger mutations outside the ligand-binding domain.	('breast tumors', 'Disease', 'MESH:D001943', (97, 110))	('E380Q', 'Var', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('E380Q', 'SUBSTITUTION', 'None', (59, 64))	('ligand', 'molecular_function', 'GO:0005488', ('197', '203'))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('binding', 'molecular_function', 'GO:0005488', ('204', '211'))	('metastases', 'Disease', (126, 136))	('breast tumors', 'Phenotype', 'HP:0100013', (97, 110))	('metastases', 'Disease', 'MESH:D009362', (126, 136))	('breast tumors', 'Disease', (97, 110))
39270	32374727	In terms of histological subtype, the ESR1 hotspot mutations in invasive ductal carcinoma reflect visceral disease (44% are D538G).	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('hotspot', 'PosReg', (43, 50))	('ESR1', 'Gene', (38, 42))	('invasive ductal carcinoma reflect visceral disease', 'Disease', (64, 114))	('invasive ductal carcinoma reflect visceral disease', 'Disease', 'MESH:D044584', (64, 114))	('D538G', 'Var', (124, 129))	('D538G', 'SUBSTITUTION', 'None', (124, 129))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (73, 89))	('ESR1', 'Gene', '2099', (38, 42))
39271	32374727	Those in invasive lobular carcinoma are enriched for E380Q mutations (22% are E380Q).	('invasive lobular carcinoma', 'Disease', (9, 35))	('E380Q', 'SUBSTITUTION', 'None', (53, 58))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (9, 35))	('E380Q', 'Var', (53, 58))	('E380Q', 'Var', (78, 83))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (18, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('E380Q', 'SUBSTITUTION', 'None', (78, 83))
39273	32374727	We find multiple significant associations between genomic alterations and the site of metastasis (Fig 3A, S4 Table), the most intriguing of which include an enrichment of ASXL1 amplifications (4.2% vs. 0.8% in local disease, p<2e-05) and PTEN deletions (11.8% vs. 5%, p<1e-04) in brain metastases; an enrichment of DNMT3A mutations in bone metastases (6.4% vs. 2.5%, p<2e-5); an enrichment of NOTCH1 mutations in skin metastases (8.8% vs. 4.5%, p = 5e-4); and enrichments of KRAS, KEAP1, STK11 and EGFR mutations in lung metastases (2.6-3.2% vs. 1.0-2.1%, p = 0.004-0.14).	('deletions', 'Var', (243, 252))	('bone metastases', 'Disease', (335, 350))	('KRAS', 'Gene', (475, 479))	('DNMT3A', 'Gene', (315, 321))	('lung metastases', 'Disease', (516, 531))	('STK11', 'Gene', (488, 493))	('ASXL1', 'Gene', '171023', (171, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('498', '502'))	('PTEN', 'Gene', '5728', (238, 242))	('EGFR', 'Gene', '1956', (498, 502))	('ASXL1', 'Gene', (171, 176))	('STK11', 'Gene', '6794', (488, 493))	('NOTCH1', 'Gene', (393, 399))	('DNMT3A', 'Gene', '1788', (315, 321))	('mutations', 'Var', (322, 331))	('skin metastases', 'Disease', 'MESH:D009362', (413, 428))	('NOTCH1', 'Gene', '4851', (393, 399))	('bone metastases', 'Disease', 'MESH:D009362', (335, 350))	('mutations', 'Var', (400, 409))	('KEAP1', 'Gene', '9817', (481, 486))	('KRAS', 'Gene', '3845', (475, 479))	('EGFR', 'Gene', (498, 502))	('lung metastases', 'Disease', 'MESH:D009362', (516, 531))	('PTEN', 'Gene', (238, 242))	('brain metastases', 'Disease', (280, 296))	('KEAP1', 'Gene', (481, 486))	('mutations', 'Var', (503, 512))	('brain metastases', 'Disease', 'MESH:D009362', (280, 296))	('skin metastases', 'Disease', (413, 428))	('STK11', 'molecular_function', 'GO:0033868', ('488', '493'))
39274	32374727	Most of these enriched alterations have been associated with primary tumors at the site of metastasis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('primary tumors', 'Disease', 'MESH:D001932', (61, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('associated', 'Reg', (45, 55))	('alterations', 'Var', (23, 34))	('primary tumors', 'Disease', (61, 75))
39275	32374727	KRAS is the most common driver mutation in lung cancer, and is highly co-occurrent with KEAP1 and STK11 mutations, NOTCH1 has a putative role in skin cancer, loss of PTEN is the most common genomic alteration in glioblastoma, and DNMT3A has been associated with leukemia and myelodysplasia.	('loss of PTEN', 'Disease', 'MESH:D006223', (158, 170))	('glioblastoma', 'Disease', (212, 224))	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('skin cancer', 'Disease', (145, 156))	('KEAP1', 'Gene', '9817', (88, 93))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('associated', 'Reg', (246, 256))	('glioblastoma', 'Phenotype', 'HP:0012174', (212, 224))	('KEAP1', 'Gene', (88, 93))	('STK11', 'Gene', (98, 103))	('myelodysplasia', 'Disease', (275, 289))	('mutations', 'Var', (104, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('leukemia', 'Disease', (262, 270))	('leukemia', 'Disease', 'MESH:D007938', (262, 270))	('DNMT3A', 'Gene', '1788', (230, 236))	('skin cancer', 'Phenotype', 'HP:0008069', (145, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('KRAS', 'Gene', '3845', (0, 4))	('NOTCH1', 'Gene', (115, 121))	('STK11', 'molecular_function', 'GO:0033868', ('98', '103'))	('myelodysplasia', 'Phenotype', 'HP:0002863', (275, 289))	('STK11', 'Gene', '6794', (98, 103))	('loss of PTEN', 'Disease', (158, 170))	('myelodysplasia', 'Disease', 'MESH:D009190', (275, 289))	('NOTCH1', 'Gene', '4851', (115, 121))	('KRAS', 'Gene', (0, 4))	('skin cancer', 'Disease', 'MESH:D012878', (145, 156))	('lung cancer', 'Disease', (43, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (212, 224))	('DNMT3A', 'Gene', (230, 236))
39276	32374727	This suggests that these alterations serve to mimic primary tumors at the site of metastasis and confer adaptation to the local tumor microenvironment.	('alterations', 'Var', (25, 36))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('primary tumors', 'Disease', (52, 66))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('primary tumors', 'Disease', 'MESH:D001932', (52, 66))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
39279	32374727	The algorithms were trained using genomic data from 500 tumors of each indication, sequenced during standard care using the FoundationOne assay, with the enriched alterations associated with each indication masked (e.g., PTEN deletions excluded from the brain classification).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('deletions', 'Var', (226, 235))	('PTEN', 'Gene', (221, 225))	('PTEN', 'Gene', '5728', (221, 225))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
39280	32374727	We then applied the algorithms to the metastatic breast tumors containing the enriched alterations, to confirm that those tumors are equally likely to originate from breast tissue relative to all other metastatic breast tumors in the dataset.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('breast tumors', 'Disease', 'MESH:D001943', (49, 62))	('breast tumors', 'Disease', (49, 62))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('breast tumors', 'Phenotype', 'HP:0100013', (49, 62))	('breast tumors', 'Disease', (213, 226))	('breast tumors', 'Disease', 'MESH:D001943', (213, 226))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('breast tumors', 'Phenotype', 'HP:0100013', (213, 226))	('tumors', 'Disease', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (122, 128))	('alterations', 'Var', (87, 98))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
39281	32374727	Fourteen percent of breast tumors with DNMT3A mutations that metastasized to bone were classified as bone, statistically indistinguishable from the 12% of all breast metastases classified as bone (p = 0.39).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('DNMT3A', 'Gene', (39, 45))	('DNMT3A', 'Gene', '1788', (39, 45))	('mutations', 'Var', (46, 55))	('breast metastases', 'Disease', (159, 176))	('breast tumors', 'Phenotype', 'HP:0100013', (20, 33))	('breast metastases', 'Disease', 'MESH:D001943', (159, 176))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('breast tumors', 'Disease', 'MESH:D001943', (20, 33))	('breast tumors', 'Disease', (20, 33))
39282	32374727	Similarly, 7% of brain metastases that harbor ASXL1 amplifications or PTEN deletions were classified as brain, less than the 9% of all breast metastases classified as brain.	('brain metastases', 'Disease', (17, 33))	('deletions', 'Var', (75, 84))	('ASXL1', 'Gene', (46, 51))	('PTEN', 'Gene', (70, 74))	('PTEN', 'Gene', '5728', (70, 74))	('breast metastases', 'Disease', (135, 152))	('breast metastases', 'Disease', 'MESH:D001943', (135, 152))	('ASXL1', 'Gene', '171023', (46, 51))	('brain metastases', 'Disease', 'MESH:D009362', (17, 33))
39283	32374727	Skin metastases that harbor NOTCH1 mutations were classified as skin cancer at a higher rate (18% vs 5%, p = 0.052), but the effect was primarily driven by differences in subtype prevalence between local tumors and skin metastases and was not significant after controlling for this (p = 0.78).	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('Skin metastases', 'Disease', (0, 15))	('Skin metastases', 'Disease', 'MESH:D009362', (0, 15))	('skin cancer', 'Disease', (64, 75))	('skin cancer', 'Disease', 'MESH:D012878', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('NOTCH1', 'Gene', '4851', (28, 34))	('skin metastases', 'Disease', 'MESH:D009362', (215, 230))	('skin cancer', 'Phenotype', 'HP:0008069', (64, 75))	('tumors', 'Disease', (204, 210))	('NOTCH1', 'Gene', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('skin metastases', 'Disease', (215, 230))	('mutations', 'Var', (35, 44))
39284	32374727	These results are consistent with the hypothesis that the enrichments for DNMT3A mutations in bone metastases, NOTCH1 mutations in skin metastases, and ASXL1 amplifications/PTEN deletions in brain metastases are biologically relevant, either as adaptations that arise in response to the local tumor microenvironment or as drivers of site-specific patterns of metastasis.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('DNMT3A', 'Gene', '1788', (74, 80))	('PTEN', 'Gene', (173, 177))	('skin metastases', 'Disease', 'MESH:D009362', (131, 146))	('brain metastases', 'Disease', 'MESH:D009362', (191, 207))	('brain metastases', 'Disease', (191, 207))	('bone metastases', 'Disease', 'MESH:D009362', (94, 109))	('NOTCH1', 'Gene', '4851', (111, 117))	('mutations', 'Var', (81, 90))	('deletions', 'Var', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('skin metastases', 'Disease', (131, 146))	('PTEN', 'Gene', '5728', (173, 177))	('bone metastases', 'Disease', (94, 109))	('ASXL1', 'Gene', '171023', (152, 157))	('DNMT3A', 'Gene', (74, 80))	('mutations', 'Var', (118, 127))	('ASXL1', 'Gene', (152, 157))	('tumor', 'Disease', (293, 298))	('NOTCH1', 'Gene', (111, 117))
39285	32374727	An alternative hypothesis for the enrichment of DNMT3A mutations is clonal hematopoiesis of unknown potential, a process in which somatic mutations in hematopoietic stem cells lead to the outgrowth of distinct subclones that have been associated with cancer; we provide evidence for this hypothesis in S3 Fig.	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('mutations', 'Var', (55, 64))	('hematopoiesis', 'biological_process', 'GO:0030097', ('75', '88'))	('DNMT3A', 'Gene', (48, 54))	('DNMT3A', 'Gene', '1788', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (251, 257))
39286	32374727	We observed a different pattern in breast tumors that metastasize to lung and harbor a mutation in KEAP1, KRAS, STK11, or EGFR (Fig 3B).	('KRAS', 'Gene', '3845', (106, 110))	('KEAP1', 'Gene', (99, 104))	('breast tumors', 'Disease', (35, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('STK11', 'Gene', '6794', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('metastasize', 'CPA', (54, 65))	('breast tumors', 'Phenotype', 'HP:0100013', (35, 48))	('KRAS', 'Gene', (106, 110))	('STK11', 'molecular_function', 'GO:0033868', ('112', '117'))	('KEAP1', 'Gene', '9817', (99, 104))	('mutation', 'Var', (87, 95))	('EGFR', 'Gene', '1956', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('EGFR', 'Gene', (122, 126))	('breast tumors', 'Disease', 'MESH:D001943', (35, 48))	('STK11', 'Gene', (112, 117))
39288	32374727	Furthermore, we observed that breast cancer metastases at any site that harbor mutations in KEAP1, KRAS, and STK11, a triplet commonly associated with lung cancer, genomically resemble lung tumors (100% vs. 18%, p = 2e-8, n = 13).	('STK11', 'Gene', (109, 114))	('lung tumors', 'Disease', 'MESH:D008175', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('lung cancer', 'Disease', (151, 162))	('associated', 'Reg', (135, 145))	('lung tumors', 'Phenotype', 'HP:0100526', (185, 196))	('KRAS', 'Gene', '3845', (99, 103))	('mutations', 'Var', (79, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('STK11', 'Gene', '6794', (109, 114))	('lung tumors', 'Disease', (185, 196))	('KRAS', 'Gene', (99, 103))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('breast cancer metastases', 'Disease', (30, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('breast cancer metastases', 'Disease', 'MESH:D001943', (30, 54))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('KEAP1', 'Gene', '9817', (92, 97))	('KEAP1', 'Gene', (92, 97))	('STK11', 'molecular_function', 'GO:0033868', ('109', '114'))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
39289	32374727	Consistent with these findings, we found enrichment for additional lung-associated alterations in this set of tumors including mutations in LRP1B (21.2% vs. 8.2%, p = 0.03) and deletions of CDKN2A/B (11.5% vs. 4.5%, p = 0.02).	('deletions', 'Var', (177, 186))	('CDKN2A/B', 'Gene', '1029;1030', (190, 198))	('LRP1B', 'Gene', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('LRP1B', 'Gene', '53353', (140, 145))	('CDKN2A/B', 'Gene', (190, 198))	('mutations', 'Var', (127, 136))	('lung-associated', 'Disease', (67, 82))
39294	32374727	We have conducted a comprehensive analysis of real-world breast cancer metastases sequenced during standard clinical care and show enrichment for (i) mechanisms of acquired resistance and (ii) alterations that may induce or accelerate metastasis.	('breast cancer metastases', 'Disease', (57, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('alterations', 'Var', (193, 204))	('accelerate', 'PosReg', (224, 234))	('induce', 'Reg', (214, 220))	('metastasis', 'CPA', (235, 245))	('breast cancer metastases', 'Disease', 'MESH:D001943', (57, 81))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
39296	32374727	Mutations in the ESR1 ligand-binding domain are the principal feature of hormone receptor-positive metastatic breast cancer, arising in response to aromatase inhibition and allowing the tumor to progress in the absence of estrogen.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('binding', 'molecular_function', 'GO:0005488', ('29', '36'))	('aromatase', 'Gene', '1588', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('hormone receptor', 'Gene', (73, 89))	('progress', 'PosReg', (195, 203))	('hormone receptor', 'Gene', '3164', (73, 89))	('tumor', 'Disease', (186, 191))	('ESR1', 'Gene', '2099', (17, 21))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('inhibition', 'NegReg', (158, 168))	('ligand', 'molecular_function', 'GO:0005488', ('22', '28'))	('breast cancer', 'Disease', (110, 123))	('ESR1', 'Gene', (17, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('aromatase', 'Gene', (148, 157))
39297	32374727	Therapies that modulate the mutant receptor are in clinical trials, and ESR1 mutations in circulating tumor DNA are a promising biomarker for disease progression.	('ESR1', 'Gene', '2099', (72, 76))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('ESR1', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
39298	32374727	We have shown that specific ESR1 hotspot mutations are associated with specific metastatic niches and disease histologies, suggesting the possibility of cofactor interactions or biological contexts that could be druggable; prior work has demonstrated functional differences between ESR1 hotspot mutations in vitro and shown that hotspots differentially respond to drug.	('ESR1', 'Gene', (28, 32))	('ESR1', 'Gene', (282, 286))	('mutations', 'Var', (295, 304))	('ESR1', 'Gene', '2099', (28, 32))	('ESR1', 'Gene', '2099', (282, 286))
39299	32374727	The development of targeted therapy against ESR1 mutations is an active area of research with great promise for treating metastatic disease, and a deeper understanding of how specific mutations function in vivo will be crucial for optimizing patient outcomes.	('mutations', 'Var', (49, 58))	('ESR1', 'Gene', '2099', (44, 48))	('patient', 'Species', '9606', (242, 249))	('metastatic disease', 'Disease', (121, 139))	('ESR1', 'Gene', (44, 48))
39301	32374727	The enrichment for CTCF mutations that we see in metastatic disease is not an anticipated resistance mechanism.	('CTCF', 'Gene', '10664', (19, 23))	('mutations', 'Var', (24, 33))	('metastatic disease', 'Disease', (49, 67))	('CTCF', 'Gene', (19, 23))
39302	32374727	CTCF binding site mutations are enriched in multiple cancers, and CTCF mutations in cancer have been shown to specifically alter interactions with promoters or insulators of genes associated with proliferation.	('interactions', 'Interaction', (129, 141))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('CTCF', 'Gene', (0, 4))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('CTCF', 'Gene', (66, 70))	('CTCF', 'Gene', '10664', (0, 4))	('alter', 'Reg', (123, 128))	('mutations', 'Var', (71, 80))	('multiple cancers', 'Disease', (44, 60))	('CTCF', 'Gene', '10664', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('binding', 'molecular_function', 'GO:0005488', ('5', '12'))	('multiple cancers', 'Disease', 'MESH:D009369', (44, 60))	('mutations', 'Var', (18, 27))
39303	32374727	The observed enrichment is consistent with the hypothesis that multiple steps in the metastatic cascade involve epigenetic transitions that allow tumor cells to co-opt biological processes to promote growth and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('promote', 'PosReg', (192, 199))	('tumor', 'Disease', (146, 151))	('epigenetic transitions', 'Var', (112, 134))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
39313	32374727	Cancer is a heterogeneous disease:each patient presents with a unique constellation of genetic and epigenetic alterations that have transformed healthy tissue into a malignancy.	('patient', 'Species', '9606', (39, 46))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('epigenetic alterations', 'Var', (99, 121))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('malignancy', 'Disease', (166, 176))
39363	28685067	Higher age at menarche, high hormonal levels, nulliparity, tobacco use and obesity are well-known risk factors associated with 47% of BC and OC cases.	('BC', 'Phenotype', 'HP:0003002', (134, 136))	('obesity', 'Disease', (75, 82))	('menarche', 'biological_process', 'GO:0042696', ('14', '22'))	('associated', 'Reg', (111, 121))	('tobacco', 'Species', '4097', (59, 66))	('obesity', 'Phenotype', 'HP:0001513', (75, 82))	('OC', 'Phenotype', 'HP:0100615', (141, 143))	('nulliparity', 'Var', (46, 57))	('obesity', 'Disease', 'MESH:D009765', (75, 82))
39364	28685067	Approximately 5-10% of the cases are attributed to genetic factors that include BRCA (BRCA1 and BRCA2) gene mutations.	('attributed', 'Reg', (37, 47))	('BRCA1', 'Gene', '672', (86, 91))	('BRCA', 'Gene', '675', (80, 84))	('mutations', 'Var', (108, 117))	('BRCA', 'Gene', '675', (86, 90))	('BRCA', 'Gene', (96, 100))	('BRCA2', 'Gene', '675', (96, 101))	('BRCA1', 'Gene', (86, 91))	('BRCA', 'Gene', '675', (96, 100))	('BRCA', 'Gene', (80, 84))	('BRCA', 'Gene', (86, 90))	('BRCA2', 'Gene', (96, 101))
39365	28685067	BRCA1/2 are autosomal dominant tumor suppressor genes present on chromosomes 17 and 13, respectively, mutated in ~30-40% of familial BC cases and in 60-85% of hereditary OC cases.	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('OC', 'Phenotype', 'HP:0100615', (170, 172))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('BC', 'Phenotype', 'HP:0003002', (133, 135))	('tumor', 'Disease', (31, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('mutated', 'Var', (102, 109))	('familial BC', 'Disease', (124, 135))	('BRCA1/2', 'Gene', (0, 7))
39374	28685067	Prognostic factors other than FIGO stage include age, American Society of Anesthesiologists score, family history positive for BRCA1/2 mutations, residual disease after surgery, tumor grade and histology, amount of ascites at debulking surgery, serum level of carbohydrate antigen (CA)-125, gene expression patterns and immunological status.	('ascites', 'Disease', 'MESH:D001201', (215, 222))	('ascites', 'Disease', (215, 222))	('BRCA1/2', 'Gene', '672;675', (127, 134))	('tumor', 'Disease', (178, 183))	('ascites', 'Phenotype', 'HP:0001541', (215, 222))	('carbohydrate antigen (CA)-125', 'Gene', '94025', (260, 289))	('gene expression', 'biological_process', 'GO:0010467', ('291', '306'))	('mutations', 'Var', (135, 144))	('carbohydrate antigen (CA)-125', 'Gene', (260, 289))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('serum', 'MPA', (245, 250))	('BRCA1/2', 'Gene', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
39378	28685067	Hormonal receptor (ER/PR) status and amplification of the HER2/neu gene are used as prognostic as well as predictive factors.	('ER', 'Gene', '2099', (59, 61))	('HER2/neu', 'Gene', (58, 66))	('amplification', 'Var', (37, 50))	('PR', 'Gene', '5241', (22, 24))	('ER', 'Gene', '2099', (19, 21))	('HER2/neu', 'Gene', '2064', (58, 66))
39386	28685067	Apart from these receptors playing a predictive role, the expression of another sex steroid hormone receptor, androgen receptor (AR), has been associated with a favorable outcome in BC and OC.	('associated', 'Reg', (143, 153))	('androgen receptor', 'Gene', (110, 127))	('BC', 'Phenotype', 'HP:0003002', (182, 184))	('AR', 'Gene', '367', (129, 131))	('expression', 'Var', (58, 68))	('androgen receptor', 'Gene', '367', (110, 127))	('hormone receptor', 'Gene', '3164', (92, 108))	('OC', 'Phenotype', 'HP:0100615', (189, 191))	('hormone receptor', 'Gene', (92, 108))
39407	28685067	A recent study identified several genomic alterations, including loss of CDH1 and phosphatase and tensin homolog, AKT activation and aberrations in T-box transcription factor 3 and forkhead box protein A1, differentiating ILC from IDC and suggesting ILC to be a distinct BC subtype.	('loss', 'NegReg', (65, 69))	('AKT', 'Gene', '207', (114, 117))	('activation', 'PosReg', (118, 128))	('CDH1', 'Gene', (73, 77))	('CDH1', 'Gene', '999', (73, 77))	('phosphatase', 'molecular_function', 'GO:0016791', ('82', '93'))	('AKT', 'Gene', (114, 117))	('IDC', 'Disease', (231, 234))	('ILC', 'Disease', (250, 253))	('transcription factor', 'molecular_function', 'GO:0000981', ('154', '174'))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('BC', 'Phenotype', 'HP:0003002', (271, 273))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('82', '112'))	('differentiating', 'Reg', (206, 221))	('ILC', 'Disease', (222, 225))	('aberrations', 'Var', (133, 144))	('T-box', 'Protein', (148, 153))	('transcription', 'biological_process', 'GO:0006351', ('154', '167'))
39408	28685067	Another study demonstrated a higher incidence of HER2, HER3 and AKT1 mutations in ILC rather than in IDC, individualizing treatment for ILC.	('AKT1', 'Gene', (64, 68))	('mutations', 'Var', (69, 78))	('HER3', 'Gene', (55, 59))	('HER3', 'Gene', '2065', (55, 59))	('ILC', 'Disease', (82, 85))	('AKT1', 'Gene', '207', (64, 68))	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (49, 53))
39412	28685067	A similar study using DNA microarray on primary breast tumors of 117 patients revealed a 70-gene signature (poor-prognosis signature) involved in cell cycle, angiogenesis, invasion and metastasis, as well as signatures that recognize tumors harboring BRCA1 mutations.	('BRCA1', 'Gene', '672', (251, 256))	('mutations', 'Var', (257, 266))	('BRCA1', 'Gene', (251, 256))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('patients', 'Species', '9606', (69, 77))	('breast tumors', 'Disease', (48, 61))	('breast tumors', 'Disease', 'MESH:D001943', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('angiogenesis', 'biological_process', 'GO:0001525', ('158', '170'))	('breast tumors', 'Phenotype', 'HP:0100013', (48, 61))	('tumors', 'Disease', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('angiogenesis', 'CPA', (158, 170))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('cell cycle', 'biological_process', 'GO:0007049', ('146', '156'))	('tumors', 'Disease', (234, 240))
39414	28685067	Genomic sequencing in BC has identified somatic and point mutations in HER2 and ESR1, respectively.	('BC', 'Phenotype', 'HP:0003002', (22, 24))	('ESR1', 'Gene', '2099', (80, 84))	('HER2', 'Gene', (71, 75))	('HER2', 'Gene', '2064', (71, 75))	('ESR1', 'Gene', (80, 84))	('point mutations', 'Var', (52, 67))
39441	28685067	An earlier study on Omani BC patients revealed no significant mutational rates in BRCA1/2, suggesting that other genes directly linked to BRCA1/2, such as BRIP1, may be involved in the onset of BC, either independently or in association with BRCA1/2.	('involved', 'Reg', (169, 177))	('BRCA1/2', 'Gene', '672;675', (82, 89))	('mutational', 'Var', (62, 72))	('patients', 'Species', '9606', (29, 37))	('BRIP1', 'Gene', (155, 160))	('BRCA1/2', 'Gene', (138, 145))	('BC', 'Phenotype', 'HP:0003002', (26, 28))	('BRCA1/2', 'Gene', (242, 249))	('BC', 'Phenotype', 'HP:0003002', (194, 196))	('BRCA1/2', 'Gene', '672;675', (138, 145))	('BRIP1', 'Gene', '83990', (155, 160))	('BRCA1/2', 'Gene', (82, 89))	('BRCA1/2', 'Gene', '672;675', (242, 249))
39460	28685067	Loss of DSP results in abnormalities of cell adhesion and is associated with tumor progression in several cancers, including BC.	('associated with', 'Reg', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('abnormalities', 'Var', (23, 36))	('cancers', 'Disease', (106, 113))	('DSP', 'Gene', (8, 11))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('BC', 'Phenotype', 'HP:0003002', (125, 127))	('abnormalities of cell adhesion', 'Phenotype', 'HP:0008352', (23, 53))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('DSP', 'Gene', '1832', (8, 11))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', (77, 82))	('cell adhesion', 'biological_process', 'GO:0007155', ('40', '53'))	('cell adhesion', 'CPA', (40, 53))
39465	28685067	While mutations in the RHPN2 gene are associated with colorectal and lung cancer, in malignant glioma RHPN2 may cause mesenchymal transformation by activating RhoA.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('cause', 'Reg', (112, 117))	('associated', 'Reg', (38, 48))	('RHPN2', 'Gene', (23, 28))	('malignant glioma RHPN2', 'Disease', (85, 107))	('RHPN2', 'Gene', (102, 107))	('RhoA', 'Gene', (159, 163))	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (54, 80))	('RHPN2', 'Gene', '85415', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RhoA', 'Gene', '387', (159, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('mesenchymal transformation', 'CPA', (118, 144))	('malignant glioma RHPN2', 'Disease', 'MESH:D005910', (85, 107))	('activating', 'PosReg', (148, 158))	('RHPN2', 'Gene', '85415', (23, 28))	('mutations', 'Var', (6, 15))
39471	28685067	FBXW7 is a TSG, silenced either due to hypermethylation or mutations/deletions, causing accumulation or increase of several oncoproteins, including c-Jun, c-myc, NOTCH, cyclin E, Aurora-A and ENO1.	('TSG', 'Gene', '57045', (11, 14))	('c-myc', 'Gene', '4609', (155, 160))	('Aurora-A', 'Gene', '6790', (179, 187))	('FBXW7', 'Gene', (0, 5))	('TSG', 'Gene', (11, 14))	('NOTCH', 'MPA', (162, 167))	('Aurora-A', 'Gene', (179, 187))	('cyclin E', 'Protein', (169, 177))	('hypermethylation', 'Var', (39, 55))	('ENO1', 'Gene', (192, 196))	('c-Jun', 'Gene', '3725', (148, 153))	('accumulation', 'PosReg', (88, 100))	('FBXW7', 'Gene', '55294', (0, 5))	('c-Jun', 'Gene', (148, 153))	('c-myc', 'Gene', (155, 160))	('ENO1', 'Gene', '2023', (192, 196))	('increase', 'PosReg', (104, 112))	('cyclin', 'molecular_function', 'GO:0016538', ('169', '175'))	('mutations/deletions', 'Var', (59, 78))
39475	28685067	Although missense mutations in FBXW7 are associated with the onset and progression of various tumors, FBXW7 was not found to be frequently mutated in OC.	('FBXW7', 'Gene', '55294', (102, 107))	('associated', 'Reg', (41, 51))	('OC', 'Phenotype', 'HP:0100615', (150, 152))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('FBXW7', 'Gene', (102, 107))	('FBXW7', 'Gene', '55294', (31, 36))	('tumors', 'Disease', (94, 100))	('FBXW7', 'Gene', (31, 36))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('missense mutations', 'Var', (9, 27))
39476	28685067	These results prompted us to suspect FBXW7 of contributing to the pathogenesis of OC through different mechanisms, such as silencing due to promoter hypermethylation.	('FBXW7', 'Gene', (37, 42))	('silencing', 'MPA', (123, 132))	('OC', 'Phenotype', 'HP:0100615', (82, 84))	('contributing', 'Reg', (46, 58))	('promoter hypermethylation', 'Var', (140, 165))	('FBXW7', 'Gene', '55294', (37, 42))	('pathogenesis', 'biological_process', 'GO:0009405', ('66', '78'))
39486	25192706	There has been some suggestion in the lay media that bra wearing may be a risk factor for breast cancer based on the potential for bras to impede lymph circulation and drainage and thus interfere with the process of waste and toxin removal.	('impede lymph circulation', 'Phenotype', 'HP:0001004', (139, 163))	('impede', 'NegReg', (139, 145))	('lymph circulation', 'biological_process', 'GO:0003017', ('146', '163'))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('bras', 'Var', (131, 135))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('interfere', 'NegReg', (186, 195))
39493	25192706	All ILC cases (identified using ICD-O histology codes of 8520, 8522, and 8524) and a random sample of 25% of the IDC cases (identified using ICD-O histology code of 8500) were targeted for recruitment in order to enroll equal numbers of ILC and IDC cases.	('IDC', 'Gene', (245, 248))	('IDC', 'Gene', '4000', (113, 116))	('8522', 'Var', (63, 67))	('IDC', 'Gene', (113, 116))	('ILC', 'Disease', (237, 240))	('ILC', 'Disease', (4, 7))	('IDC', 'Gene', '4000', (245, 248))
39543	22662240	While beta-catenin is rapidly degraded upon loss of E-cadherin, p120 translocates and resides in the cytosol, where it regulates anchorage-independent tumor growth and metastasis through Mrip-dependent activation of the Rock pathway.	('E-cadherin', 'Protein', (52, 62))	('Rock', 'Gene', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('p120', 'Gene', '1500', (64, 68))	('beta-catenin', 'Gene', '1499', (6, 18))	('regulates', 'Reg', (119, 128))	('p120', 'Gene', (64, 68))	('tumor', 'Disease', (151, 156))	('Rock', 'Gene', '6093', (220, 224))	('cytosol', 'cellular_component', 'GO:0005829', ('101', '108'))	('loss', 'Var', (44, 48))	('Mrip', 'Gene', '23164', (187, 191))	('cadherin', 'molecular_function', 'GO:0008014', ('54', '62'))	('Mrip', 'Gene', (187, 191))	('beta-catenin', 'Gene', (6, 18))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
39568	22662240	Next, cells were transfected with either 600 ng of the Kaiso-specific reporter (pGL3-4XKBS), a mutated Kaiso reporter (pGL3-4XKBS CAmut) or empty vector (pGL3-Control) and co-transfected with 5 ng Renilla (pRL-CMV, Promega, Leiden, The Netherlands) for normalization of transfection efficiency, using Lipofectamine 2000 (Invitrogen) according to manufactures instructions.	('pGL3', 'Gene', '6391', (119, 123))	('pGL3', 'Gene', '6391', (154, 158))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (301, 319))	('pGL', 'molecular_function', 'GO:0004598', ('154', '157'))	('pGL3', 'Gene', (80, 84))	('Kaiso', 'Gene', '56805', (55, 60))	('Kaiso', 'Gene', '56805', (103, 108))	('mutated', 'Var', (95, 102))	('pGL', 'molecular_function', 'GO:0004598', ('119', '122'))	('pGL3', 'Gene', '6391', (80, 84))	('Kaiso', 'Gene', (103, 108))	('pGL', 'molecular_function', 'GO:0004598', ('80', '83'))	('pGL3', 'Gene', (154, 158))	('Kaiso', 'Gene', (55, 60))	('pGL3', 'Gene', (119, 123))
39595	22662240	Although Kaiso expression was observed in E-cadherin-expressing as well as in E-cadherin-mutant cells, nuclear Kaiso was enriched in MCF10a cells, whereas IPH-926 virtually lacked nuclear Kaiso (Figure 3A).	('Kaiso', 'Gene', (9, 14))	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('MCF10a', 'CellLine', 'CVCL:0598', (133, 139))	('Kaiso', 'Gene', '56805', (188, 193))	('IPH', 'Chemical', 'MESH:D019800', (155, 158))	('Kaiso', 'Gene', '56805', (111, 116))	('nuclear', 'MPA', (103, 110))	('Kaiso', 'Gene', (188, 193))	('E-cadherin-mutant', 'Var', (78, 95))	('Kaiso', 'Gene', '56805', (9, 14))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('Kaiso', 'Gene', (111, 116))
39600	22662240	In line with our expression data, we observed that Kaiso-dependent transcriptional repression was significantly higher in Trp53Delta/Delta-4 than in mILC-1 cells (p = 0.015; Figure 3D).	('Kaiso', 'Gene', (51, 56))	('higher', 'PosReg', (112, 118))	('Trp53Delta/Delta-4', 'Var', (122, 140))	('Kaiso', 'Gene', '56805', (51, 56))
39601	22662240	Furthermore, transcriptional repression of the 4XKBS reporter was attenuated by exogenous Kaiso expression in mILC-1 cells (Figure 3D).	('exogenous', 'Var', (80, 89))	('attenuated', 'NegReg', (66, 76))	('Kaiso', 'Gene', '56805', (90, 95))	('transcriptional repression', 'MPA', (13, 39))	('Kaiso', 'Gene', (90, 95))
39606	22662240	In this setting, PLZF confers oncogenic potential through fusion to the hormone-binding domain of RARalpha, subsequent binding to its target sites and local recruitment of histone deacetylases.	('PLZF', 'Gene', (17, 21))	('histone deacetylases', 'Protein', (172, 192))	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('fusion', 'Var', (58, 64))	('recruitment', 'PosReg', (157, 168))	('RARalpha', 'Gene', '5914', (98, 106))	('hormone-binding', 'molecular_function', 'GO:0042562', ('72', '87'))	('PLZF', 'Gene', '7704', (17, 21))	('oncogenic potential', 'CPA', (30, 49))	('binding', 'Interaction', (119, 126))	('RARalpha', 'Gene', (98, 106))
39608	22662240	In contrast, HIC1 is a candidate tumor suppressor that is often found mutated or hypermethylated in human cancer.	('HIC1', 'Gene', (13, 17))	('HIC1', 'Gene', '3090', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('hypermethylated', 'Var', (81, 96))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('human', 'Species', '9606', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('cancer', 'Disease', (106, 112))	('tumor', 'Disease', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
39613	22662240	Interestingly, genetic Kaiso ablation results in a delay in intestinal tumorigenesis in the context of APC MIN/+ mice, which suggests that Kaiso may indeed contribute to intestinal tumor progression through silencing of tumor suppressors.	('intestinal tumor', 'Disease', 'MESH:D007414', (170, 186))	('ablation', 'Var', (29, 37))	('tumor', 'Disease', (220, 225))	('intestinal tumor', 'Disease', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('intestinal tumor', 'Disease', (170, 186))	('contribute', 'Reg', (156, 166))	('APC MIN', 'Disease', 'MESH:D011125', (103, 110))	('delay', 'NegReg', (51, 56))	('APC', 'cellular_component', 'GO:0005680', ('103', '106'))	('Kaiso', 'Gene', '56805', (23, 28))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('Kaiso', 'Gene', (23, 28))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (181, 186))	('intestinal tumor', 'Disease', 'MESH:D007414', (60, 76))	('silencing', 'NegReg', (207, 216))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Kaiso', 'Gene', '56805', (139, 144))	('APC MIN', 'Disease', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('Kaiso', 'Gene', (139, 144))
39625	22662240	These tumors were also associated with high EGFR expression, which is associated with worse prognosis for basal/triple-negative breast cancers.	('high', 'Var', (39, 43))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('expression', 'MPA', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('breast cancers', 'Disease', 'MESH:D001943', (128, 142))	('EGFR', 'Gene', (44, 48))	('breast cancers', 'Disease', (128, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
39633	22662240	ILC is characterized by loss of the AJ complex through early mutational inactivation of E-cadherin and subsequent translocation of p120 to the cytosol.	('cytosol', 'cellular_component', 'GO:0005829', ('143', '150'))	('cadherin', 'molecular_function', 'GO:0008014', ('90', '98'))	('p120', 'Gene', (131, 135))	('AJ complex', 'Protein', (36, 46))	('E-cadherin', 'Protein', (88, 98))	('loss', 'NegReg', (24, 28))	('mutational', 'Var', (61, 71))	('ILC', 'Disease', (0, 3))	('translocation', 'MPA', (114, 127))	('p120', 'Gene', '1500', (131, 135))
39637	22662240	Recent data have indicated that phosphorylation of p120 can increase its binding to Kaiso and induce inhibition of canonical Wnt signaling.	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('inhibition', 'NegReg', (101, 111))	('phosphorylation', 'Var', (32, 47))	('p120', 'Gene', '1500', (51, 55))	('binding', 'Interaction', (73, 80))	('increase', 'PosReg', (60, 68))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('canonical Wnt signaling', 'Pathway', (115, 138))	('p120', 'Gene', (51, 55))	('Kaiso', 'Gene', '56805', (84, 89))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))	('Kaiso', 'Gene', (84, 89))
39650	25889560	The SUVmax was higher with EGFR positivity compared with EGFR negativity (P = 0.013) in IDC and higher with Ki-67 positivity compared with Ki-67 negativity in IDC and ILC (P < 0.001 and P = 0.002, respectively).	('EGFR', 'Gene', '1956', (27, 31))	('IDC', 'Gene', '4000', (88, 91))	('EGFR', 'Gene', (27, 31))	('IDC', 'Gene', (88, 91))	('higher', 'PosReg', (15, 21))	('SUVmax', 'MPA', (4, 10))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('Ki-67', 'Var', (108, 113))	('positivity', 'Var', (114, 124))	('EGFR', 'Gene', '1956', (57, 61))	('IDC', 'Gene', '4000', (159, 162))	('IDC', 'Gene', (159, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('higher', 'PosReg', (96, 102))	('EGFR', 'Gene', (57, 61))
39653	25889560	The SUVmax was significantly different according to the tumor grade, ER, EGFR, and Ki-67 for IDCs.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EGFR', 'Gene', '1956', (73, 77))	('Ki-67', 'Var', (83, 88))	('tumor', 'Disease', (56, 61))	('EGFR', 'Gene', (73, 77))	('ER', 'Gene', '2099', (69, 71))	('different', 'Reg', (29, 38))	('IDC', 'Gene', '4000', (93, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('IDC', 'Gene', (93, 96))
39694	25889560	The SUVmax was higher with EGFR positivity compared with EGFR negativity (6.92 +- 5.55 vs. 3.26 +- 3.22; P = 0.013) in the IDC group (Figure 1) and higher with Ki-67 positivity compared with Ki-67 negativity (5.58 +- 4.66 vs. 2.19 +- 2.15, IDC, P < 0.001; 4.18 +- 0.88 vs. 1.45 +- 1.22, ILC, P = 0.002) in both the IDC and ILC groups (Figures 1 and 2).	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('SUVmax', 'MPA', (4, 10))	('higher', 'PosReg', (15, 21))	('IDC', 'Gene', '4000', (123, 126))	('IDC', 'Gene', '4000', (315, 318))	('IDC', 'Gene', (123, 126))	('IDC', 'Gene', (315, 318))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('EGFR', 'Gene', '1956', (57, 61))	('IDC', 'Gene', '4000', (240, 243))	('IDC', 'Gene', (240, 243))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))	('positivity', 'Var', (32, 42))	('EGFR', 'Gene', (57, 61))	('higher', 'PosReg', (148, 154))
39714	25889560	The high rate of missing values for HER2 was due to lack of FISH results for cases showing HER2 score of 2+ on IHC staining, because the FISH was not a routine exam but an ancillary test based on request by clinicians.	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', '2064', (36, 40))	('HER2', 'Gene', (91, 95))	('score of 2+', 'Var', (96, 107))	('HER2', 'Gene', '2064', (91, 95))
39716	25889560	The SUVmax was significantly different according to the tumor grade, ER, EGFR, and Ki-67 in IDCs, but only for Ki-67 in ILCs.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EGFR', 'Gene', '1956', (73, 77))	('SUVmax', 'MPA', (4, 10))	('IDC', 'Gene', '4000', (92, 95))	('Ki-67', 'Var', (83, 88))	('IDC', 'Gene', (92, 95))	('tumor', 'Disease', (56, 61))	('EGFR', 'Gene', (73, 77))	('ER', 'Gene', '2099', (69, 71))	('different', 'Reg', (29, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
39731	19172584	The observed impact of CPM on contralateral breast cancer reduction is in agreement with findings on familial breast cancer.	('familial breast cancer', 'Disease', 'MESH:D001943', (101, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CPM', 'Var', (23, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('familial breast cancer', 'Disease', (101, 123))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (30, 57))	('reduction', 'NegReg', (58, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('contralateral breast cancer', 'Disease', (30, 57))
39733	19172584	Van Sprundel et al reported that CPM reduced the risk for contralateral breast cancer in BRCA1 or BRCA2 mutation carriers by 91%.	('CPM', 'Var', (33, 36))	('contralateral breast cancer', 'Disease', (58, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRCA1', 'Gene', (89, 94))	('BRCA2', 'Gene', (98, 103))	('mutation', 'Var', (104, 112))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (58, 85))	('reduced', 'NegReg', (37, 44))	('BRCA1', 'Gene', '672', (89, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('BRCA2', 'Gene', '675', (98, 103))
39734	19172584	Although CPM significantly reduces the risk of contralateral breast cancer, the procedure is aggressive and irreversible and is also unnecessary for patients who are not likely to develop contralateral disease.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (149, 157))	('contralateral disease', 'Disease', 'MESH:D009069', (188, 209))	('reduces', 'NegReg', (27, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (47, 74))	('contralateral breast cancer', 'Disease', (47, 74))	('contralateral disease', 'Disease', (188, 209))	('CPM', 'Var', (9, 12))
39762	19172584	Of the 542 unilateral breast cancer patients who underwent CPM, 25 patients (4.6%) had an occult malignancy, 8 were diagnosed with invasive carcinomas (1.5%), and 17 were diagnosed with ductal carcinoma in situ (DCIS) (3.1%), in the contralateral breast on final pathology.	('DCIS', 'Phenotype', 'HP:0030075', (212, 216))	('invasive carcinomas', 'Disease', 'MESH:D009361', (131, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('malignancy', 'Disease', (97, 107))	('ductal carcinoma in situ', 'Disease', (186, 210))	('patients', 'Species', '9606', (36, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('diagnosed', 'Reg', (116, 125))	('invasive carcinomas', 'Disease', (131, 150))	('unilateral breast cancer', 'Disease', 'MESH:D000069584', (11, 35))	('patients', 'Species', '9606', (67, 75))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (186, 210))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('unilateral breast cancer', 'Disease', (11, 35))	('CPM', 'Var', (59, 62))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (193, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (186, 202))	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('unilateral breast', 'Phenotype', 'HP:0012813', (11, 28))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (186, 210))
39771	19172584	At a median follow-up of 32.7 months, 67 patients who underwent CPM had developed 36 local, 13 regional, and 36 systemic recurrences, but no patients had developed a contralateral breast cancer.	('CPM', 'Var', (64, 67))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (166, 193))	('patients', 'Species', '9606', (41, 49))	('contralateral breast cancer', 'Disease', (166, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('patients', 'Species', '9606', (141, 149))
39796	19172584	This finding suggests that, in our cohort, CPM led to early detection and resection of already existing contralateral breast cancers more than prevention of expected contralateral cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('contralateral breast cancers', 'Disease', (104, 132))	('CPM', 'Var', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('contralateral cancers', 'Disease', (166, 187))	('contralateral breast cancers', 'Disease', 'MESH:D001943', (104, 132))	('contralateral cancers', 'Disease', 'MESH:D009369', (166, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
39823	19172584	Page et al found that invasive carcinoma occurred 3 times more frequently in contralateral breasts with ALH than without ALH, suggesting that ALH is an intermediate between a precursor and a marker of generalized risk of cancer in both breasts.	('ALH', 'Chemical', '-', (121, 124))	('ALH', 'Var', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('cancer', 'Disease', (221, 227))	('invasive carcinoma', 'Disease', 'MESH:D009361', (22, 40))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('invasive carcinoma', 'Disease', (22, 40))	('ALH', 'Chemical', '-', (104, 107))	('ALH', 'Chemical', '-', (142, 145))
39835	19172584	In conclusion, we found that unilateral breast cancer patients who underwent CPM had a low risk of developing contralateral breast cancer.	('contralateral breast cancer', 'Disease', 'MESH:D001943', (110, 137))	('CPM', 'Var', (77, 80))	('unilateral breast', 'Phenotype', 'HP:0012813', (29, 46))	('unilateral breast cancer', 'Disease', (29, 53))	('patients', 'Species', '9606', (54, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('unilateral breast cancer', 'Disease', 'MESH:D000069584', (29, 53))	('contralateral breast cancer', 'Disease', (110, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
39838	23270564	FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('breast carcinoma', 'Phenotype', 'HP:0003002', (73, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('haematogenous lobular breast carcinoma', 'Disease', 'MESH:D018275', (51, 89))	('haematogenous lobular breast carcinoma', 'Disease', (51, 89))	('lacks', 'NegReg', (177, 182))	('Lobular breast carcinoma', 'Disease', 'MESH:D018275', (90, 114))	('Lobular breast carcinoma', 'Disease', (90, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('breast carcinoma', 'Phenotype', 'HP:0003002', (98, 114))	('metastatic lymph-nodal', 'Disease', (24, 46))	('amplification', 'Var', (7, 20))	('FGFR-1', 'Gene', (0, 6))	('FGFR-1', 'Gene', '2260', (0, 6))
39845	23270564	We distinguished amplification (>6 or cluster of signals) versus gains (3-6 signals) of the locus specific FGFR-1 gene.	('FGFR-1', 'Gene', '2260', (107, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('amplification', 'Var', (17, 30))	('gains', 'PosReg', (65, 70))	('FGFR-1', 'Gene', (107, 113))
39847	23270564	The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification.	('breast carcinoma', 'Phenotype', 'HP:0003002', (69, 85))	('FGFR-1', 'Gene', '2260', (21, 27))	('FGFR', 'molecular_function', 'GO:0005007', ('95', '99'))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('breast carcinomas', 'Disease', 'MESH:D001943', (69, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('breast carcinomas', 'Disease', (69, 86))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGFR-1', 'Gene', (95, 101))	('FGFR-1', 'Gene', '2260', (95, 101))	('breast carcinomas', 'Phenotype', 'HP:0003002', (69, 86))	('amplification', 'Var', (28, 41))	('FGFR-1', 'Gene', (21, 27))
39851	23270564	1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR1 amplification could be approached to the new target biological therapy such as emerging FGFR-1 inhibitors.	('breast carcinoma', 'Phenotype', 'HP:0003002', (292, 308))	('breast carcinoma', 'Disease', (292, 308))	('breast carcinoma', 'Disease', 'MESH:D001943', (34, 50))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (26, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('carcinomas', 'Disease', 'MESH:D002277', (199, 209))	('FGFR1', 'Gene', '2260', (314, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('lobular breast carcinoma', 'Disease', (26, 50))	('FGFR-1', 'Gene', (408, 414))	('breast carcinoma', 'Phenotype', 'HP:0003002', (34, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('FGFR', 'molecular_function', 'GO:0005007', ('314', '318'))	('FGFR-1', 'Gene', (59, 65))	('amplification', 'Var', (320, 333))	('breast carcinoma', 'Disease', 'MESH:D001943', (292, 308))	('FGFR1', 'Gene', (314, 319))	('patients', 'Species', '9606', (248, 256))	('FGFR-1', 'Gene', '2260', (408, 414))	('carcinomas', 'Disease', (199, 209))	('chromogenic signals', 'MPA', (97, 116))	('FGFR-1', 'Gene', '2260', (59, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('gains', 'PosReg', (88, 93))	('FGFR', 'molecular_function', 'GO:0005007', ('408', '412'))
39885	23270564	The data reported herein, show that: 1) FGFR-1 amplification is observed in a subset of lymph-nodal and haematogenous metastases from lobular breast carcinoma; 2) minor heterogeneity is scored in matched primary and metastatic lobular breast carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR-1 amplification may be considered a potential patients' subset benefiting from FGFR-1 inhibitor.	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (227, 251))	('breast carcinomas', 'Phenotype', 'HP:0003002', (235, 252))	('breast carcinoma', 'Disease', 'MESH:D001943', (335, 351))	('breast carcinoma', 'Phenotype', 'HP:0003002', (235, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('FGFR-1', 'Gene', '2260', (40, 46))	('FGFR-1', 'Gene', '2260', (357, 363))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('lobular breast carcinomas', 'Disease', 'MESH:D018275', (227, 252))	('patients', 'Species', '9606', (408, 416))	('FGFR-1', 'Gene', (441, 447))	('patients', 'Species', '9606', (291, 299))	('breast carcinoma', 'Phenotype', 'HP:0003002', (335, 351))	('breast carcinoma', 'Disease', 'MESH:D001943', (142, 158))	('lobular breast carcinomas', 'Disease', (227, 252))	('breast carcinoma', 'Disease', (335, 351))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('FGFR-1', 'Gene', '2260', (441, 447))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (134, 158))	('breast carcinoma', 'Phenotype', 'HP:0003002', (142, 158))	('breast carcinoma', 'Disease', 'MESH:D001943', (235, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('metastases', 'Disease', (118, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('441', '445'))	('FGFR-1', 'Gene', (40, 46))	('lobular breast carcinoma', 'Disease', (134, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('FGFR', 'molecular_function', 'GO:0005007', ('357', '361'))	('amplification', 'Var', (364, 377))	('FGFR-1', 'Gene', (357, 363))
39894	23270564	concluded that amplification and overexpression of FGFR1 may be a major contributor to poor prognosis in luminal-type breast cancers, driving anchorage-independent proliferation and endocrine therapy resistance .	('overexpression', 'PosReg', (33, 47))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('amplification', 'Var', (15, 28))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('anchorage-independent proliferation', 'CPA', (142, 177))	('FGFR1', 'Gene', (51, 56))	('driving', 'Reg', (134, 141))	('endocrine therapy resistance', 'CPA', (182, 210))	('luminal-type breast cancers', 'Disease', 'MESH:D001943', (105, 132))	('luminal-type breast cancers', 'Disease', (105, 132))	('FGFR1', 'Gene', '2260', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
39895	23270564	In our study we found a subset of lobular breast carcinoma, be characterized by FGFR-1 amplification or gains of chromogenic signals, not only in primary tumours but also in the metastatic tissue.	('FGFR-1', 'Gene', (80, 86))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (34, 58))	('FGFR-1', 'Gene', '2260', (80, 86))	('primary tumours', 'Disease', 'MESH:D009369', (146, 161))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('breast carcinoma', 'Phenotype', 'HP:0003002', (42, 58))	('gains', 'PosReg', (104, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('FGFR', 'molecular_function', 'GO:0005007', ('80', '84'))	('chromogenic signals', 'MPA', (113, 132))	('primary tumours', 'Disease', (146, 161))	('lobular breast carcinoma', 'Disease', (34, 58))	('amplification', 'Var', (87, 100))
39902	23270564	Intratumor heterogeneity may foster tumor adaptation and therapeutic failure .	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('therapeutic failure', 'CPA', (57, 76))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('heterogeneity', 'Var', (11, 24))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (5, 10))	('foster', 'PosReg', (29, 35))	('tumor', 'Disease', (36, 41))
39903	23270564	We found no significant heterogeneity in matched primary and metastatic lobular breast carcinomas in regard to FGFR-1 gains or amplification.	('FGFR-1', 'Gene', (111, 117))	('breast carcinomas', 'Phenotype', 'HP:0003002', (80, 97))	('FGFR-1', 'Gene', '2260', (111, 117))	('lobular breast carcinomas', 'Disease', (72, 97))	('breast carcinoma', 'Phenotype', 'HP:0003002', (80, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('gains', 'Var', (118, 123))	('amplification', 'Var', (127, 140))	('lobular breast carcinomas', 'Disease', 'MESH:D018275', (72, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
39912	23270564	They identified a group of carcinomas with amplifications at 11q13 and/or 8p12 and was predominantly composed of estrogen receptor-positive tumors and presented a large proportion of lobular cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('carcinomas', 'Disease', (27, 37))	('carcinomas', 'Disease', 'MESH:D002277', (27, 37))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('lobular cancers', 'Disease', 'MESH:D013274', (183, 198))	('amplifications at 11q13', 'Var', (43, 66))	('estrogen receptor', 'Gene', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('estrogen receptor', 'Gene', '2099', (113, 130))	('lobular cancers', 'Disease', (183, 198))
39913	23270564	Coamplifications of the 11q13 and 8p12 regions are common in breast carcinomas, suggesting synergy between the amplicons .	('breast carcinomas', 'Disease', 'MESH:D001943', (61, 78))	('common', 'Reg', (51, 57))	('breast carcinomas', 'Disease', (61, 78))	('breast carcinomas', 'Phenotype', 'HP:0003002', (61, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('breast carcinoma', 'Phenotype', 'HP:0003002', (61, 77))	('Coamplifications', 'Var', (0, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
39916	23270564	suggested that FGFR-1 amplification may be an independent predictor of overall survival in patients affected by breast carcinoma .	('breast carcinoma', 'Disease', (112, 128))	('patients', 'Species', '9606', (91, 99))	('breast carcinoma', 'Disease', 'MESH:D001943', (112, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('amplification', 'Var', (22, 35))	('FGFR-1', 'Gene', (15, 21))	('FGFR-1', 'Gene', '2260', (15, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('breast carcinoma', 'Phenotype', 'HP:0003002', (112, 128))
39920	23270564	suggested that FGFR-1 amplification or protein overexpression in breast cancers may be an indicator for brivanib treatment, where it may have direct anti-proliferative effects in addition to its' anti-angiogenic effects .	('brivanib', 'Chemical', 'MESH:C509922', (104, 112))	('anti-proliferative effects', 'CPA', (149, 175))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('overexpression', 'PosReg', (47, 61))	('breast cancers', 'Phenotype', 'HP:0003002', (65, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('amplification', 'Var', (22, 35))	('FGFR-1', 'Gene', (15, 21))	('breast cancers', 'Disease', 'MESH:D001943', (65, 79))	('FGFR-1', 'Gene', '2260', (15, 21))	('breast cancers', 'Disease', (65, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('protein', 'Protein', (39, 46))
39922	23270564	suggested that the addition of FGFR inhibitors to ER-targeted therapy will yield a superior antitumor effect .	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inhibitors', 'Var', (36, 46))	('tumor', 'Disease', (96, 101))	('FGFR', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
39923	23270564	reported the increased frequency of FGFR1 amplification in invasive carcinomas compared with pure in situ ductal carcinoma .	('situ ductal carcinoma', 'Disease', 'MESH:D002285', (101, 122))	('increased frequency of FGFR1', 'Phenotype', 'HP:0030269', (13, 41))	('invasive carcinomas', 'Disease', (59, 78))	('invasive carcinomas', 'Disease', 'MESH:D009361', (59, 78))	('FGFR1', 'Gene', (36, 41))	('pure', 'molecular_function', 'GO:0034023', ('93', '97'))	('FGFR1', 'Gene', '2260', (36, 41))	('situ ductal carcinoma', 'Disease', (101, 122))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (106, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('situ ductal carcinoma', 'Phenotype', 'HP:0030075', (101, 122))	('amplification', 'Var', (42, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
39924	23270564	They suggested a role for FGFR1 amplification in the progression of breast cancer including in situ-to-invasive transition.	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('amplification', 'Var', (32, 45))	('breast cancer', 'Disease', (68, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
39926	23270564	reported around 20-30% of invasive ductal breast carcinoma harboring FGFR-1 amplification (ratio >1.3) .	('FGFR-1', 'Gene', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('FGFR-1', 'Gene', '2260', (69, 75))	('breast carcinoma', 'Phenotype', 'HP:0003002', (42, 58))	('invasive ductal breast carcinoma', 'Disease', (26, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('69', '73'))	('invasive ductal breast carcinoma', 'Disease', 'MESH:D018270', (26, 58))	('amplification', 'Var', (76, 89))
39928	23270564	In the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR-1 amplification could be approached to the new target biological therapy such as FGFR-1 inhibitor, with promising clinical efficacy.	('amplification', 'Var', (107, 120))	('FGFR-1', 'Gene', (100, 106))	('breast carcinoma', 'Disease', (78, 94))	('FGFR-1', 'Gene', '2260', (100, 106))	('breast carcinoma', 'Disease', 'MESH:D001943', (78, 94))	('FGFR-1', 'Gene', (186, 192))	('FGFR-1', 'Gene', '2260', (186, 192))	('breast carcinoma', 'Phenotype', 'HP:0003002', (78, 94))	('patients', 'Species', '9606', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('FGFR', 'molecular_function', 'GO:0005007', ('100', '104'))
39930	23270564	In our study, we observed the presence of FGFR-1 genomic abnormalities such as gains and amplification in a significant subset of metastatic lobular breast carcinoma, with clear implications for targeted therapy use.	('genomic abnormalities', 'Disease', (49, 70))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (141, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('FGFR-1', 'Gene', (42, 48))	('genomic abnormalities', 'Disease', 'MESH:D042822', (49, 70))	('breast carcinoma', 'Phenotype', 'HP:0003002', (149, 165))	('gains', 'Var', (79, 84))	('amplification', 'Var', (89, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('lobular breast carcinoma', 'Disease', (141, 165))	('FGFR-1', 'Gene', '2260', (42, 48))
39966	29921323	In addition, Ki-67 is associated with overall and disease-free survival of patients with BC.	('BC', 'Phenotype', 'HP:0003002', (89, 91))	('patients', 'Species', '9606', (75, 83))	('disease-free survival', 'CPA', (50, 71))	('associated', 'Reg', (22, 32))	('Ki-67', 'Var', (13, 18))
39994	26418423	The CD151-/alpha3beta1- patients had 3.12-fold higher risk of death from BCa in comparison with the rest of the ILC N(-) patients.	('BCa', 'Phenotype', 'HP:0003002', (73, 76))	('BCa', 'Disease', (73, 76))	('death', 'Disease', 'MESH:D003643', (62, 67))	('patients', 'Species', '9606', (24, 32))	('death', 'Disease', (62, 67))	('CD151-/alpha3beta1-', 'Var', (4, 23))	('patients', 'Species', '9606', (121, 129))
39999	26418423	In breast cancer (BCa), in particular, high expression of tetraspanin CD151 was shown to correlate with axillary lymph node involvement and patient poor overall survival.	('CD151', 'Gene', (70, 75))	('high', 'Var', (39, 43))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('patient', 'Species', '9606', (140, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('overall survival', 'CPA', (153, 169))	('axillary lymph node involvement', 'Disease', 'MESH:D000072717', (104, 135))	('axillary lymph node involvement', 'Disease', (104, 135))	('BCa', 'Phenotype', 'HP:0003002', (18, 21))
40026	26418423	We observed four distinct patterns of immunoreactivity for CD151/alpha3beta1: (1) CD151+/alpha3beta1+ in 55 out of 117 (23.94%) cases; (2) CD151+/alpha3b1- in 28 out of 117 (23.94%) cases; (3) CD151-/alpha3beta1- in 20 out of 117 (17.09%) cases and (4) CD151-/alpha3beta1+ in 14 out of 117 (11.96%) cases (Figure 1B-E).	('CD151/alpha3beta1', 'Gene', (59, 76))	('CD151-/alpha3beta1-', 'Var', (193, 212))	('CD151/alpha3beta1', 'Gene', '977', (59, 76))	('CD151-/alpha3beta1+', 'Var', (253, 272))	('CD151+/alpha3b1-', 'Var', (139, 155))	('CD151+/alpha3beta1+', 'Var', (82, 101))
40029	26418423	On the other hand, expression of CD151 assessed alone was inversely associated with tumour size (P=0.047) and stage (P=0.019), thus indicating that CD151 might have an ability to suppress proliferation of cells and progression of disease.	('tumour', 'Disease', (84, 90))	('expression', 'MPA', (19, 29))	('CD151', 'Gene', (33, 38))	('progression of disease', 'CPA', (215, 237))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('inversely', 'NegReg', (58, 67))	('proliferation of cells', 'CPA', (188, 210))	('CD151', 'Var', (148, 153))	('suppress', 'NegReg', (179, 187))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
40031	26418423	We have also demonstrated that, when assessed in combination, positivity for CD151 and/or alpha3beta1 correlated closer than CD151 alone with stage of disease (P<0.001 vs P=0.03 for CD151/alpha3beta1 vs CD151, respectively).	('CD151/alpha3beta1', 'Gene', (182, 199))	('CD151/alpha3beta1', 'Gene', '977', (182, 199))	('positivity', 'Var', (62, 72))	('stage of disease', 'Disease', (142, 158))	('CD151', 'Gene', (77, 82))	('closer', 'PosReg', (113, 119))	('alpha3beta1', 'Protein', (90, 101))
40041	26418423	Furthermore, in the ILC N(-) subgroup, the data were suggestive that the presence of either CD151 or alpha3beta1 could be favourable to the prognosis but their coexpression had no additive effect on patient survival.	('alpha3beta1', 'Protein', (101, 112))	('presence', 'Var', (73, 81))	('patient', 'Species', '9606', (199, 206))	('ILC N', 'Disease', (20, 25))	('CD151', 'Gene', (92, 97))
40043	26418423	Table 6B demonstrates that, as in the whole group, significant correlations between (1) expression of CD151 and alpha3beta1 (P=0.018); (2) CD151 and tumour size (P=0.035); and (3) CD151/alpha3beta1 and grade (P=0.029) were maintained.	('CD151/alpha3beta1', 'Gene', (180, 197))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('alpha3beta1', 'Protein', (112, 123))	('CD151/alpha3beta1', 'Gene', '977', (180, 197))	('CD151', 'Gene', (102, 107))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))	('CD151', 'Var', (139, 144))
40047	26418423	Here we demonstrate that, in contrast to IDC, loss of CD151 expression in complex with that of its principal molecular partner, the integrin alpha3beta1, is significantly associated with poor survival in patients with lymph node-negative ILC.	('expression', 'MPA', (60, 70))	('poor', 'NegReg', (187, 191))	('patients', 'Species', '9606', (204, 212))	('ILC', 'Disease', (238, 241))	('IDC', 'Gene', '4000', (41, 44))	('loss', 'Var', (46, 50))	('IDC', 'Gene', (41, 44))	('CD151', 'Gene', (54, 59))	('associated', 'Reg', (171, 181))
40057	26418423	As demonstrated by several genomic studies, the only consistent finding characterising ILC tumours is inactivation of CDH1 (E-cadherin, cadherin-1) and, indeed, lack of E-cadherin expression is considered a hallmark of ILC.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('cadherin-1', 'Gene', (136, 146))	('lack', 'NegReg', (161, 165))	('inactivation', 'Var', (102, 114))	('cadherin-1', 'Gene', '999', (136, 146))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('ILC tumours', 'Disease', 'MESH:D009369', (87, 98))	('cadherin', 'molecular_function', 'GO:0008014', ('171', '179'))	('ILC tumours', 'Disease', (87, 98))	('expression', 'MPA', (180, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('126', '134'))	('CDH1', 'Gene', (118, 122))	('CDH1', 'Gene', '999', (118, 122))	('ILC', 'Disease', (219, 222))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
40058	26418423	Although the role of E-cadherin in tumour onset and progression is still largely unknown, its inactivation alone is clearly not sufficient to induce neoplastic growth.	('neoplastic growth', 'CPA', (149, 166))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('induce', 'Reg', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('inactivation', 'Var', (94, 106))	('E-cadherin', 'Protein', (21, 31))	('cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))	('tumour', 'Disease', (35, 41))
40062	26418423	Similarly, in A431 epithelial carcinoma cells, near total silencing of CD151 destabilised E-cadherin-dependent cell-cell junctions.	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (19, 39))	('epithelial carcinoma', 'Disease', (19, 39))	('A431', 'CellLine', 'CVCL:0037', (14, 18))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (19, 39))	('CD151', 'Gene', (71, 76))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('destabilised', 'NegReg', (77, 89))	('E-cadherin-dependent cell-cell junctions', 'CPA', (90, 130))	('silencing', 'Var', (58, 67))
40063	26418423	However, it was not the disruption of the E-cadherin regulatory complex but an excessive RhoA activation and disorganisation of actin fibres at the cell-cell junctions, induced by loss of CD151, that led to the enhancement of cell migration.	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('RhoA', 'Gene', '387', (89, 93))	('disorganisation', 'NegReg', (109, 124))	('loss', 'Var', (180, 184))	('disorganisation of actin fibres', 'Phenotype', 'HP:0025200', (109, 140))	('cell migration', 'biological_process', 'GO:0016477', ('226', '240'))	('enhancement', 'PosReg', (211, 222))	('RhoA', 'Gene', (89, 93))	('CD151', 'Gene', (188, 193))	('cell migration', 'CPA', (226, 240))
40065	26418423	Activation of Rho/ROCK signalling axis triggered by loss of E-cadherin was recently demonstrated to be responsible for induction of anoikis resistance and invasive phenotype in a mouse model of human ILC.	('mouse', 'Species', '10090', (179, 184))	('anoikis', 'biological_process', 'GO:0043276', ('132', '139'))	('ILC', 'Disease', (200, 203))	('loss', 'Var', (52, 56))	('cadherin', 'molecular_function', 'GO:0008014', ('62', '70'))	('ROCK', 'Gene', '6093', (18, 22))	('signalling', 'biological_process', 'GO:0023052', ('23', '33'))	('human', 'Species', '9606', (194, 199))	('Activation', 'PosReg', (0, 10))	('E-cadherin', 'Protein', (60, 70))	('ROCK', 'Gene', (18, 22))	('anoikis resistance', 'CPA', (132, 150))
40070	26418423	However, it is conceivable that in this particular biological context, as in the settings described above, the CD151/alpha3beta1 complex is controlling cell-cell adhesion and loss of E-cadherin contributes but is not decisive in destabilisation of cell-cell contacts and enhancement of cell migration.	('enhancement', 'PosReg', (271, 282))	('cell migration', 'biological_process', 'GO:0016477', ('286', '300'))	('cell migration', 'CPA', (286, 300))	('cell-cell', 'CPA', (152, 161))	('E-cadherin', 'Protein', (183, 193))	('CD151/alpha3beta1', 'Gene', (111, 128))	('CD151/alpha3beta1', 'Gene', '977', (111, 128))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('152', '170'))	('loss', 'Var', (175, 179))	('cadherin', 'molecular_function', 'GO:0008014', ('185', '193'))
40075	26418423	Whatever the underlying mechanisms, the results of our study indicate that loss of CD151-alpha3beta1 may serve as a potential prognostic marker of poor survival in a subgroup of patients deemed to carry a low risk of cancer-related death (ie, lymph node negative).	('death', 'Disease', 'MESH:D003643', (232, 237))	('death', 'Disease', (232, 237))	('CD151-alpha3beta1', 'Gene', (83, 100))	('patients', 'Species', '9606', (178, 186))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('loss', 'Var', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
40104	30009076	After a poor response to therapy, further evaluation including immunostaining for CK7, estrogen receptor alpha, CK20, and E-cadherin changed the diagnosis to metastatic breast carcinoma.	('cadherin', 'molecular_function', 'GO:0008014', ('124', '132'))	('metastatic breast carcinoma', 'Disease', (158, 185))	('CK20', 'Var', (112, 116))	('CK7', 'Protein', (82, 85))	('E-cadherin', 'Gene', (122, 132))	('E-cadherin', 'Gene', '999', (122, 132))	('breast carcinoma', 'Phenotype', 'HP:0003002', (169, 185))	('estrogen receptor alpha', 'Gene', '2099', (87, 110))	('changed', 'Reg', (133, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('estrogen receptor alpha', 'Gene', (87, 110))
40298	18457326	Multivariate analysis revealed that Caucasian race, tumor located in the inner half of the breast, clinical T1 tumors, and mixed ductal and lobular histology significantly increased the number of SLNs that needed to be removed to identify 99% of positive SLNs (Table 5).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Caucasian race', 'Var', (36, 50))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('increased', 'PosReg', (172, 181))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
40342	25757734	With mutational or epigenetic inactivation of the cell adhesion molecule E-cadherin (CDH1) being confined almost exclusively to ILC, this tumor entity stands out from all other types of breast cancers.	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('50', '72'))	('ILC', 'Disease', (128, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cell adhesion', 'biological_process', 'GO:0007155', ('50', '63'))	('tumor', 'Disease', (138, 143))	('breast cancers', 'Phenotype', 'HP:0003002', (186, 200))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('mutational', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancers', 'Disease', 'MESH:D001943', (186, 200))	('breast cancers', 'Disease', (186, 200))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('CDH1', 'Gene', (85, 89))	('epigenetic inactivation', 'Var', (19, 42))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
40343	25757734	The molecular basis of ILC is linked to loss of E-cadherin, as evidenced by human CDH1 germline mutations and conditional knockout mouse models.	('mouse', 'Species', '10090', (131, 136))	('loss', 'NegReg', (40, 44))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('human', 'Species', '9606', (76, 81))	('ILC', 'Disease', (23, 26))	('CDH1', 'Gene', (82, 86))	('mutations', 'Var', (96, 105))	('E-cadherin', 'Protein', (48, 58))
40354	25757734	Cases of LCIS and ILC associated with CDH1 germline mutation without gastric cancer are also increasingly recognized.	('gastric cancer', 'Disease', (69, 83))	('CDH1', 'Gene', (38, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('germline mutation', 'Var', (43, 60))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('LCIS', 'Phenotype', 'HP:0030076', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('LCIS', 'Disease', (9, 13))	('ILC', 'Disease', (18, 21))
40355	25757734	In addition to genetically engineered mouse (GEM) models (see below), these findings from medical genetics have provided evidence that E-cadherin functions as a tumor suppressor and that its inactivation underpins ILC etiology.	('tumor', 'Disease', (161, 166))	('mouse', 'Species', '10090', (38, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('161', '177'))	('E-cadherin', 'Protein', (135, 145))	('cadherin', 'molecular_function', 'GO:0008014', ('137', '145'))	('ILC', 'Disease', (214, 217))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('inactivation', 'Var', (191, 203))	('underpins', 'Reg', (204, 213))	('tumor suppressor', 'biological_process', 'GO:0051726', ('161', '177'))
40356	25757734	These changes include loss of beta-catenin and aberrant cytoplasmic and/or nuclear localization of p120-catenin (p120).	('beta-catenin', 'Gene', '1499', (30, 42))	('p120-catenin', 'Gene', (99, 111))	('p120', 'Var', (113, 117))	('loss', 'NegReg', (22, 26))	('p120-catenin', 'Gene', '1500', (99, 111))	('localization', 'biological_process', 'GO:0051179', ('83', '95'))	('cytoplasmic', 'MPA', (56, 67))	('beta-catenin', 'Gene', (30, 42))
40359	25757734	In contrast, mutational activation of the PIK3CA oncogene is a dominant feature in ILC.	('ILC', 'Disease', (83, 86))	('PIK3CA', 'Gene', '5290', (42, 48))	('PIK3CA', 'Gene', (42, 48))	('mutational', 'Var', (13, 23))
40360	25757734	TP53 mutations are rare, except for a more aggressive ILC variant termed pleomorphic ILC, which is more often ER-negative and occasionally ERBB2-positive.	('pleomorphic ILC', 'Disease', (73, 88))	('TP53', 'Gene', '7157', (0, 4))	('ERBB2', 'Gene', '2064', (139, 144))	('TP53', 'Gene', (0, 4))	('ER', 'Gene', '2099', (110, 112))	('ER', 'Gene', '2099', (139, 141))	('mutations', 'Var', (5, 14))	('ERBB2', 'Gene', (139, 144))
40374	25757734	MDA-MB-134 harbors a homozygous deletion of CDH1 exon 6, which results in a frameshift and a premature stop codon.	('results in', 'Reg', (63, 73))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (0, 10))	('frameshift', 'Var', (76, 86))	('CDH1', 'Gene', (44, 48))
40377	25757734	MDA-MB-134 overexpresses FGFR1, which maps to chromosome 8p11-p12, and small interfering RNA-mediated silencing or inhibition of FGFR1 increases sensitivity to estrogen withdrawal or tamoxifen.	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('FGFR1', 'Gene', (25, 30))	('tamoxifen', 'CPA', (183, 192))	('p11', 'Gene', '6281', (58, 61))	('tamoxifen', 'Chemical', 'MESH:D013629', (183, 192))	('sensitivity to estrogen withdrawal', 'MPA', (145, 179))	('p12', 'Gene', (62, 65))	('small interfering', 'Var', (71, 88))	('FGFR1', 'Gene', '2260', (129, 134))	('p11', 'Gene', (58, 61))	('FGFR', 'molecular_function', 'GO:0005007', ('129', '133'))	('increases', 'PosReg', (135, 144))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (0, 10))	('FGFR1', 'Gene', '2260', (25, 30))	('FGFR1', 'Gene', (129, 134))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('overexpresses', 'PosReg', (11, 24))	('p12', 'Gene', '56655', (62, 65))	('inhibition', 'Var', (115, 125))
40381	25757734	The ZNF703 gene is located <1 Mb upstream of FGFR1 and small interfering RNA-mediated silencing of ZNF703 also decreases viability of MDA-MB-134.	('ZNF703', 'Gene', '80139', (4, 10))	('silencing', 'Var', (86, 95))	('ZNF703', 'Gene', (4, 10))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (134, 144))	('RNA', 'cellular_component', 'GO:0005562', ('73', '76'))	('viability', 'CPA', (121, 130))	('decreases', 'NegReg', (111, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('FGFR1', 'Gene', (45, 50))	('ZNF703', 'Gene', '80139', (99, 105))	('ZNF703', 'Gene', (99, 105))	('FGFR1', 'Gene', '2260', (45, 50))
40385	25757734	SUM-44PE is E-cadherin-negative and ER-positive and was derived from a malignant pleural effusion.	('pleural effusion', 'Disease', (81, 97))	('pleural effusion', 'Phenotype', 'HP:0002202', (81, 97))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('SUM-44PE', 'Var', (0, 8))	('ER', 'Gene', '2099', (36, 38))	('pleural effusion', 'Disease', 'MESH:D010996', (81, 97))
40387	25757734	Compared with MDA-MB-134, SUM-44PE has a shorter doubling time (approximately 1 day), which may be due to amplification of cyclin D1 (CCND1), and is also responsive to steroid hormones.	('cyclin', 'molecular_function', 'GO:0016538', ('123', '129'))	('shorter', 'NegReg', (41, 48))	('steroid', 'Chemical', 'MESH:D013256', (168, 175))	('CCND1', 'Gene', (134, 139))	('SUM-44PE', 'Var', (26, 34))	('doubling time', 'MPA', (49, 62))	('cyclin D1', 'Gene', '595', (123, 132))	('cyclin D1', 'Gene', (123, 132))	('amplification', 'PosReg', (106, 119))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (14, 24))	('CCND1', 'Gene', '595', (134, 139))
40388	25757734	SUM-44PE harbors homozygous frameshift mutations in the CDH1 and TP53 tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('CDH1', 'Gene', (56, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('homozygous frameshift mutations', 'Var', (17, 48))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
40392	25757734	Contrary to MDA-MB-134, silencing of FGFR1 only modestly increases sensitivity to estrogen withdrawal or tamoxifen.	('FGFR1', 'Gene', (37, 42))	('FGFR1', 'Gene', '2260', (37, 42))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (12, 22))	('sensitivity to estrogen withdrawal', 'MPA', (67, 101))	('tamoxifen', 'Chemical', 'MESH:D013629', (105, 114))	('increases', 'PosReg', (57, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('silencing', 'Var', (24, 33))
40399	25757734	IPH-926 harbors a unique homozygous CDH1 frameshift mutation and lacks E-cadherin.	('cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('CDH1', 'Gene', (36, 40))	('IPH', 'Chemical', 'MESH:D019800', (0, 3))	('frameshift mutation', 'Var', (41, 60))
40400	25757734	Detection of the same CDH1 mutation in archival tissue of the original ER-positive breast tumor verified the clonal origin of IPH-926 from ILC.	('breast tumor', 'Disease', 'MESH:D001943', (83, 95))	('breast tumor', 'Disease', (83, 95))	('IPH', 'Chemical', 'MESH:D019800', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutation', 'Var', (27, 35))	('ER', 'Gene', '2099', (71, 73))	('CDH1', 'Gene', (22, 26))	('breast tumor', 'Phenotype', 'HP:0100013', (83, 95))
40408	25757734	In their in vivo clonal ancestry, IPH-926 cells acquired an additional TP53 mutation.	('TP53', 'Gene', '7157', (71, 75))	('mutation', 'Var', (76, 84))	('IPH', 'Chemical', 'MESH:D019800', (34, 37))	('TP53', 'Gene', (71, 75))
40409	25757734	The p53 mutant expressed in IPH-926, E285K, has temperature-sensitive loss of function characteristics.	('E285K', 'Var', (37, 42))	('E285K', 'Mutation', 'rs112431538', (37, 42))	('IPH', 'Chemical', 'MESH:D019800', (28, 31))	('loss of function', 'NegReg', (70, 86))	('p53', 'Gene', (4, 7))
40411	25757734	Notably, p53 E285K is also evident in a subclone of MDA-MB-134 and has repeatedly been detected in therapy-refractory ILC.	('p53 E285K', 'Var', (9, 18))	('detected', 'Reg', (87, 95))	('E285K', 'Mutation', 'rs112431538', (13, 18))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (52, 62))	('MDA-MB-134', 'Gene', (52, 62))
40412	25757734	The MDA-MB-330 cell line expresses wild-type but dysfunctional E-cadherin due to a biallelic mutation in alpha-catenin (CTNNA1), which may represent an alternate mechanism to impair E-cadherin function.	('cadherin', 'molecular_function', 'GO:0008014', ('184', '192'))	('E-cadherin', 'Protein', (63, 73))	('E-cadherin', 'Protein', (182, 192))	('impair', 'NegReg', (175, 181))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (4, 14))	('CTNNA1', 'Gene', '1495', (120, 126))	('dysfunctional', 'NegReg', (49, 62))	('biallelic mutation', 'Var', (83, 101))	('CTNNA1', 'Gene', (120, 126))	('cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))
40415	25757734	These commonalities include a metastatic origin, mutation of CDH1 and TP53, a luminal molecular subtype and amplification of chromosome 8p12-p11.	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('p12', 'Gene', (137, 140))	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (49, 57))	('p11', 'Gene', (141, 144))	('metastatic origin', 'CPA', (30, 47))	('TP53', 'Gene', (70, 74))	('p12', 'Gene', '56655', (137, 140))	('CDH1', 'Gene', (61, 65))	('p11', 'Gene', '6281', (141, 144))
40416	25757734	All three cell lines lack PIK3CA hot-spot mutations common in primary ILC.	('PIK3CA', 'Gene', '5290', (26, 32))	('mutations', 'Var', (42, 51))	('PIK3CA', 'Gene', (26, 32))	('primary ILC', 'Disease', (62, 73))
40417	25757734	As stated above, TP53 mutations are rare in primary ILC, except for the pleomorphic variant.	('primary ILC', 'Disease', (44, 55))	('TP53', 'Gene', '7157', (17, 21))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (17, 21))
40418	25757734	The accumulation of TP53 mutations in the few available ILC cell lines may suggest a selection bias.	('mutations', 'Var', (25, 34))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))
40420	25757734	Establishment of a cell line from human nonmetastatic ILC with wild-type p53 and an activating PIK3CA mutation has not been achieved.	('mutation', 'Var', (102, 110))	('human', 'Species', '9606', (34, 39))	('PIK3CA', 'Gene', (95, 101))	('PIK3CA', 'Gene', '5290', (95, 101))
40450	25757734	This is exemplified by knockout of Cdh1 in the mouse germline.	('knockout', 'Var', (23, 31))	('mouse', 'Species', '10090', (47, 52))	('Cdh1', 'Gene', (35, 39))
40453	25757734	Although conventional Cdh1 knockout was of little immediate value for elucidating the tumor suppressor function of E-cadherin, it inspired many decisive studies on the important roles of E-cadherin in murine embryonic stem cells and embryonic development.	('murine', 'Species', '10090', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('86', '102'))	('knockout', 'Var', (27, 35))	('cadherin', 'molecular_function', 'GO:0008014', ('117', '125'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('86', '102'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('Cdh1', 'Gene', (22, 26))	('cadherin', 'molecular_function', 'GO:0008014', ('189', '197'))
40456	25757734	This study clearly implicated loss of E-cadherin as a second and collaborating hit in tumor formation and provided a compelling example of how genetic and environmental factors cooperate in the initiation of distinct tumors.	('initiation of distinct tumors', 'Disease', 'MESH:D009369', (194, 223))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Disease', (86, 91))	('loss', 'Var', (30, 34))	('initiation of distinct tumors', 'Disease', (194, 223))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))	('E-cadherin', 'Protein', (38, 48))
40461	25757734	A number of different approaches have been employed, using different promoter elements driving Cre recombinase expression to cell type-specific Cdh1 ablation in the mouse mammary gland and gastrointestinal tract (Table 2).	('ablation', 'Var', (149, 157))	('mouse', 'Species', '10090', (165, 170))	('Cdh1', 'Gene', (144, 148))	('Cre', 'Gene', '2777477', (95, 98))	('Cre', 'Gene', (95, 98))	('gastrointestinal tract', 'Disease', (189, 211))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (189, 211))
40464	25757734	Depending on the promoter driving Cre, E-cadherin ablation will result in massive apoptosis (MMTV) or nearly undetectable clearance of E-cadherin-deficient luminal cells (K14).	('MMTV', 'Species', '11757', (93, 97))	('apoptosis', 'CPA', (82, 91))	('Cre', 'Gene', (34, 37))	('cadherin', 'molecular_function', 'GO:0008014', ('137', '145'))	('ablation', 'Var', (50, 58))	('E-cadherin', 'Protein', (39, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('K14', 'Gene', '16664', (171, 174))	('K14', 'Gene', (171, 174))	('Cre', 'Gene', '2777477', (34, 37))	('clearance', 'CPA', (122, 131))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))	('cadherin', 'molecular_function', 'GO:0008014', ('41', '49'))
40467	25757734	Cdh1 knockout in the basal stratified and follicular epidermal cells of the skin induces a compensatory upregulation of P-cadherin (Cdh3) that rescues epithelial integrity in the basal layer of the epidermis, but not in the hair follicle.	('upregulation', 'PosReg', (104, 116))	('Cdh1', 'Gene', (0, 4))	('rescues', 'PosReg', (143, 150))	('knockout', 'Var', (5, 13))	('Cdh3', 'Gene', '1001', (132, 136))	('Cdh3', 'Gene', (132, 136))	('P-cadherin', 'Protein', (120, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('122', '130'))
40468	25757734	Cdh1 ablation in the gastric mucosa also did not result in gastric cancer, although noninvasive E-cadherin-negative cell aggregates occurred.	('result in', 'Reg', (49, 58))	('Cdh1', 'Gene', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('ablation', 'Var', (5, 13))	('gastric mucosa', 'Disease', 'MESH:D013274', (21, 35))	('gastric mucosa', 'Disease', (21, 35))	('cadherin', 'molecular_function', 'GO:0008014', ('98', '106'))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Disease', (59, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))
40469	25757734	Together, conditional GEM models imply that additional oncogenic hits are compulsory in the mammary gland before Cdh1 inactivation can be tolerated and unleash its full tumorigenic potential.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('inactivation', 'Var', (118, 130))	('tumor', 'Disease', (169, 174))	('Cdh1', 'Gene', (113, 117))
40470	25757734	Somatic inactivation of p53 also allowed study of the E-cadherin function in tumor progression, because mammary-specific inactivation of p53 alone resulted in nonmetastatic, locally expansive tumors.	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', (77, 82))	('nonmetastatic', 'CPA', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cadherin', 'molecular_function', 'GO:0008014', ('56', '64'))	('inactivation', 'Var', (121, 133))	('resulted in', 'Reg', (147, 158))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('p53', 'Gene', (137, 140))
40471	25757734	In contrast, dual conditional knockout of E-cadherin and p53 using either K14cre or WAPcre synergized with p53 loss and induced a dramatic shift from expansive to infiltrating growth.	('shift', 'Reg', (139, 144))	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('loss', 'NegReg', (111, 115))	('p53', 'Gene', (107, 110))	('knockout', 'Var', (30, 38))	('induced', 'Reg', (120, 127))	('K14', 'Gene', (74, 77))	('K14', 'Gene', '16664', (74, 77))	('WAP', 'Gene', (84, 87))	('p53', 'Gene', (57, 60))	('WAP', 'Gene', '22373', (84, 87))	('expansive', 'MPA', (150, 159))	('E-cadherin', 'Protein', (42, 52))
40482	25757734	Follow-up studies showed that, unlike beta-catenin, p120 is not proteosomically degraded in ILC but instead resides in the cytosol and nucleus upon E-cadherin loss.	('beta-catenin', 'Gene', (38, 50))	('resides', 'Reg', (108, 115))	('E-cadherin', 'Protein', (148, 158))	('loss', 'NegReg', (159, 163))	('beta-catenin', 'Gene', '1499', (38, 50))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('cytosol', 'cellular_component', 'GO:0005829', ('123', '130'))	('nucleus', 'cellular_component', 'GO:0005634', ('135', '142'))	('p120', 'Var', (52, 56))
40484	25757734	Our unpublished data have also identified noncanonical Wnt11 as a Kaiso target driving autocrine Rho-dependent anoikis resistance (van de Ven RAH, unpublished data), suggesting that p120 is a multifaceted oncoprotein in ILC.	('anoikis', 'biological_process', 'GO:0043276', ('111', '118'))	('ILC', 'Disease', (220, 223))	('van de Ven RAH', 'Disease', (131, 145))	('Wnt11', 'Gene', (55, 60))	('Wnt11', 'Gene', '7481', (55, 60))	('van de Ven RAH', 'Disease', 'MESH:D005862', (131, 145))	('p120', 'Var', (182, 186))
40485	25757734	Interestingly, indirect mammary-specific loss of E-cadherin function through ablation of p120 did not induce murine ILC.	('E-cadherin', 'Protein', (49, 59))	('ablation', 'Var', (77, 85))	('murine', 'Species', '10090', (109, 115))	('cadherin', 'molecular_function', 'GO:0008014', ('51', '59'))	('p120', 'Gene', (89, 93))	('function', 'MPA', (60, 68))	('loss', 'NegReg', (41, 45))
40486	25757734	In this context, p120 functioned as a tumor suppressor, and its loss in WAPcre;Ctnnd1F/F;Trp53F/F female mice led to dismantling of the E-cadherin-dependent cell-cell adhesion and formation of metastatic tumors that resembled metaplastic triple-negative BC.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('WAP', 'Gene', (72, 75))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('157', '175'))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('formation', 'biological_process', 'GO:0009058', ('180', '189'))	('WAP', 'Gene', '22373', (72, 75))	('p120', 'Var', (17, 21))	('tumors', 'Disease', (204, 210))	('mice', 'Species', '10090', (105, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('BC', 'Phenotype', 'HP:0003002', (254, 256))	('loss', 'NegReg', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Disease', (38, 43))	('E-cadherin-dependent', 'Protein', (136, 156))	('dismantling', 'NegReg', (117, 128))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
40487	25757734	These studies also showed that inactivation of the AJ partially controls anchorage independence through hypersensitization of endogenous growth factor receptors.	('inactivation', 'Var', (31, 43))	('hypersensitization', 'Disease', (104, 122))	('hypersensitization', 'Disease', 'MESH:D004342', (104, 122))	('endogenous', 'Protein', (126, 136))	('anchorage independence', 'CPA', (73, 95))	('controls', 'Reg', (64, 72))
40491	25757734	Inactivation of E-cadherin and p53 in ATP4Bcre;Cdh1F/F;Trp53F/F mice resulted in the progression of E-cadherin-negative gastric mucosal cell aggregates to invasive and metastatic tumors resembling human DGC (Table 2).	('p53', 'Gene', (31, 34))	('progression', 'PosReg', (85, 96))	('gastric mucosal', 'Disease', 'MESH:D013274', (120, 135))	('DGC', 'cellular_component', 'GO:0016010', ('203', '206'))	('cadherin', 'molecular_function', 'GO:0008014', ('18', '26'))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('gastric mucosal', 'Disease', (120, 135))	('E-cadherin', 'Protein', (16, 26))	('mice', 'Species', '10090', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('human', 'Species', '9606', (197, 202))	('Inactivation', 'Var', (0, 12))	('cadherin', 'molecular_function', 'GO:0008014', ('102', '110'))
40494	25757734	Follow-up studies showed that Cdh1 inactivation releases p120 from AJs to the cytosol and nucleus, where it controls tumor progression through distinct and druggable signaling pathways.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Cdh1', 'Gene', (30, 34))	('cytosol', 'cellular_component', 'GO:0005829', ('78', '85'))	('tumor', 'Disease', (117, 122))	('inactivation', 'Var', (35, 47))	('nucleus', 'cellular_component', 'GO:0005634', ('90', '97'))	('controls', 'Reg', (108, 116))	('p120', 'Var', (57, 61))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
40495	25757734	With mutational or epigenetic inactivation of E-cadherin being confined almost exclusively to ILC and LCIS, this tumor entity stands out from all other kinds of BCs.	('LCIS', 'Disease', (102, 106))	('ILC', 'Disease', (94, 97))	('tumor', 'Disease', (113, 118))	('cadherin', 'molecular_function', 'GO:0008014', ('48', '56'))	('LCIS', 'Phenotype', 'HP:0030076', (102, 106))	('E-cadherin', 'Protein', (46, 56))	('BC', 'Phenotype', 'HP:0003002', (161, 163))	('mutational', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('epigenetic inactivation', 'Var', (19, 42))
40500	25757734	These include FGFR1, ZNF703, ERRgamma, BCAR4 and ABCB1/MDR1 as mediators of therapy resistance and mutant p53 as the gatekeeper towards pleomorphic ILC.	('MDR1', 'Gene', '5243', (55, 59))	('p53', 'Gene', (106, 109))	('ZNF703', 'Gene', (21, 27))	('BC', 'Phenotype', 'HP:0003002', (50, 52))	('BCAR4', 'Gene', '400500', (39, 44))	('FGFR1', 'Gene', (14, 19))	('ABCB1', 'Gene', (49, 54))	('ABCB1', 'Gene', '5243', (49, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('BC', 'Phenotype', 'HP:0003002', (39, 41))	('ERRgamma', 'Gene', '2104', (29, 37))	('MDR1', 'Gene', (55, 59))	('MDR', 'molecular_function', 'GO:0004745', ('55', '58'))	('ERRgamma', 'Gene', (29, 37))	('FGFR1', 'Gene', '2260', (14, 19))	('gatekeeper', 'Species', '111938', (117, 127))	('mutant', 'Var', (99, 105))	('ZNF703', 'Gene', '80139', (21, 27))	('BCAR4', 'Gene', (39, 44))
40504	25757734	In the field of GEM models, conditional inactivation of Cdh1 combined with activation of latent mutant Pik3caH1047R promises tumors with unique, perhaps ILC-like properties.	('Pik3', 'Gene', (103, 107))	('Pik3', 'Gene', '5294', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('conditional inactivation', 'Var', (28, 52))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('Cdh1', 'Gene', (56, 60))
40554	18043894	also reported that findings on MRI in 12 patients with ILC would have resulted in two unnecessary mastectomies.	('ILC', 'Disease', (55, 58))	('findings', 'Var', (19, 27))	('patients', 'Species', '9606', (41, 49))	('MRI', 'Gene', (31, 34))	('resulted in', 'Reg', (70, 81))	('mastectomies', 'Disease', (98, 110))
40618	32028173	Mutational load and chromosome integrity number (CIN) were also evaluated as illustrated in previous studies.	('chromosome integrity number', 'CPA', (20, 47))	('CIN', 'Disease', (49, 52))	('CIN', 'Disease', 'MESH:D007674', (49, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('Mutational load', 'Var', (0, 15))
40625	32028173	At the multivariate analysis, T-category (1-2) and negative nodal status were independent predictors for longer DFS; age at diagnosis <60 years, negative nodal status and Ki67 < 5% were independent factors for longer OS.	('nodal', 'Gene', (154, 159))	('Ki67', 'Var', (171, 175))	('nodal', 'Gene', (60, 65))	('nodal', 'Gene', '4838', (154, 159))	('nodal', 'Gene', '4838', (60, 65))
40640	32028173	When grouping the molecular alterations involved in the regulation of G1/S phase cell cycle progression herein evaluated (CDK4 and CCND1 gain or CDKN2A mutation), this signature was significantly more associated with poor prognosis in the whole patients' sample (OR 6.24, 95%CI 1.59-24.5, p = 0.009), and in the RB1 wild type population (32 patients, OR 5.33, 95%CI 1.33-21.28, p = 0.018).	('poor prognosis', 'CPA', (217, 231))	('CCND1', 'Gene', (131, 136))	('RB1', 'Gene', '5925', (312, 315))	('patients', 'Species', '9606', (341, 349))	('CDKN2A', 'Gene', '1029', (145, 151))	('patients', 'Species', '9606', (245, 253))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('S phase', 'biological_process', 'GO:0051320', ('73', '80'))	('CCND1', 'Gene', '595', (131, 136))	('cell cycle', 'biological_process', 'GO:0007049', ('81', '91'))	('CDK4', 'Gene', '1019', (122, 126))	('CDK4', 'Gene', (122, 126))	('RB1', 'Gene', (312, 315))	('CDK', 'molecular_function', 'GO:0004693', ('122', '125'))	('gain', 'PosReg', (137, 141))	('mutation', 'Var', (152, 160))	('CDKN2A', 'Gene', (145, 151))
40643	32028173	S3, Panel A) was detected in the 10% of patients at poor prognosis (those presenting also CDK4 gain at NGS), while no CDK4 gain was detected in patients at good, without a significant difference between the two groups.	('CDK', 'molecular_function', 'GO:0004693', ('90', '93'))	('CDK4', 'Gene', '1019', (90, 94))	('CDK4', 'Gene', (90, 94))	('CDK4', 'Gene', (118, 122))	('patients', 'Species', '9606', (40, 48))	('CDK4', 'Gene', '1019', (118, 122))	('patients', 'Species', '9606', (144, 152))	('CDK', 'molecular_function', 'GO:0004693', ('118', '121'))	('NGS', 'Var', (103, 106))	('gain', 'PosReg', (95, 99))
40648	32028173	Patients with poor prognosis resulted to have a significantly higher chance to be cumulatively associated with abnormalities in CDK4/CDK6 overall expression or CNV (Fig.	('CDK4', 'Gene', '1019', (128, 132))	('CDK6', 'Gene', (133, 137))	('CNV', 'MPA', (160, 163))	('abnormalities', 'Var', (111, 124))	('CDK6', 'Gene', '1021', (133, 137))	('CDK', 'molecular_function', 'GO:0004693', ('128', '131'))	('Patients', 'Species', '9606', (0, 8))	('expression', 'MPA', (146, 156))	('CDK4', 'Gene', (128, 132))	('CDK', 'molecular_function', 'GO:0004693', ('133', '136'))
40655	32028173	Regarding OS, age and Ki67 represent the variables included in the prognostic model, besides the nodal status.	('nodal', 'Gene', (97, 102))	('Ki67', 'Var', (22, 26))	('nodal', 'Gene', '4838', (97, 102))
40662	32028173	The involvement of CDK4 amplification/gain in tumorigenesis has been found in various tumours including malignant gliomas and sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('CDK', 'molecular_function', 'GO:0004693', ('19', '22'))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CDK4', 'Gene', (19, 23))	('gliomas', 'Phenotype', 'HP:0009733', (114, 121))	('sarcomas', 'Disease', (126, 134))	('malignant gliomas', 'Disease', (104, 121))	('amplification/gain', 'PosReg', (24, 42))	('tumor', 'Disease', (46, 51))	('amplification/gain', 'Var', (24, 42))	('CDK4', 'Gene', '1019', (19, 23))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('malignant gliomas', 'Disease', 'MESH:D005910', (104, 121))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
40663	32028173	In the context of BC, a previous analysis, conducted in 95 patients undergone surgery (80 carcinoma of NST and 15 ILC), suggested that CDK4 amplification (detected in 15.8% of patients) was associated with high tumor cell proliferation.	('CDK', 'molecular_function', 'GO:0004693', ('135', '138'))	('patients', 'Species', '9606', (176, 184))	('CDK4', 'Gene', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('CDK4', 'Gene', '1019', (135, 139))	('carcinoma', 'Disease', (90, 99))	('amplification', 'Var', (140, 153))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Disease', (211, 216))	('associated', 'Reg', (190, 200))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('cell proliferation', 'biological_process', 'GO:0008283', ('217', '235'))	('carcinoma', 'Disease', 'MESH:D009369', (90, 99))
40670	32028173	As expected in the lobular histotype, the most frequent alteration is represented by the CDH1 mutation and loss of heterozygosity, without a different distribution in the two prognostic groups.	('loss of heterozygosity', 'Var', (107, 129))	('CDH1', 'Gene', '999', (89, 93))	('mutation', 'Var', (94, 102))	('CDH1', 'Gene', (89, 93))
40671	32028173	Similarly, mutations in PIK3CA, TP53, CDKN2A and FOXA1 does not present a different distribution according to prognosis.	('mutations', 'Var', (11, 20))	('PIK3CA', 'Gene', (24, 30))	('FOXA1', 'Gene', (49, 54))	('TP53', 'Gene', '7157', (32, 36))	('PIK3CA', 'Gene', '5290', (24, 30))	('TP53', 'Gene', (32, 36))	('CDKN2A', 'Gene', (38, 44))	('FOXA1', 'Gene', '3169', (49, 54))	('CDKN2A', 'Gene', '1029', (38, 44))
40672	32028173	The incidence of FOXA1 mutation and ESR1 gain are similar to that reported by Desmedt et al.	('gain', 'PosReg', (41, 45))	('mutation', 'Var', (23, 31))	('FOXA1', 'Gene', (17, 22))	('ESR1', 'Gene', '2099', (36, 40))	('FOXA1', 'Gene', '3169', (17, 22))	('ESR1', 'Gene', (36, 40))
40675	32028173	In a recent study, the observation that knockdown of METTL17 reduces BC cell growth suggests that METTL17 regulates the cancer cell growth possibly through modulation of ERalpha function as well as the expression of ERalpha/beta target genes.	('ERalpha', 'Gene', (170, 177))	('ERalpha', 'Gene', (216, 223))	('cancer', 'Disease', (120, 126))	('METTL17', 'Gene', (98, 105))	('ERalpha', 'Gene', '2099', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('regulates', 'Reg', (106, 115))	('ERalpha', 'Gene', '2099', (216, 223))	('METTL17', 'Gene', '64745', (53, 60))	('modulation', 'Reg', (156, 166))	('METTL17', 'Gene', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cell growth', 'biological_process', 'GO:0016049', ('127', '138'))	('BC cell growth', 'CPA', (69, 83))	('ERalpha/beta', 'Gene', '2099', (216, 228))	('knockdown', 'Var', (40, 49))	('METTL17', 'Gene', '64745', (98, 105))	('reduces', 'NegReg', (61, 68))	('cell growth', 'biological_process', 'GO:0016049', ('72', '83'))	('ERalpha/beta', 'Gene', (216, 228))
40693	30180878	Comparative analysis of luminal A ILC and IDC identified genomic and transcriptional differences between the two histological subtypes, including frequency of FOXA1 and GATA3 mutations, and activation of immune and metabolism pathways.	('activation', 'PosReg', (190, 200))	('GATA3', 'Gene', (169, 174))	('metabolism', 'biological_process', 'GO:0008152', ('215', '225'))	('FOXA1', 'Gene', (159, 164))	('GATA3', 'Gene', '2625', (169, 174))	('mutations', 'Var', (175, 184))	('FOXA1', 'Gene', '3169', (159, 164))
40697	30180878	Mediators of endocrine resistance include loss of expression or genomic aberration (for example, mutations) of ER, altered expression of ER co-regulators and cell cycle signaling molecules, increased signaling of growth factor receptor pathways, and enhanced autophagy.	('mutations', 'Var', (97, 106))	('autophagy', 'biological_process', 'GO:0016236', ('259', '268'))	('expression', 'MPA', (123, 133))	('enhanced', 'PosReg', (250, 258))	('autophagy', 'CPA', (259, 268))	('ER', 'Gene', '2099', (111, 113))	('increased', 'PosReg', (190, 199))	('altered', 'Reg', (115, 122))	('signaling', 'biological_process', 'GO:0023052', ('200', '209'))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('cell cycle', 'biological_process', 'GO:0007049', ('158', '168'))	('autophagy', 'biological_process', 'GO:0006914', ('259', '268'))	('signaling', 'MPA', (200, 209))	('growth factor receptor pathways', 'Pathway', (213, 244))	('ER', 'Gene', '2099', (137, 139))	('expression', 'MPA', (50, 60))	('loss', 'NegReg', (42, 46))
40704	30180878	Briefly, SUM44PE cells were cultured in 1:1 DMEM: L-15 + 10% FBS for 3 months to generate SUM44F cells, which have a stronger proliferative response to 17beta-estradiol (E2).	('FBS', 'Disease', 'MESH:D005198', (61, 64))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (152, 168))	('proliferative', 'CPA', (126, 139))	('SUM44F', 'Var', (90, 96))	('stronger', 'PosReg', (117, 125))	('FBS', 'Disease', (61, 64))	('DMEM', 'Chemical', '-', (44, 48))
40713	30180878	ICI 182,780 (ICI/fulvestrant) (1047; Tocris Bioscience, Avonmouth, Bristol, UK), etomoxir (E1905; Sigma-Aldrich), orlistat (O4139; Sigma-Aldrich), Fatostatin (F8932; Sigma-Aldrich), and TOFA (T6575; Sigma-Aldrich) were dissolved in dimethylsulfoxide (DMSO) (4-X; ATCC).	('Fatostatin', 'Chemical', 'MESH:C545733', (147, 157))	('Tocris Bioscience', 'Disease', (37, 54))	('Tocris Bioscience', 'Disease', 'None', (37, 54))	('TOFA', 'Chemical', 'MESH:C014289', (186, 190))	('O4139;', 'Var', (124, 130))	('DMSO', 'Chemical', 'MESH:D004121', (251, 255))	('E1905;', 'Var', (91, 97))	('etomoxir', 'Chemical', 'MESH:C054207', (81, 89))	('dimethylsulfoxide', 'Chemical', 'MESH:D004121', (232, 249))	('fulvestrant', 'Chemical', 'MESH:D000077267', (17, 28))
40731	30180878	Pathway analysis was conducted with Ingenuity Pathway Analysis (IPA) using genes that were differentially expressed in at least three MM134 LTED variants or both SUM44 LTED variants.	('variants', 'Var', (145, 153))	('MM134', 'Gene', (134, 139))	('MM134', 'Chemical', '-', (134, 139))
40739	30180878	The following transitions were used for cholesterol, 27-hydroxylcholesterol, and cholesterol esters: 369.3 161.3 cholesterol and cholesterol esters, 376.4 161.3 cholesterol-d7 and 16:0-cholesterol ester-d7, and 385.3 215.1 27-hydroxylcholesterol.	('cholesterol ester-d7', 'Chemical', '-', (185, 205))	('16:0-cholesterol ester', 'Chemical', 'MESH:C026651', (180, 202))	('cholesterol', 'Chemical', 'MESH:D002784', (40, 51))	('cholesterol', 'Chemical', 'MESH:D002784', (64, 75))	('cholesterol', 'Chemical', 'MESH:D002784', (81, 92))	('cholesterol', 'Chemical', 'MESH:D002784', (129, 140))	('cholesterol', 'Chemical', 'MESH:D002784', (113, 124))	('cholesterol', 'Chemical', 'MESH:D002784', (161, 172))	('27-hydroxylcholesterol', 'Chemical', '-', (53, 75))	('27-hydroxylcholesterol', 'MPA', (223, 245))	('27-hydroxylcholesterol', 'Chemical', '-', (223, 245))	('cholesterol', 'Chemical', 'MESH:D002784', (234, 245))	('cholesterol', 'Chemical', 'MESH:D002784', (185, 196))	('376.4 161.3', 'Var', (149, 160))	('cholesterol-d7', 'Chemical', '-', (161, 175))	('cholesterol esters', 'Chemical', 'MESH:D002788', (81, 99))	('cholesterol esters', 'Chemical', 'MESH:D002788', (129, 147))
40758	30180878	Whereas MM134 LTED and SUM44 LTED cells shared a significant number of DE genes (n = 437, P <2.2e-16), the majority of DE genes were unique for MM134 LTED or SUM44 LTED cells (Additional file 1: Figure S3C), indicating that the two cell line models have acquired some shared but also many different mechanisms of endocrine resistance.	('SUM44 LTED', 'Var', (158, 168))	('MM134', 'Chemical', '-', (144, 149))	('MM134', 'Chemical', '-', (8, 13))	('MM134 LTED', 'Var', (144, 154))
40770	30180878	Although we were unable to quantify 27-HC because the levels were below the limit of detection in our assays, growth assays showed that the cholesterol metabolites 25-HC and 27-HC could promote the proliferation of SUM44 LTED cells, as well as MM134 and SUM44 parental cells grown in CSS, suggesting a potential similar role of cholesterol metabolites in endocrine-resistant ER+ ILC models (Fig.	('promote', 'PosReg', (186, 193))	('cholesterol', 'Chemical', 'MESH:D002784', (140, 151))	('27-HC', 'Var', (174, 179))	('ER', 'Gene', '2099', (375, 377))	('CSS', 'Chemical', '-', (284, 287))	('cholesterol', 'Chemical', 'MESH:D002784', (328, 339))	('25-HC', 'Var', (164, 169))	('proliferation', 'CPA', (198, 211))	('MM134', 'Chemical', '-', (244, 249))
40774	30180878	We identified SREBP1 as one of the only five genes (SREBP1, FASN, FGFR4, AKR7A3, and FKBP11) that were commonly upregulated in MM134 LTED, SUM44 LTED, and SUM44 TamR cells (previously described by Riggins et al.).	('MM134', 'Var', (127, 132))	('AKR7A3', 'Gene', '22977', (73, 79))	('FGFR4', 'Gene', '2264', (66, 71))	('FGFR4', 'Gene', (66, 71))	('FASN', 'Gene', '2194', (60, 64))	('FKBP11', 'Gene', '51303', (85, 91))	('upregulated', 'PosReg', (112, 123))	('FKBP11', 'Gene', (85, 91))	('SREBP1', 'Gene', (14, 20))	('SREBP1', 'Gene', (52, 58))	('FKBP', 'molecular_function', 'GO:0030051', ('85', '89'))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('MM134', 'Chemical', '-', (127, 132))	('FASN', 'Gene', (60, 64))	('AKR7A3', 'Gene', (73, 79))
40777	30180878	At the protein level, the precursor SREBP1 (pre-SREBP1) was increased in MM134 LTED but not in SUM44 LTED cells (Fig.	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('MM134', 'Chemical', '-', (73, 78))	('MM134 LTED', 'Var', (73, 83))	('pre', 'molecular_function', 'GO:0003904', ('44', '47'))	('increased', 'PosReg', (60, 69))
40779	30180878	Our cell fractionation and immunoblot analyses showed upregulation of mSREBP1 in the nucleus in MM134 LTED cells compared with parental cells (Fig.	('nucleus', 'cellular_component', 'GO:0005634', ('85', '92'))	('mSREBP1', 'Gene', (70, 77))	('upregulation', 'PosReg', (54, 66))	('MM134', 'Var', (96, 101))	('MM134', 'Chemical', '-', (96, 101))	('mSREBP1', 'Gene', '20787', (70, 77))
40782	30180878	RNA and protein analysis showed significant upregulation of FASN in all four MM134 LTED lines (Fig.	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('FASN', 'Gene', '2194', (60, 64))	('upregulation', 'PosReg', (44, 56))	('MM134', 'Chemical', '-', (77, 82))	('MM134', 'Var', (77, 82))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('FASN', 'Gene', (60, 64))
40789	30180878	However, MM134 LTED cells were significantly more sensitive to etomoxir, an inhibitor of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme in beta-oxidation, than their parental cells (Fig.	('sensitive', 'MPA', (50, 59))	('CPT-1', 'Gene', (123, 128))	('MM134', 'Chemical', '-', (9, 14))	('CPT-1', 'Gene', '1374', (123, 128))	('MM134 LTED', 'Var', (9, 19))	('carnitine palmitoyltransferase 1', 'Gene', (89, 121))	('more', 'PosReg', (45, 49))	('CPT', 'molecular_function', 'GO:0004142', ('123', '126'))	('CPT', 'molecular_function', 'GO:0004095', ('123', '126'))	('etomoxir', 'MPA', (63, 71))	('carnitine palmitoyltransferase 1', 'Gene', '1374', (89, 121))	('etomoxir', 'Chemical', 'MESH:C054207', (63, 71))
40792	30180878	Successful knockdown was confirmed by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR), which also showed that SREBP knockdown resulted in decreased levels of the target gene FASN, as expected (Fig.	('FASN', 'Gene', '2194', (198, 202))	('FASN', 'Gene', (198, 202))	('decreased', 'NegReg', (162, 171))	('SREBP', 'Gene', (134, 139))	('reverse transcription', 'biological_process', 'GO:0001171', ('51', '72'))	('knockdown', 'Var', (140, 149))	('levels', 'MPA', (172, 178))
40794	30180878	MM134 LTED cells were also significantly more sensitive than their parental cells to PF429242 (Fig.	('MM134 LTED', 'Var', (0, 10))	('PF429242', 'Chemical', 'MESH:C570314', (85, 93))	('sensitive', 'MPA', (46, 55))	('MM134', 'Chemical', '-', (0, 5))
40795	30180878	When treated with PF429242, the SUM44 LTED cells were more sensitive than their parental cells (Fig.	('PF429242', 'Var', (18, 26))	('sensitive', 'MPA', (59, 68))	('PF429242', 'Chemical', 'MESH:C570314', (18, 26))
40804	30180878	In this study, we comprehensively characterized a total of six ILC LTED variants from MM134 and SUM44PE (SUM44F), the two most commonly used ER+ ILC cell lines.	('MM134', 'Chemical', '-', (86, 91))	('ILC', 'Gene', (63, 66))	('ER', 'Gene', '2099', (141, 143))	('variants', 'Var', (72, 80))
40807	30180878	We found that MM134 and SUM44 LTED cells acquired some shared but also unique adaptive mechanisms of resistance to estrogen deprivation.	('resistance to estrogen deprivation', 'MPA', (101, 135))	('MM134', 'Chemical', '-', (14, 19))	('MM134', 'Var', (14, 19))
40814	30180878	recently reported that SUM44 LTED cells have higher fatty acid dependency than their parental cells, which was hypothesized to be due to increased expression of fatty acid metabolism genes as a result of an ESR1 mutation in this set of LTED cells.	('fatty acid', 'Chemical', 'MESH:D005227', (52, 62))	('ESR1', 'Gene', '2099', (207, 211))	('expression', 'MPA', (147, 157))	('mutation', 'Var', (212, 220))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('161', '182'))	('fatty acid dependency', 'MPA', (52, 73))	('ESR1', 'Gene', (207, 211))	('increased', 'PosReg', (137, 146))	('higher', 'PosReg', (45, 51))	('fatty acid', 'Chemical', 'MESH:D005227', (161, 171))
40821	30180878	And whereas one study showed that FASN inhibition could reverse anti-estrogen resistance in MCF7 cells, others showed that FASN blockade increased the sensitivity of ER to E2 and thus there might be context-dependent effects that need to be elucidated further.	('FASN', 'Gene', (123, 127))	('FASN', 'Gene', (34, 38))	('sensitivity', 'MPA', (151, 162))	('FASN', 'Gene', '2194', (123, 127))	('MCF7', 'CellLine', 'CVCL:0031', (92, 96))	('FASN', 'Gene', '2194', (34, 38))	('ER', 'Gene', '2099', (166, 168))	('increased', 'PosReg', (137, 146))	('anti-estrogen resistance', 'MPA', (64, 88))	('blockade', 'Var', (128, 136))
40824	30180878	This has been reported in prostate cancer cells, which could be inhibited only by C75 and SB204990, inhibitors of FASN and ACLY, respectively, in the absence of lipoprotein, the transporter of exogenous fatty acid and cholesterol.	('FASN', 'Gene', '2194', (114, 118))	('fatty acid', 'Chemical', 'MESH:D005227', (203, 213))	('SB204990', 'Chemical', 'MESH:C112852', (90, 98))	('prostate cancer', 'Disease', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cholesterol', 'Chemical', 'MESH:D002784', (218, 229))	('SB204990', 'Gene', (90, 98))	('lipoprotein', 'Protein', (161, 172))	('ACLY', 'Gene', '47', (123, 127))	('FASN', 'Gene', (114, 118))	('ACLY', 'Gene', (123, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('C75', 'Var', (82, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))
40826	30180878	Similarly, gene expression changes were more pronounced in MM134 LTED cells.	('gene expression', 'MPA', (11, 26))	('gene expression', 'biological_process', 'GO:0010467', ('11', '26'))	('changes', 'Reg', (27, 34))	('MM134', 'Chemical', '-', (59, 64))	('MM134', 'Var', (59, 64))
40917	30621656	Alterations in the mechanisms governing the cell cycle induces uncontrolled cellular proliferation and CDK4/6 are recognized as potential target in ER+ BC.	('uncontrolled', 'MPA', (63, 75))	('cell cycle', 'biological_process', 'GO:0007049', ('44', '54'))	('Alterations', 'Var', (0, 11))	('CDK4/6', 'Gene', '1019;1021', (103, 109))	('ER', 'Gene', '2099', (148, 150))	('induces', 'Reg', (55, 62))	('CDK', 'molecular_function', 'GO:0004693', ('103', '106'))	('CDK4/6', 'Gene', (103, 109))	('BC', 'Phenotype', 'HP:0003002', (152, 154))
40937	29088785	Histologically, non-cohesive cancer cells are observed in ILC due to the loss of E-cadherin, either due to mutations inactivating the E-cadherin gene (CDH1), CDH1 haploisufficiency, but this is not observed in other breast cancer subtypes.	('CDH1', 'Gene', (151, 155))	('CDH1', 'Gene', '999', (158, 162))	('cancer', 'Disease', (223, 229))	('CDH1', 'Gene', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('CDH1 haploisufficiency', 'Disease', 'None', (158, 180))	('CDH1 haploisufficiency', 'Disease', (158, 180))	('inactivating', 'NegReg', (117, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('loss', 'NegReg', (73, 77))	('cancer', 'Disease', (29, 35))	('E-cadherin', 'Gene', (81, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('E-cadherin', 'Gene', '999', (81, 91))	('ILC', 'Disease', (58, 61))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('CDH1', 'Gene', '999', (151, 155))	('mutations', 'Var', (107, 116))	('breast cancer', 'Disease', (216, 229))	('E-cadherin', 'Gene', (134, 144))	('E-cadherin', 'Gene', '999', (134, 144))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
41015	27846863	In the low MUC1 group (n = 11), larger tumors, higher nuclear grade, lymph node metastasis, and negativity for estrogen receptor was more frequently identified compared to the high MUC1 group (n = 11; p = 0.01, p = 0.002, p = 0.008, and p = 0.02, respectively).	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('nuclear grade', 'CPA', (54, 67))	('MUC1', 'Gene', '4582', (11, 15))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('estrogen receptor', 'Gene', (111, 128))	('estrogen receptor', 'Gene', '2099', (111, 128))	('MUC1', 'Gene', (181, 185))	('MUC1', 'Gene', '4582', (181, 185))	('negativity', 'Var', (96, 106))	('tumors', 'Disease', (39, 45))	('MUC1', 'Gene', (11, 15))	('lymph node metastasis', 'CPA', (69, 90))
41030	27846863	The aberrant expression of mucins could be associated with cancer growth, differentiation, transformation, and invasion.	('mucin', 'Gene', '100508689', (27, 32))	('aberrant', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mucin', 'Gene', (27, 32))	('transformation', 'CPA', (91, 105))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('associated', 'Reg', (43, 53))	('differentiation', 'CPA', (74, 89))	('cancer', 'Disease', (59, 65))	('invasion', 'CPA', (111, 119))
41092	27846863	Nine patients in the group with low MUC1 expression had larger tumors, whereas 8 patients in the high MUC1 expression group had small-sized tumors (p = 0.01).	('low', 'Var', (32, 35))	('tumors', 'Disease', (140, 146))	('MUC1', 'Gene', (36, 40))	('MUC1', 'Gene', '4582', (36, 40))	('patients', 'Species', '9606', (5, 13))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (81, 89))	('MUC1', 'Gene', (102, 106))	('MUC1', 'Gene', '4582', (102, 106))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
41094	27846863	Seven patients in the group with low MUC1 expression had metastatic carcinoma in the axillary lymph nodes, whereas only 1 patient had a positive lymph node in the high MUC1 group (p = 0.008).	('carcinoma', 'Disease', (68, 77))	('patient', 'Species', '9606', (122, 129))	('patient', 'Species', '9606', (6, 13))	('MUC1', 'Gene', (37, 41))	('low', 'Var', (33, 36))	('MUC1', 'Gene', '4582', (37, 41))	('metastatic', 'CPA', (57, 67))	('carcinoma', 'Disease', 'MESH:D002277', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('patients', 'Species', '9606', (6, 14))	('MUC1', 'Gene', (168, 172))	('MUC1', 'Gene', '4582', (168, 172))
41096	27846863	In the group with low MUC1 expression, 6 cases were negative for ER, while 10 cases were positive for ER in the group with high MUC1 expression (p = 0.02).	('ER', 'Gene', '2099', (102, 104))	('ER', 'Gene', '2099', (65, 67))	('MUC1', 'Gene', (128, 132))	('MUC1', 'Gene', (22, 26))	('MUC1', 'Gene', '4582', (22, 26))	('low', 'Var', (18, 21))	('MUC1', 'Gene', '4582', (128, 132))
41119	27846863	and others showed that the presence of MUC1 at the apical cellular site of the ductal epithelium is an indicator of intact MUC-pathway associated with good prognosis, whereas aberrant patterns of expression are indicators of defective MUC1 pathway associated with worse prognosis.	('MUC-pathway', 'Pathway', (123, 134))	('MUC1', 'Gene', (235, 239))	('aberrant patterns of', 'Var', (175, 195))	('MUC1', 'Gene', '4582', (235, 239))	('MUC1', 'Gene', (39, 43))	('MUC1', 'Gene', '4582', (39, 43))	('associated', 'Reg', (135, 145))
41147	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.	('cadherin', 'molecular_function', 'GO:0008014', ('184', '192'))	('lobular carcinoma', 'Disease', 'MESH:D018275', (28, 45))	('E-cadherin', 'Gene', '999', (182, 192))	('tumour', 'Disease', (208, 214))	('pre', 'molecular_function', 'GO:0003904', ('129', '132'))	('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))
41161	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))	('PLC', 'cellular_component', 'GO:0042824', ('262', '265'))	('associated', 'Reg', (94, 104))	('variants', 'Var', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (290, 296))
41170	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))
41171	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.	('cadherin', 'molecular_function', 'GO:0008014', ('198', '206'))	('growth pattern', 'biological_process', 'GO:0040007', ('31', '45'))	('growth pattern', 'biological_process', 'GO:0007150', ('31', '45'))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('91', '109'))	('E-cadherin', 'Gene', (196, 206))	('E-cadherin', 'Gene', '999', (196, 206))	('discohesive growth pattern', 'CPA', (19, 45))	('cell-cell adhesion properties', 'CPA', (91, 120))	('disruption', 'Var', (155, 165))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('173', '195'))	('cell adhesion', 'biological_process', 'GO:0007155', ('173', '186'))
41177	25849106	In contrast, approximately 90% of LNs and ILCs, including variants, completely lack E-cadherin protein expression.	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('variants', 'Var', (58, 66))	('lack', 'NegReg', (79, 83))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('cadherin', 'molecular_function', 'GO:0008014', ('86', '94'))
41182	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.	('cadherin', 'molecular_function', 'GO:0008014', ('6', '14'))	('catenin complex', 'cellular_component', 'GO:0016342', ('15', '30'))	('dysfunctional', 'Reg', (38, 51))	('beta-catenin', 'Gene', '1499', (213, 225))	('aberrant/loss', 'NegReg', (124, 137))	('binding', 'molecular_function', 'GO:0005488', ('167', '174'))	('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))
41183	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))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('CDH1', 'Gene', '999', (193, 197))	('E-cadherin', 'Gene', (0, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('210', '220'))	('E-cadherin', 'Gene', '999', (0, 10))	('ALH', 'Chemical', '-', (103, 106))
41184	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))	('loss of heterozygosity', 'Var', (174, 196))	('tumour', 'Disease', (101, 107))	('mutation', 'Var', (140, 148))	('CDH1', 'Gene', (135, 139))	('methylation', 'Var', (155, 166))	('loss', 'NegReg', (40, 44))	('methylation', 'biological_process', 'GO:0032259', ('155', '166'))	('cadherin', 'molecular_function', 'GO:0008014', ('31', '39'))	('CDH1', 'Gene', '999', (135, 139))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
41185	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.	('ILCs', 'Disease', (111, 115))	('CDH1', 'Gene', '999', (61, 65))	('regulation', 'biological_process', 'GO:0065007', ('47', '57'))	('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))
41186	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))
41187	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))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumours', 'Phenotype', 'HP:0002664', (171, 178))	('CDH1', 'Gene', (46, 50))	('tumours', 'Disease', 'MESH:D009369', (171, 178))	('lobular tumours', 'Disease', (73, 88))	('tumours', 'Disease', (81, 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))
41190	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))	('LCIS', 'Disease', (55, 59))
41191	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))
41192	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))
41193	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))	('cadherin', 'molecular_function', 'GO:0008014', ('228', '236'))	('E-cadherin', 'Gene', (226, 236))	('E-cadherin', 'Gene', '999', (226, 236))	('CDH1', 'Gene', (102, 106))
41194	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))
41195	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))
41196	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))	('growth pattern', 'biological_process', 'GO:0007150', ('165', '179'))	('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))	('growth pattern', 'biological_process', 'GO:0040007', ('165', '179'))	('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))
41197	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))	('ILC', 'Disease', (148, 151))	('CDH1', 'Gene', (83, 87))	('caused by', 'Reg', (50, 59))	('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))
41199	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', 'MESH:D013274', (130, 160))	('bilateral ILC', 'Disease', (194, 207))	('CDH1', 'Gene', (95, 99))	('account', 'Reg', (168, 175))	('variants', 'Var', (109, 117))	('familial lobular breast cancer', 'Disease', (130, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))
41201	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))	('lobular breast cancer', 'Disease', 'MESH:D013274', (55, 76))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (17, 50))	('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))
41202	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))	('cadherin', 'molecular_function', 'GO:0008014', ('14', '22'))	('adhesion', 'CPA', (135, 143))	('E-cadherin', 'Gene', '999', (12, 22))	('more', 'PosReg', (154, 158))	('polarity', 'CPA', (122, 130))	('invasive', 'CPA', (173, 181))	('associated', 'Reg', (31, 41))	('wound healing', 'biological_process', 'GO:0042060', ('217', '230'))	('EMT', 'biological_process', 'GO:0001837', ('100', '103'))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('62', '98'))	('embryonic morphogenesis', 'biological_process', 'GO:0048598', ('189', '212'))	('lose', 'NegReg', (117, 121))	('loss', 'Var', (4, 8))
41222	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).	('ERBB2', 'Gene', '2064', (289, 294))	('CCND1', 'Gene', '595', (271, 276))	('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))
41223	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))
41226	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))	('PLC', 'cellular_component', 'GO:0042824', ('20', '23'))	('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))
41230	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))
41231	25849106	Conversely, tumours in IntClust 4 showed infrequent 1q + and 16q-.	('16q-', 'Var', (61, 65))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('1q +', 'Var', (52, 56))	('tumours', 'Disease', (12, 19))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))
41236	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))
41238	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))
41239	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))
41241	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))
41242	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))	('ERBB2', 'Gene', '2064', (199, 204))	('HER2', 'Gene', '2064', (194, 198))	('HER2', 'Gene', (194, 198))	('genetic alterations', 'Var', (205, 224))	('ERBB2', 'Gene', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
41256	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.	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('FGFR1', 'Gene', '2260', (171, 176))	('tumour', 'Disease', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('ESR1', 'Gene', '2099', (130, 134))	('ESR1', 'Gene', (130, 134))	('mutations', 'Var', (117, 126))	('FGFR1', 'Gene', (171, 176))	('tumours', 'Disease', (78, 85))	('ERBB2', 'Gene', (138, 143))	('CCND1', 'Gene', '595', (188, 193))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('ERBB2', 'Gene', '2064', (138, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('CCND1', 'Gene', (188, 193))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
41259	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))
41290	32546838	Engraftment success associated with the following clinicopathologic features: high-grade, low-ER expression (<=15%), HER2-negativity, germline BRCA1/2 mutation, previous systemic treatment and presence of axillary lymph node (ALN) metastases (Supplementary Fig.	('BRCA1/2', 'Gene', '672;675', (143, 150))	('HER2', 'Gene', (117, 121))	('HER2', 'Gene', '2064', (117, 121))	('low-ER', 'Var', (90, 96))	('axillary lymph node', 'CPA', (205, 224))	('mutation', 'Var', (151, 159))	('metastases', 'Disease', (231, 241))	('Engraftment success', 'CPA', (0, 19))	('metastases', 'Disease', 'MESH:D009362', (231, 241))	('BRCA1/2', 'Gene', (143, 150))	('high-grade', 'Var', (78, 88))
41294	32546838	One patient had three PDX models derived from their tumors:two sublines from distinct histological regions from their primary tumor (GCRC1784Xd/c, discussed below) and one from mediastinal lymph node metastasis (GCRC2054X) that developed at a later time point.	('PD', 'Disease', 'MESH:D010300', (22, 24))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('GCRC1784Xd/c', 'Var', (133, 145))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (126, 131))
41295	32546838	Another patient had two PDXs developed from their tumors:one from their primary tumor (GCRC1915X) and another from a lung metastasis (GCRC2076X), which was sampled at the time of recurrence.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GCRC1915', 'CellLine', 'CVCL:1505', (87, 95))	('tumor', 'Disease', (80, 85))	('GCRC2076X', 'Var', (134, 143))	('PD', 'Disease', 'MESH:D010300', (24, 26))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patient', 'Species', '9606', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (50, 55))	('GCRC1915X', 'Var', (87, 96))
41303	32546838	Two lines were found to contain primary xenografts that were CD45+ (GCRC1924 and GCRC2034), both of which were derived from tumors with florid lymphocytic infiltrate (Supplementary Fig.	('CD45', 'Gene', '5788', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('GCRC2034', 'Var', (81, 89))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('CD45', 'Gene', (61, 65))
41304	32546838	Although one of the four GCRC1924 primary outgrowths established as a pan-KRT+/CD45- tumor and could be serially propagated as such, all P1 transplants of GCRC2034 were pan-KRT-/CD45+ and therefore this line was excluded from the final series.	('tumor', 'Disease', (85, 90))	('CD45', 'Gene', (79, 83))	('GCRC1924', 'Gene', (25, 33))	('CD45', 'Gene', '5788', (79, 83))	('CD45', 'Gene', '5788', (178, 182))	('KRT', 'Gene', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('KRT', 'Gene', '643865', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('KRT', 'Gene', (74, 77))	('GCRC2034', 'Var', (155, 163))	('CD45', 'Gene', (178, 182))	('KRT', 'Gene', '643865', (74, 77))
41315	32546838	The median whole-genome single-nucleotide variant (SNV) load was 10,773 (range 2103-68,363), consistent with previous breast cancer analyses (Fig.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('single-nucleotide variant', 'Var', (24, 49))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
41316	32546838	C>A, C>G, C>T, T>A, T>C, T>G) were well-preserved in PDXs (Fig.	('PD', 'Disease', 'MESH:D010300', (53, 55))	('C>A', 'Var', (0, 3))	('C>T', 'Var', (10, 13))
41317	32546838	Variability across models was also observed in small insertions and deletions (indels), with a median of 1268 per tumor (range 304-2841) (Fig.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('deletions', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('insertions', 'Var', (53, 63))
41318	32546838	When only coding regions were considered, there was a median of 113 non-synonymous, truncating or splice-site mutations per tumor (range 20-662) (Fig.	('truncating', 'MPA', (84, 94))	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('non-synonymous', 'MPA', (68, 82))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
41320	32546838	For example, GCRC1863 (r = 0.72, p < 2.2 x 10-16) and GCRC1915 (r = 0.71, p < 2.2 x 10-16) showed strong preservation of mutation prevalence, in contrast to the GCRC2001 model, which displayed marked shifts in VAFs (r = -0.21, p = 1.21 x 10-77).	('mutation prevalence', 'MPA', (121, 140))	('GCRC1863', 'Var', (13, 21))	('GCRC1915', 'Var', (54, 62))	('GCRC1915', 'CellLine', 'CVCL:1505', (54, 62))
41321	32546838	Larger structural variants (SV), including duplications, insertions, deletions, inversions and translocations, were observed with median of 415 events per tumor (range 51-1253), with marked similarity in genomic structures between parental tumors and PDXs (Fig.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('parental tumors', 'Disease', 'MESH:D063129', (231, 246))	('duplications', 'Var', (43, 55))	('parental tumors', 'Disease', (231, 246))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', (155, 160))	('PD', 'Disease', 'MESH:D010300', (251, 253))	('deletions', 'Var', (69, 78))	('translocations', 'Var', (95, 109))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('insertions', 'Var', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
41323	32546838	Several of the rare histological subtypes were noted to display quiet copy number profiles, including the ACC (GCRC1828), ILC (GCRC1971), NE carcinoma (GCRC1979) and mucinous (GCRC2007) models, consistent with previous observations in these tumor types.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('GCRC1971', 'Var', (127, 135))	('GCRC1979', 'Var', (152, 160))	('tumor', 'Disease', (241, 246))	('NE carcinoma', 'Disease', 'MESH:D009369', (138, 150))	('ILC', 'Disease', (122, 125))	('NE carcinoma', 'Disease', (138, 150))	('copy number', 'MPA', (70, 81))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('GCRC1828', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
41324	32546838	Arm-length CNAs previously associated with breast cancer (gains in 1q, 3q, 8q, 10p, 12p, 20q; losses in 5q, 8p, 11q, 16q), as well as amplifications/deletions (amplification of ERBB2, ZNF703/FGFR1, CCND1, MYC, EGFR; deletion of RB1, PTEN, CDKN2A/B), were represented within the cohort and recapitulated in the PDXs (Fig.	('MYC', 'Gene', '4609', (205, 208))	('ERBB2', 'Gene', (177, 182))	('EGFR', 'Gene', (210, 214))	('RB1', 'Gene', (228, 231))	('PD', 'Disease', 'MESH:D010300', (310, 312))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('CDKN2A/B', 'Gene', (239, 247))	('FGFR1', 'Gene', (191, 196))	('ERBB2', 'Gene', '2064', (177, 182))	('ZNF703', 'Gene', '80139', (184, 190))	('EGFR', 'molecular_function', 'GO:0005006', ('210', '214'))	('CCND1', 'Gene', '595', (198, 203))	('RB1', 'Gene', '5925', (228, 231))	('PTEN', 'Gene', (233, 237))	('EGFR', 'Gene', '1956', (210, 214))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('CCND1', 'Gene', (198, 203))	('CDKN2A/B', 'Gene', '1029;1030', (239, 247))	('ZNF703', 'Gene', (184, 190))	('MYC', 'Gene', (205, 208))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('gains', 'PosReg', (58, 63))	('breast cancer', 'Disease', (43, 56))	('PTEN', 'Gene', '5728', (233, 237))	('FGFR1', 'Gene', '2260', (191, 196))	('losses', 'NegReg', (94, 100))	('associated', 'Reg', (27, 37))	('deletion', 'Var', (216, 224))	('FGFR', 'molecular_function', 'GO:0005007', ('191', '195'))
41326	32546838	Hotspot oncogenic drivers, truncating loss-of-function mutations and CNAs were identified in members of critical breast cancer pathways, including P53, receptor tyrosine kinase (RTK), PI3K and MAPK signaling, as well as cell cycle, transcriptional and epigenetic regulators and were highly conserved in PDXs (Fig.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('193', '197'))	('cell cycle', 'biological_process', 'GO:0007049', ('220', '230'))	('mutations', 'Var', (55, 64))	('breast cancer', 'Disease', (113, 126))	('loss-of-function', 'NegReg', (38, 54))	('P53', 'Gene', (147, 150))	('RTK', 'Gene', '5979', (178, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('MAPK signaling', 'biological_process', 'GO:0000165', ('193', '207'))	('PI3K', 'molecular_function', 'GO:0016303', ('184', '188'))	('receptor tyrosine kinase', 'Gene', (152, 176))	('receptor tyrosine kinase', 'Gene', '5979', (152, 176))	('P53', 'Gene', '7157', (147, 150))	('PD', 'Disease', 'MESH:D010300', (303, 305))	('RTK', 'Gene', (178, 181))
41334	32546838	Subtype switching from normal-like in human to basal-like in PDX was observed in tumors with high stromal content (GCRC1828 and GCRC1886), which was lost upon engraftment (Fig.	('PD', 'Disease', 'MESH:D010300', (61, 63))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('human', 'Species', '9606', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('GCRC1828', 'Var', (115, 123))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('GCRC1886', 'Var', (128, 136))
41335	32546838	The other two subtype switches were basal-like in human to HER2E in PDX (GCRC2001 and GCRC2029).	('HER2', 'Gene', '2064', (59, 63))	('PD', 'Disease', 'MESH:D010300', (68, 70))	('GCRC2029', 'Var', (86, 94))	('human', 'Species', '9606', (50, 55))	('HER2', 'Gene', (59, 63))	('GCRC2001', 'Var', (73, 81))
41379	32546838	DNA-level candidates supported by compelling clinical evidence included PIK3CA hotspot mutations (H1047R in GCRC1715X, GCRC1944X, GCRC1991X, GCRC2001X and GCRC2029X; E545K in GCRC1971X) and ERBB2 hotspot mutation (L755S in GCRC1715X) (Fig.	('GCRC2001X', 'Var', (141, 150))	('ERBB2', 'Gene', (190, 195))	('H1047R', 'Mutation', 'rs121913279', (98, 104))	('GCRC2029X; E545K', 'Var', (155, 171))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('PIK3CA', 'Gene', (72, 78))	('H1047R', 'Var', (98, 104))	('E545K', 'Mutation', 'rs104886003', (166, 171))	('E545K', 'Var', (166, 171))	('L755S', 'Var', (214, 219))	('GCRC1991X', 'Var', (130, 139))	('L755S', 'Mutation', 'rs121913470', (214, 219))	('PIK3CA', 'Gene', '5290', (72, 78))	('ERBB2', 'Gene', '2064', (190, 195))	('GCRC1944X', 'Var', (119, 128))
41380	32546838	Other potentially actionable alterations were FGFR1, MYC and MDM2 amplifications, ATM, ARID1A, CDH1 and PIK3R1 truncating mutations and PTEN and INPP4B losses, which have demonstrated fair preclinical data.	('CDH1', 'Gene', '999', (95, 99))	('PIK3R1', 'Gene', '5295', (104, 110))	('INPP4B', 'Gene', '8821', (145, 151))	('MDM2', 'Gene', (61, 65))	('ATM', 'Gene', (82, 85))	('FGFR1', 'Gene', (46, 51))	('CDH1', 'Gene', (95, 99))	('MYC', 'Gene', '4609', (53, 56))	('MDM2', 'Gene', '4193', (61, 65))	('INPP4B', 'Gene', (145, 151))	('losses', 'NegReg', (152, 158))	('PIK3R1', 'Gene', (104, 110))	('truncating mutations', 'Var', (111, 131))	('PTEN', 'Gene', (136, 140))	('ARID1A', 'Gene', (87, 93))	('ATM', 'Gene', '472', (82, 85))	('FGFR1', 'Gene', '2260', (46, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('amplifications', 'Var', (66, 80))	('ARID1A', 'Gene', '8289', (87, 93))	('MYC', 'Gene', (53, 56))	('PTEN', 'Gene', '5728', (136, 140))
41382	32546838	For the GCRC1971X model, an ER + ILC that displayed skull-base metastases and multi-chemoresistance in vivo, WGS revealed multiple candidates (PIK3CA hotspot, FGFR1 amplification, CDH1 truncating mutation) (Figs.	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('FGFR1', 'Gene', (159, 164))	('PIK3CA', 'Gene', (143, 149))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('CDH1', 'Gene', (180, 184))	('amplification', 'Var', (165, 178))	('CDH1', 'Gene', '999', (180, 184))	('PIK3CA', 'Gene', '5290', (143, 149))	('GCRC1971X', 'Var', (8, 17))	('FGFR1', 'Gene', '2260', (159, 164))	('metastases', 'Disease', (63, 73))
41384	32546838	A small PCT was initiated to evaluate the efficacy of BGJ398, an orally available FGFR inhibitor, among a subset of PDXs displaying the highest FGFR1 copy number and/or RNA expression across the PDX library (Fig.	('BGJ398', 'Gene', (54, 60))	('RNA expression', 'MPA', (169, 183))	('FGFR', 'Gene', (82, 86))	('PD', 'Disease', 'MESH:D010300', (116, 118))	('PD', 'Disease', 'MESH:D010300', (195, 197))	('RNA', 'cellular_component', 'GO:0005562', ('169', '172'))	('copy number', 'Var', (150, 161))	('FGFR1', 'Gene', (144, 149))	('FGFR', 'Gene', (144, 148))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('FGFR', 'Gene', '2260;14182', (82, 86))	('FGFR1', 'Gene', '2260', (144, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('BGJ398', 'Chemical', 'MESH:C568950', (54, 60))	('FGFR', 'Gene', '2260;14182', (144, 148))
41385	32546838	Although GCRC1971X achieved a CR within a week of initiating treatment, responses were poor for the four other models with lower levels of FGFR1 amplification/expression (Fig.	('FGFR1', 'Gene', (139, 144))	('FGFR1', 'Gene', '2260', (139, 144))	('FGFR', 'molecular_function', 'GO:0005007', ('139', '143'))	('GCRC1971X', 'Var', (9, 18))
41391	32546838	The GCRC1979X PDX ranked highest for an RPPA-based PI3K/mTOR activation signature (Fig.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (56, 60))	('RPPA-based', 'MPA', (40, 50))	('PD', 'Disease', 'MESH:D010300', (14, 16))	('GCRC1979X', 'Var', (4, 13))
41393	32546838	Overall, everolimus response correlated with PI3K/mTOR activation score, where the GCRC1979X displayed a strong and durable response to this agent (Fig.	('everolimus', 'Chemical', 'MESH:D000068338', (9, 19))	('mTOR', 'Gene', (50, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('mTOR', 'Gene', '2475', (50, 54))	('GCRC1979X', 'Var', (83, 92))
41394	32546838	This 38-year-old patient with TNBC and a germline BRCA1 mutation (c.2002C>T) reported as benign, failed to respond to neoadjuvant doxorubicin, cyclophosphamide and paclitaxel (Fig.	('BRCA1', 'Gene', (50, 55))	('doxorubicin', 'Chemical', 'MESH:D004317', (130, 141))	('patient', 'Species', '9606', (17, 24))	('c.2002C>T', 'Mutation', 'rs80357250', (66, 75))	('TNBC', 'Disease', 'None', (30, 34))	('c.2002C>T', 'Var', (66, 75))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (143, 159))	('BRCA1', 'Gene', '672', (50, 55))	('paclitaxel', 'Chemical', 'MESH:D017239', (164, 174))	('TNBC', 'Disease', (30, 34))
41425	32546838	Breast cancer patients over the age of 18 with (1) ER-; (2) HER2+; (3) high-grade ER+; (4) metastatic; or (5) rare histological variants of breast cancer undergoing diagnosis and/or management at McGill University Health Centre or Jewish General Hospital, Montreal, QC, Canada were recruited for this study.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('HER2', 'Gene', (60, 64))	('variants', 'Var', (128, 136))	('ER-', 'Var', (51, 54))	('metastatic', 'CPA', (91, 101))	('HER2', 'Gene', '2064', (60, 64))	('Breast cancer', 'Disease', (0, 13))	('patients', 'Species', '9606', (14, 22))
41440	32546838	The following samples were not included in genomic analyses: GCRC1924T (WGS/RNA-seq; tumor sample unavailable), GCRC1944T (RNA-seq; low-quality RNA), GCRC1979T (WGS/RNA-seq; tumor sample unavailable), GCRC1986T (WGS/RNA-seq; tumor and germline samples unavailable), GCRC1986X (WGS; patient germline sample unavailable for alignment), GCRC2054T (WGS/RNA-seq; tumor sample unavailable), GCRC2076T (WGS/RNA-seq; tumor sample unavailable), GCRC2089T (RNA-seq; low-quality RNA).	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', (409, 414))	('GCRC2076T', 'CellLine', 'CVCL:K838', (385, 394))	('GCRC1986X', 'Var', (266, 275))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('tumor', 'Disease', (225, 230))	('RNA', 'cellular_component', 'GO:0005562', ('144', '147'))	('GCRC1986T', 'CellLine', 'CVCL:9I26', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('RNA', 'cellular_component', 'GO:0005562', ('447', '450'))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('GCRC2076T', 'Var', (385, 394))	('RNA', 'cellular_component', 'GO:0005562', ('349', '352'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('RNA', 'cellular_component', 'GO:0005562', ('216', '219'))	('GCRC1986T', 'Var', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('RNA', 'cellular_component', 'GO:0005562', ('165', '168'))	('GCRC2089T', 'CellLine', 'CVCL:K851', (436, 445))	('tumor', 'Disease', (358, 363))	('GCRC2054T', 'CellLine', 'CVCL:X087', (334, 343))	('RNA', 'cellular_component', 'GO:0005562', ('400', '403'))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (358, 363))	('RNA', 'cellular_component', 'GO:0005562', ('468', '471'))	('GCRC2089T', 'Var', (436, 445))	('patient', 'Species', '9606', (282, 289))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('RNA', 'cellular_component', 'GO:0005562', ('123', '126'))	('GCRC2054T', 'Var', (334, 343))	('GCRC1979T', 'CellLine', 'CVCL:V554', (150, 159))
41444	32546838	Variants were annotated with hg38 database using SnpEff (version 4.3).	('Variants', 'Var', (0, 8))	('hg38', 'Gene', (29, 33))	('hg38', 'Gene', '8549', (29, 33))
41445	32546838	CRAVAT 5.2.4 was used to identify potential pathogenic and cancer driver variants.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('variants', 'Var', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
41451	32546838	GCRC1784Xc (derived from a metaplastic tumor with chondroid differentiation) was not included in the analysis because it was an outlier (Correction Factor 1: 0.33) sample for total protein content.	('GCRC1784Xc', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))
41466	32546838	generated patient-derived xenografts; P.S., L.L., V.P., A.A-.M., M.D.	('A.A-.M.', 'Var', (56, 63))	('patient', 'Species', '9606', (10, 17))	('P.S.', 'Var', (38, 42))
41469	32546838	provided access to patient material; P.S., P.M.S., S.P.S., S.A., M.B., S.M.	('patient', 'Species', '9606', (19, 26))	('M.B.', 'Var', (65, 69))	('S.A.', 'Var', (59, 63))	('P.S.', 'Var', (37, 41))	('P.M.S.', 'Var', (43, 49))	('S.P.S.', 'Var', (51, 57))
41518	31814295	Lung, brain, liver, and multiorgan metastatic tumors have similar gene features.13 Another research found that the genomic mutations were originated from the primary tumor and maintained through metastatic spreading, of which TP53 mutation was a recurrent founding mutation in primary and metastatic tumors.14 We also reported genes like NAMPT, SREBP1, and MTDH could drive metastatic progression in TNBC.15, 16, 17 The alteration of genes cluster could not only influence malignant behaviors, but also transform pathomorphological features.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('TP53', 'Gene', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('NAMPT', 'Gene', '10135', (338, 343))	('malignant behaviors', 'CPA', (473, 492))	('tumors', 'Disease', (300, 306))	('tumors.14', 'Disease', 'MESH:C535488', (300, 309))	('tumors', 'Disease', (46, 52))	('MTDH', 'Gene', (357, 361))	('NAMPT', 'Gene', (338, 343))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('MTDH', 'Gene', '92140', (357, 361))	('pathomorphological features', 'CPA', (513, 540))	('alteration', 'Var', (420, 430))	('TP53', 'Gene', '7157', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('SREBP1', 'Gene', '6720', (345, 351))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('transform', 'Reg', (503, 512))	('tumor', 'Disease', (300, 305))	('influence', 'Reg', (463, 472))	('SREBP1', 'Gene', (345, 351))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumors.14', 'Disease', (300, 309))
41519	31814295	Histologic subtypes of breast cancer were the consequence of genes alteration, which were greatly different in morphology, behavior, and mechanism.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('consequence', 'Reg', (46, 57))	('genes alteration', 'Var', (61, 77))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
41524	31814295	Considering the correlation between HER-2 and lung metastasis, we found that HER-2 inactivation contributed to lung metastasis,26 and the inactivation of HER-2 pathway in MBC could result in more lung-specific distant metastasis.	('contributed', 'Reg', (96, 107))	('HER-2', 'Gene', '2064', (77, 82))	('inactivation', 'Var', (138, 150))	('HER-2', 'Gene', '2064', (36, 41))	('lung-specific distant metastasis', 'CPA', (196, 228))	('inactivation', 'Var', (83, 95))	('HER-2', 'Gene', '2064', (154, 159))	('HER-2', 'Gene', (77, 82))	('HER-2', 'Gene', (36, 41))	('HER-2', 'Gene', (154, 159))	('more', 'PosReg', (191, 195))
41585	30389994	In contrast, the effective linear degree-of-polarization of the output light after interaction with the collagen in samples shows the opposite trend (0.806 +- 0.130 and 0.653 +- 0.245, respectively), agreeing with work that highlights DOPL.	('0.653', 'Var', (169, 174))	('DOPL', 'Chemical', '-', (235, 239))	('collagen', 'molecular_function', 'GO:0005202', ('104', '112'))	('interaction', 'Interaction', (83, 94))
41651	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))
41874	28365833	Furthermore, studies investigating progesterone as a predictive marker for response to endocrine therapy show that loss of PR expression predicts relative resistance to tamoxifen, whereas maintenance of response to aromatase inhibitors can be observed, suggesting a selective role of this treatment in this subgroup.	('progesterone', 'Chemical', 'MESH:D011374', (35, 47))	('expression', 'MPA', (126, 136))	('loss', 'Var', (115, 119))	('resistance to tamoxifen', 'MPA', (155, 178))	('PR', 'Gene', '5241', (123, 125))	('tamoxifen', 'Chemical', 'MESH:D013629', (169, 178))
41927	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))
42074	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))
42076	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))
42082	22112476	Originally described by Foote and Stewart in 1941, many variants ofLCIS have now been identified, based on nuclear grade, pleomorphism and necrosis.	('necrosis', 'biological_process', 'GO:0070265', ('139', '147'))	('variants', 'Var', (56, 64))	('necrosis', 'biological_process', 'GO:0008219', ('139', '147'))	('necrosis', 'Disease', (139, 147))	('necrosis', 'biological_process', 'GO:0019835', ('139', '147'))	('ofLCIS', 'Gene', (65, 71))	('necrosis', 'biological_process', 'GO:0008220', ('139', '147'))	('LCIS', 'Phenotype', 'HP:0030076', (67, 71))	('necrosis', 'Disease', 'MESH:D009336', (139, 147))	('necrosis', 'biological_process', 'GO:0001906', ('139', '147'))
42093	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', 'MPA', (219, 227))	('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))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('transcriptional', 'MPA', (178, 193))	('methylation', 'biological_process', 'GO:0032259', ('228', '239'))	('regulation', 'biological_process', 'GO:0065007', ('194', '204'))
42095	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))
42096	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))	('methylation', 'biological_process', 'GO:0032259', ('183', '194'))	('e-cadherin', 'Gene', '999', (241, 251))	('cadherin', 'molecular_function', 'GO:0008014', ('162', '170'))	('alterations', 'Var', (67, 78))	('cadherin', 'molecular_function', 'GO:0008014', ('243', '251'))	('protein', 'Protein', (22, 29))	('protein', 'cellular_component', 'GO:0003675', ('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))
42097	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))
42100	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))
42102	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))
42105	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))
42106	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))
42113	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))	('ADH', 'molecular_function', 'GO:0004022', ('26', '29'))	('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))	('ADH', 'molecular_function', 'GO:0047636', ('26', '29'))
42120	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))	('ductal carcinoma in situ', 'Disease', (93, 117))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (100, 117))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (129, 154))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (93, 117))	('invasive ductal carcinoma', 'Disease', (129, 154))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (138, 154))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (93, 117))
42124	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))	('ADH', 'molecular_function', 'GO:0047636', ('174', '177'))	('DCIS', 'Disease', (125, 129))	('amplification', 'Var', (32, 45))	('ADH', 'molecular_function', 'GO:0004022', ('174', '177'))	('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))
42125	22112476	Additionally, mutations in the p53 tumor suppressor gene, also found in a subset of DCIS and invasive cancers, are not seen in ADH.	('ADH', 'molecular_function', 'GO:0047636', ('127', '130'))	('AD', 'Disease', (127, 129))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('p53', 'Gene', '7157', (31, 34))	('tumor', 'Disease', (35, 40))	('AD', 'Disease', 'MESH:D000544', (127, 129))	('invasive cancers', 'Disease', 'MESH:D009362', (93, 109))	('found', 'Reg', (63, 68))	('invasive cancers', 'Disease', (93, 109))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('p53', 'Gene', (31, 34))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('ADH', 'molecular_function', 'GO:0004022', ('127', '130'))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('DCIS', 'Disease', (84, 88))
42130	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))
42134	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))
42135	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))
42136	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))
42141	22112476	SlOOA7 has been demonstrated to act as a chemoattractant for T-lymphocytes and neutrophils, and induces serum antibody responses.	('induces', 'PosReg', (96, 103))	('antibody', 'cellular_component', 'GO:0019815', ('110', '118'))	('antibody', 'cellular_component', 'GO:0019814', ('110', '118'))	('antibody', 'molecular_function', 'GO:0003823', ('110', '118'))	('SlOOA7', 'Var', (0, 6))	('serum antibody responses', 'MPA', (104, 128))	('antibody', 'cellular_component', 'GO:0042571', ('110', '118'))	('neu', 'Gene', '2064', (79, 82))	('neu', 'Gene', (79, 82))
42159	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))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('78', '98'))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('histone modifications', 'Var', (51, 72))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('aberrant', 'Var', (110, 118))	('DNA methylation', 'Var', (34, 49))	('DNA methylation', 'biological_process', 'GO:0006306', ('34', '49'))	('chromatin', 'cellular_component', 'GO:0000785', ('78', '87'))
42160	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))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', (72, 77))	('hallmark of many cancers', 'Disease', 'MESH:D009369', (133, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('dinucleotides', 'Chemical', 'MESH:D015226', (23, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('DNA', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
42163	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))	('gene silencing', 'biological_process', 'GO:0016458', ('25', '39'))	('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))
42164	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))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('inactivate', 'NegReg', (38, 48))	('tumor', 'Disease', (73, 78))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('tumor', 'Disease', (128, 133))
42166	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))
42167	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))	('cadherin', 'molecular_function', 'GO:0008014', ('156', '164'))	('beta-catenin', 'Gene', (166, 178))	('N-cadherin', 'Gene', '1000', (154, 164))	('drug resistance', 'biological_process', 'GO:0042493', ('109', '124'))	('WNTll genes', 'Gene', (183, 194))	('Hypomethylation', 'Var', (0, 15))	('synuclein gamma', 'Gene', (126, 141))	('drug resistance', 'biological_process', 'GO:0009315', ('109', '124'))	('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))
42171	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))	('pre', 'molecular_function', 'GO:0003904', ('245', '248'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
42231	32697770	The surrogate molecular subtypes were luminal A-like, luminal B-like, luminal B-like/HER2, HER2-type, and triple-negative in 5, 4, 3, 5, and 14 cases, respectively.	('luminal', 'Chemical', 'MESH:D010634', (70, 77))	('luminal', 'Chemical', 'MESH:D010634', (38, 45))	('HER2', 'Gene', (85, 89))	('HER2', 'Gene', (91, 95))	('luminal', 'Chemical', 'MESH:D010634', (54, 61))	('HER2', 'Gene', '2064', (85, 89))	('HER2', 'Gene', '2064', (91, 95))	('luminal', 'Var', (70, 77))
42233	32697770	Disease-specific survival was worse in patients with histological grade 3 PLCs than in those with histological grade 2 PLCs (p = 0.007).	('worse', 'NegReg', (30, 35))	('Disease-specific survival', 'CPA', (0, 25))	('patients', 'Species', '9606', (39, 47))	('histological grade 3', 'Var', (53, 73))
42287	32697770	The rates of positivity for ER, PgR, and HER2 were 38.7% (12/31), 12.9% (4/31), and 25.8% (8/31), respectively.	('positivity', 'Var', (13, 23))	('ER', 'Gene', '2099', (42, 44))	('PgR', 'Gene', '5241', (32, 35))	('ER', 'Gene', '2099', (28, 30))	('PgR', 'Gene', (32, 35))	('HER2', 'Gene', (41, 45))	('HER2', 'Gene', '2064', (41, 45))
42288	32697770	The PLC subtypes of the cohort included luminal A-like, luminal B-like, luminal B-like /HER2, HER2-type, and triple-negative in 5, 4, 3, 5, and 14 cases, respectively (Table 3).	('PLC', 'cellular_component', 'GO:0042824', ('4', '7'))	('HER2', 'Gene', '2064', (94, 98))	('luminal', 'Chemical', 'MESH:D010634', (72, 79))	('HER2', 'Gene', (88, 92))	('luminal', 'Chemical', 'MESH:D010634', (56, 63))	('HER2', 'Gene', '2064', (88, 92))	('luminal', 'Chemical', 'MESH:D010634', (40, 47))	('luminal', 'Var', (72, 79))	('HER2', 'Gene', (94, 98))
42297	32697770	In this small cohort, DSS was better in patients with histological grade 2 PLC than in those with histological grade 3 via univariate analysis.	('better', 'PosReg', (30, 36))	('patients', 'Species', '9606', (40, 48))	('PLC', 'cellular_component', 'GO:0042824', ('75', '78'))	('DSS', 'Chemical', '-', (22, 25))	('PLC', 'Disease', (75, 78))	('histological', 'Var', (54, 66))	('DSS', 'MPA', (22, 25))
42314	32697770	This characteristic, which highlights the apocrine features, indicates that triple-negative PLC can be classified as the LAR subtype.	('triple-negative', 'Var', (76, 91))	('LAR', 'Gene', '5792', (121, 124))	('PLC', 'cellular_component', 'GO:0042824', ('92', '95'))	('LAR', 'Gene', (121, 124))
42570	26935613	Among 13 ILC patients with tumor size <=1.5 cm (32.5%), multifocal disease was observed on histopatological examination in 8 patients (61.5%), which is almost the same as in 27 patients with ILC index lesion larger than 1.5 cm (70.4%) (19/27).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('ILC', 'Disease', (9, 12))	('patients', 'Species', '9606', (177, 185))	('patients', 'Species', '9606', (13, 21))	('multifocal disease', 'Disease', (56, 74))	('<=1.5', 'Var', (38, 43))	('multifocal disease', 'Disease', 'None', (56, 74))	('observed', 'Reg', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patients', 'Species', '9606', (125, 133))
42620	19583841	Inhibition of c-Src may also affect ILC cells thought to have a high metastatic potential and to be capable of initiating/maintaining tumor growth.	('ILC', 'Disease', (36, 39))	('affect', 'Reg', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('c-Src', 'Gene', (14, 19))	('c-Src', 'Gene', '6714', (14, 19))	('tumor', 'Disease', (134, 139))
42622	19583841	Antagonists of the kinase c-Src are gaining increased attention as chemotherapeutic agents in breast cancer.	('Antagonists', 'Var', (0, 11))	('c-Src', 'Gene', (26, 31))	('c-Src', 'Gene', '6714', (26, 31))	('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))
42633	19583841	Indeed, germline mutation of the E-cadherin gene (CDH1) predisposes to both diffuse gastric cancer and LBC.	('gastric cancer', 'Disease', (84, 98))	('predisposes to', 'Reg', (56, 70))	('E-cadherin', 'Gene', (33, 43))	('E-cadherin', 'Gene', '999', (33, 43))	('germline mutation', 'Var', (8, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('CDH1', 'Gene', (50, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('CDH1', 'Gene', '999', (50, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('35', '43'))	('LBC', 'Phenotype', 'HP:0006625', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('LBC', 'Disease', (103, 106))
42647	19583841	AH00551) and phospho-(P)-Fak (against pY861-Fak, 1:50, 44-626G) were from Biosource (Camarillo, CA, USA).	('Fak', 'Gene', '5747', (25, 28))	('Fak', 'Gene', (44, 47))	('Fak', 'molecular_function', 'GO:0004717', ('25', '28'))	('Fak', 'Gene', (25, 28))	('Fak', 'molecular_function', 'GO:0004717', ('44', '47'))	('AH00551', 'Var', (0, 7))	('Fak', 'Gene', '5747', (44, 47))
42650	19583841	Vimentin (1:400, M0725) and N-cadherin (1:50, M3613) were from Dako (Glostrup, Denmark).	('Vimentin', 'Gene', '7431', (0, 8))	('Vimentin', 'cellular_component', 'GO:0045098', ('0', '8'))	('N-cadherin', 'Gene', (28, 38))	('Vimentin', 'cellular_component', 'GO:0045099', ('0', '8'))	('1:50', 'Var', (40, 44))	('N-cadherin', 'Gene', '1000', (28, 38))	('cadherin', 'molecular_function', 'GO:0008014', ('30', '38'))	('1:400', 'Var', (10, 15))	('Vimentin', 'Gene', (0, 8))
42651	19583841	Additional antibodies were beta-casein (1:400, ab6408, Abcam, Cambridge, UK), Cxcr-4 (1;50, 35-8800, Zymed Laboratories, San Francisco, CA, USA), osteopontin (1:100, 499265, Calbiochem, San Diego, CA, USA), and Aldh1 (1:150, EP1932Y, Epitomics, Burlingame, CA, USA).	('Aldh1', 'Gene', '216', (211, 216))	('beta-casein', 'Protein', (27, 38))	('osteopontin', 'Gene', '6696', (146, 157))	('Cxcr-4', 'Gene', (78, 84))	('Cxcr-4', 'Gene', '7852', (78, 84))	('osteopontin', 'Gene', (146, 157))	('Aldh1', 'Gene', (211, 216))	('1:400', 'Var', (40, 45))	('Aldh', 'molecular_function', 'GO:0004030', ('211', '215'))	('Cxcr-4', 'molecular_function', 'GO:0038147', ('78', '84'))	('1:150', 'Var', (218, 223))	('1:100', 'Var', (159, 164))
42685	19583841	Strong Opn expression was present in more than 90% of ILC cells with activated c-Src, consistent with the proposed role of c-Src in the regulation of OPN expression and in physiologic bone metabolism.	('metabolism', 'biological_process', 'GO:0008152', ('189', '199'))	('activated', 'Var', (69, 78))	('Opn', 'Gene', '6696', (7, 10))	('c-Src', 'Gene', '6714', (79, 84))	('regulation', 'biological_process', 'GO:0065007', ('136', '146'))	('OPN', 'Gene', '6696', (150, 153))	('c-Src', 'Gene', (123, 128))	('c-Src', 'Gene', (79, 84))	('c-Src', 'Gene', '6714', (123, 128))	('Opn', 'Gene', (7, 10))	('OPN', 'Gene', (150, 153))
42705	19583841	Among the various novel targeted approaches in cancer chemotherapy, inhibition of c-Src kinase appears to hold promise in counteracting invasive stages that ultimately lead to the spread and metastasis of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('metastasis of cancer', 'Disease', (191, 211))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('metastasis of cancer', 'Disease', 'MESH:D009362', (191, 211))	('cancer', 'Disease', (205, 211))	('inhibition', 'Var', (68, 78))	('cancer', 'Disease', (47, 53))	('c-Src kinase', 'Gene', '1445', (82, 94))	('spread', 'CPA', (180, 186))	('lead to', 'Reg', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('c-Src kinase', 'Gene', (82, 94))
42729	19583841	Consistent with this notion, E-cadherin degradation by Ca2+ depletion has been shown to lead to c-Src activation in breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('E-cadherin', 'Gene', (29, 39))	('E-cadherin', 'Gene', '999', (29, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('Ca2+', 'Chemical', 'MESH:D000069285', (55, 59))	('degradation', 'MPA', (40, 51))	('Ca2+ depletion', 'Var', (55, 69))	('activation', 'PosReg', (102, 112))	('cadherin', 'molecular_function', 'GO:0008014', ('31', '39'))	('degradation', 'biological_process', 'GO:0009056', ('40', '51'))	('c-Src', 'Gene', (96, 101))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('c-Src', 'Gene', '6714', (96, 101))
42738	19583841	It thus remains possible that inhibition of c-Src could result in the abrogation of an EMT along with a reduced number of Aldh1-positive cells and the suppression of Opn and Cxcr4 production.	('suppression', 'NegReg', (151, 162))	('abrogation', 'NegReg', (70, 80))	('reduced', 'NegReg', (104, 111))	('inhibition', 'Var', (30, 40))	('Aldh1', 'Gene', '216', (122, 127))	('EMT', 'biological_process', 'GO:0001837', ('87', '90'))	('Opn', 'Gene', (166, 169))	('Aldh1', 'Gene', (122, 127))	('Cxcr4', 'Gene', (174, 179))	('c-Src', 'Gene', (44, 49))	('Opn', 'Gene', '6696', (166, 169))	('Cxcr4', 'molecular_function', 'GO:0038147', ('174', '179'))	('c-Src', 'Gene', '6714', (44, 49))	('Cxcr4', 'Gene', '7852', (174, 179))	('Aldh', 'molecular_function', 'GO:0004030', ('122', '126'))
42741	19583841	A larger patient cohort will be needed to determine whether high c-Src activity is indeed associated with a higher likelihood of relapse in LBC.	('high', 'Var', (60, 64))	('LBC', 'Phenotype', 'HP:0006625', (140, 143))	('LBC', 'Disease', (140, 143))	('activity', 'MPA', (71, 79))	('patient', 'Species', '9606', (9, 16))	('c-Src', 'Gene', (65, 70))	('c-Src', 'Gene', '6714', (65, 70))
42744	19583841	Together, it appears likely that inhibitors of c-Src kinase will interfere with the spread of malignant LBC cells and affect the outcome of patients with lobular carcinoma.	('c-Src kinase', 'Gene', (47, 59))	('affect', 'Reg', (118, 124))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (154, 171))	('lobular carcinoma', 'Disease', (154, 171))	('lobular carcinoma', 'Disease', 'MESH:D018275', (154, 171))	('c-Src kinase', 'Gene', '1445', (47, 59))	('LBC', 'Phenotype', 'HP:0006625', (104, 107))	('patients', 'Species', '9606', (140, 148))	('interfere', 'NegReg', (65, 74))	('spread of malignant LBC cells', 'CPA', (84, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('inhibitors', 'Var', (33, 43))
42777	18454879	Other study reported that high nm23 expression is associated with older age (> 35 years) and smaller tumor size.	('high', 'Var', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('nm23', 'Gene', '4830', (31, 35))	('expression', 'MPA', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('nm23', 'Gene', (31, 35))
42821	18454879	Also several breast carcinoma studies have shown that low nm23 expression correlates with poor prognosis but the dynamics of its expression pattern and compartmentalization in breast cancer remains poorly understood.	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('breast carcinoma', 'Disease', 'MESH:D001943', (13, 29))	('breast carcinoma', 'Disease', (13, 29))	('low', 'Var', (54, 57))	('expression', 'MPA', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast carcinoma', 'Phenotype', 'HP:0003002', (13, 29))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('nm23', 'Gene', '4830', (58, 62))	('breast cancer', 'Disease', (176, 189))	('nm23', 'Gene', (58, 62))
42838	18454879	While, in addition, abnormal cytoplasmic and nuclear localization of this protein in node positive and metastatic cases suggest a possible role of altered nm23 which is functionally inactive with longer half-life.	('nm23', 'Gene', (155, 159))	('nm23', 'Gene', '4830', (155, 159))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('localization', 'biological_process', 'GO:0051179', ('53', '65'))	('altered', 'Var', (147, 154))
42849	16507159	Medium potency estrogen-progestin was associated with increased risks for all subtypes, but the estimates for lobular and tubular cancer were higher compared with ductal cancer.	('lobular and tubular cancer', 'Disease', 'MESH:D013274', (110, 136))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Medium potency', 'Var', (0, 14))	('ductal cancer', 'Disease', 'MESH:D009369', (163, 176))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ductal cancer', 'Disease', (163, 176))
42851	16507159	Low potency oral estrogen (mainly estriol) appeared to be associated with an increased risk for lobular cancer, but the association was strongest for short-term use.	('Low potency', 'Var', (0, 11))	('lobular cancer', 'Phenotype', 'HP:0030076', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('estriol', 'Chemical', 'MESH:D004964', (34, 41))	('lobular cancer', 'Disease', (96, 110))	('lobular cancer', 'Disease', 'MESH:D013274', (96, 110))
42857	16507159	Use of menopausal hormone therapy has been shown to increase the risk of breast cancer, and data indicate that combined medium potency estrogen-progestin therapy (mainly estradiol or conjugated estrogens combined with progestin) is associated with a higher risk for breast cancer than medium potency estrogen alone therapy.	('breast cancer', 'Disease', (266, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (266, 279))	('medium potency', 'Var', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('estradiol', 'Chemical', 'MESH:D004958', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('breast cancer', 'Disease', 'MESH:D001943', (266, 279))
42859	16507159	Furthermore, studies from the United States have rather consistently found medium potency estrogen-progestin therapy to be more strongly associated with lobular than with ductal breast cancer risk.	('associated', 'Reg', (137, 147))	('medium potency', 'Var', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('lobular', 'Disease', (153, 160))	('ductal breast cancer', 'Disease', (171, 191))	('ductal breast cancer', 'Disease', 'MESH:D001943', (171, 191))
42900	16507159	Use of medium potency estrogen-progestin was associated with increased risks of all three subtypes of breast cancer, with the highest risks among >=5 years and current exclusive use (Table 2).	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('medium potency', 'Var', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
42902	16507159	Women who used medium potency estrogen-progestin for >=5 years (of whom > 80% were current users) had an OR of 2.3 for ductal cancer (95% CI 1.6-3.3), OR 5.6 for lobular cancer (95% CI 3.2-9.7), and OR 6.5 (95% CI 2.8-14.9) for tubular cancer compared with those who never used menopausal hormone therapy (Table 2).	('tubular cancer', 'Disease', 'MESH:D009369', (228, 242))	('OR 6.5', 'Gene', '442185', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Women', 'Species', '9606', (0, 5))	('medium potency', 'Var', (15, 29))	('lobular cancer', 'Disease', 'MESH:D013274', (162, 176))	('ductal cancer', 'Disease', (119, 132))	('ductal cancer', 'Disease', 'MESH:D009369', (119, 132))	('lobular cancer', 'Phenotype', 'HP:0030076', (162, 176))	('tubular cancer', 'Disease', (228, 242))	('lobular cancer', 'Disease', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('OR 6.5', 'Gene', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))
42909	16507159	Non-exclusive and exclusive ever use of low potency oral estrogen was associated with an increased risk for lobular (OR 2.0, 95% CI 1.3-3.2) but not ductal (OR 1.2, 95% CI 0.9-1.5) or tubular (OR 1.0, 95% CI 0.3-2.8) breast cancer (Table 2).	('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))	('lobular', 'Disease', (108, 115))	('low potency', 'Var', (40, 51))
42926	16507159	Medium potency estrogen-progestin therapy, but not medium potency estrogen alone therapy, was significantly more strongly related to lobular than to ductal breast cancer.	('lobular', 'Disease', (133, 140))	('ductal breast cancer', 'Disease', (149, 169))	('ductal breast cancer', 'Disease', 'MESH:D001943', (149, 169))	('related', 'Reg', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Medium potency', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))
42949	16507159	To our knowledge, this is the first study to report on the risk of different histological subtypes of breast cancer after use of low potency oral estrogen or local estrogen therapy.	('breast cancer', 'Disease', (102, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('low', 'Var', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
42963	16507159	In addition, we found alcohol to be strongly associated with tubular cancer, with increasing trend over categories, a finding previously not reported in the literature.	('tubular cancer', 'Disease', 'MESH:D009369', (61, 75))	('alcohol', 'Chemical', 'MESH:D000438', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('associated', 'Reg', (45, 55))	('tubular cancer', 'Disease', (61, 75))	('alcohol', 'Var', (22, 29))
42971	16507159	Our findings of an association between low potency oral estrogen and lobular breast cancer, as well as the strong associations between tubular cancer and both medium potency estrogen-progestin therapy and alcohol intake is notable but has yet to be confirmed or refuted by other studies.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('low potency', 'Var', (39, 50))	('tubular cancer', 'Disease', (135, 149))	('lobular breast cancer', 'Disease', (69, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lobular breast cancer', 'Disease', 'MESH:D013274', (69, 90))	('tubular cancer', 'Disease', 'MESH:D009369', (135, 149))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (69, 90))	('alcohol', 'Chemical', 'MESH:D000438', (205, 212))
43067	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))
43089	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))
43150	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))
43152	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))
43264	25421310	We used murine invasive lobular breast carcinoma cells (KEP) that were generated by targeted deletion of E-cadherin and p53 in a conditional K14cre;Cdh1(F/F);Trp53(F/F) mouse model of de novo mammary tumour formation.	('cadherin', 'molecular_function', 'GO:0008014', ('107', '115'))	('Trp53', 'Gene', '22059', (158, 163))	('Trp53', 'Gene', (158, 163))	('p53', 'Gene', (160, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('p53', 'Gene', (120, 123))	('deletion', 'Var', (93, 101))	('tumour', 'Disease', (200, 206))	('lobular breast carcinoma', 'Disease', 'MESH:D018275', (24, 48))	('formation', 'biological_process', 'GO:0009058', ('207', '216'))	('rat', 'Species', '10116', (75, 78))	('breast carcinoma', 'Phenotype', 'HP:0003002', (32, 48))	('E-cadherin', 'Gene', (105, 115))	('lobular breast carcinoma', 'Disease', (24, 48))	('E-cadherin', 'Gene', '12550', (105, 115))	('p53', 'Gene', '22059', (160, 163))	('mouse', 'Species', '10090', (169, 174))	('p53', 'Gene', '22059', (120, 123))	('murine', 'Species', '10090', (8, 14))
43283	25421310	Moreover, tissue-specific induction of mutations gives rise to orthotopic tumours in the context of a functional, competent microenvironment, thus recapitulating the crosstalk between the tumour and its stroma.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('orthotopic tumours', 'Disease', (63, 81))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('tumour', 'Disease', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('mutations', 'Var', (39, 48))	('tumour', 'Disease', (188, 194))	('gives rise to', 'Reg', (49, 62))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('orthotopic tumours', 'Disease', 'MESH:D009369', (63, 81))
43290	25421310	In many preclinical breast cancer models, pharmacological inhibition of TGFbeta signalling was found to reduce metastasis to lung and bone in GEMMs and xenograft mouse models.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('metastasis to lung', 'Disease', 'MESH:D009362', (111, 129))	('breast cancer', 'Disease', (20, 33))	('mouse', 'Species', '10090', (162, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('TGFbeta signalling', 'Gene', (72, 90))	('reduce', 'NegReg', (104, 110))	('signalling', 'biological_process', 'GO:0023052', ('80', '90'))	('pharmacological inhibition', 'Var', (42, 68))	('metastasis to lung', 'Disease', (111, 129))
43291	25421310	The murine invasive lobular carcinoma cell line (KEP) was generated by targeted deletion of E-cadherin and p53 in a conditional K14cre;Cdh1(F/F);Trp53(F/F) mouse model as described previously.	('invasive lobular carcinoma', 'Disease', (11, 37))	('deletion', 'Var', (80, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('E-cadherin', 'Gene', (92, 102))	('p53', 'Gene', (107, 110))	('E-cadherin', 'Gene', '12550', (92, 102))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (11, 37))	('Trp53', 'Gene', (145, 150))	('p53', 'Gene', '22059', (147, 150))	('p53', 'Gene', '22059', (107, 110))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (20, 37))	('cadherin', 'molecular_function', 'GO:0008014', ('94', '102'))	('murine', 'Species', '10090', (4, 10))	('mouse', 'Species', '10090', (156, 161))	('rat', 'Species', '10116', (62, 65))	('Trp53', 'Gene', '22059', (145, 150))	('p53', 'Gene', (147, 150))
43328	25421310	Orthotopic inoculation of athymic nude mice with either KEP11/Luc or KEP23/Luc cells resulted in 100% tumour take rate (Figures 1A and 1B).	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('rat', 'Species', '10116', (114, 117))	('KEP11/Luc', 'Var', (56, 65))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('nude mice', 'Species', '10090', (34, 43))	('KEP23/Luc', 'Var', (69, 78))
43334	25421310	Inoculation of KEP11/Luc and KEP23/Luc cells into the left cardiac ventricle led to the rapid development of bone metastases with a comparable distribution pattern and 100% distant tumour take rate (Figures 1D and 1E and Supplementary Figure 3).	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('rat', 'Species', '10116', (193, 196))	('bone metastases', 'Disease', 'MESH:D009362', (109, 124))	('KEP23/Luc', 'Var', (29, 38))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('KEP11/Luc', 'Var', (15, 24))	('tumour', 'Disease', (181, 187))	('bone metastases', 'Disease', (109, 124))
43370	25421310	While the 61% increase (from 12.8 to 20.5 cells/mm2, p < 0.001) in the number of proliferating cells upon SD-208 treatment in the central region did not reach statistical significance, SD-208 treatment significantly increased the number of proliferating cells by 121% (from 24.7 to 55.2 cells/mm2, p < 0.001) in the periphery of the tumour (Figure 6C).	('tumour', 'Phenotype', 'HP:0002664', (333, 339))	('tumour', 'Disease', 'MESH:D009369', (333, 339))	('SD-208', 'Var', (185, 191))	('rat', 'Species', '10116', (88, 91))	('SD-208', 'Gene', (106, 112))	('tumour', 'Disease', (333, 339))	('SD-208', 'Chemical', 'MESH:C511004', (106, 112))	('rat', 'Species', '10116', (247, 250))	('SD-208', 'Chemical', 'MESH:C511004', (185, 191))	('increased', 'PosReg', (216, 225))
43390	25421310	Using 4 T1 and MDA-MB-231 IDC cells, Liu et al recently reported that TGFbeta blockade not only inhibited orthotopic tumour growth, but also improved the penetration of chemotherapeutic drugs by normalization of the intratumoural vascularization and decreasing collagen I production.	('tumour', 'Disease', (221, 227))	('TGFbeta', 'Gene', (70, 77))	('decreasing', 'NegReg', (250, 260))	('collagen', 'molecular_function', 'GO:0005202', ('261', '269'))	('orthotopic tumour growth', 'Disease', 'MESH:D006130', (106, 130))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (15, 25))	('improved', 'PosReg', (141, 149))	('inhibited', 'NegReg', (96, 105))	('rat', 'Species', '10116', (219, 222))	('normalization', 'PosReg', (195, 208))	('blockade', 'Var', (78, 86))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('collagen I production', 'MPA', (261, 282))	('penetration', 'MPA', (154, 165))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('orthotopic tumour growth', 'Disease', (106, 130))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('decreasing collagen I', 'Phenotype', 'HP:0030095', (250, 271))	('tumour', 'Disease', (117, 123))	('rat', 'Species', '10116', (159, 162))	('tumour', 'Disease', 'MESH:D009369', (221, 227))
43439	24348393	Although positivity for ER and PR is suggestive of metastatic breast carcinoma, this immunohistochemical result has been reported in 12-32% of primary neoplasms of the stomach.	('breast carcinoma', 'Phenotype', 'HP:0003002', (62, 78))	('neoplasms', 'Disease', 'MESH:D009369', (151, 160))	('neoplasms of the stomach', 'Phenotype', 'HP:0006753', (151, 175))	('neoplasms', 'Disease', (151, 160))	('breast carcinoma', 'Disease', (62, 78))	('positivity', 'Var', (9, 19))	('breast carcinoma', 'Disease', 'MESH:D001943', (62, 78))	('neoplasms', 'Phenotype', 'HP:0002664', (151, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('neoplasm', 'Phenotype', 'HP:0002664', (151, 159))
43530	28894575	In contrast, the ILC had no rearrangements of 6q or MYB-NFIB gene fusion but showed instead gain of 1q21.1-qter, loss of 16q11.2-qter, and 22q12.2-q12.3 as the sole genomic imbalances.	('MYB', 'Gene', '4602', (52, 55))	('NFIB', 'Gene', (56, 60))	('MYB', 'Gene', (52, 55))	('1q21.1-qter', 'Var', (100, 111))	('22q12.2-q12.3', 'Var', (139, 152))	('loss', 'NegReg', (113, 117))	('NFIB', 'Gene', '4781', (56, 60))	('imbalance', 'Phenotype', 'HP:0002172', (173, 182))	('gain', 'PosReg', (92, 96))	('imbalances', 'Phenotype', 'HP:0002172', (173, 183))	('16q11.2-qter', 'Var', (121, 133))
43537	28894575	Risk factors for BBC include young age, family history (e.g., BRCA1/2 germline mutations), lobular type of cancer, and multicentric tumors.	('lobular type of cancer', 'Phenotype', 'HP:0030076', (91, 113))	('multicentric tumors', 'Disease', 'MESH:D030981', (119, 138))	('BRCA1/2', 'Gene', '672;675', (62, 69))	('lobular type of cancer', 'Disease', (91, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BBC', 'Disease', (17, 20))	('multicentric tumors', 'Disease', (119, 138))	('BBC', 'Chemical', '-', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('lobular type of cancer', 'Disease', 'MESH:D013274', (91, 113))	('BRCA1/2', 'Gene', (62, 69))	('germline mutations', 'Var', (70, 88))
43567	28894575	Genome-wide array-based comparative genomic hybridization (arrayCGH) analysis of DNAs isolated from the formalin-fixed paraffin-embedded (FFPE) blocks of the ACC and ILC lesions (containing >75% tumor cells) was performed with the Human Genome CGH Microarray 244K oligonucleotide arrays (G4411B; Agilent Technologies, Palo Alto, CA, USA) as previously described.	('tumor', 'Disease', (195, 200))	('G4411B', 'Var', (288, 294))	('paraffin', 'Chemical', 'MESH:D010232', (119, 127))	('Human', 'Species', '9606', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('formalin', 'Chemical', 'MESH:D005557', (104, 112))	('G4411B', 'SUBSTITUTION', 'None', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
43568	28894575	The centromeric breakpoint was located in the 3'-part of the MYB gene with deletion of the last coding exon of MYB including the 3'-UTR and flanking sequences (Fig.	('MYB', 'Gene', '4602', (111, 114))	('deletion', 'Var', (75, 83))	('MYB', 'Gene', (111, 114))	('MYB', 'Gene', '4602', (61, 64))	('MYB', 'Gene', (61, 64))
43569	28894575	There was no evidence of amplifications or homozygous deletions in any of the tumors.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('homozygous deletions', 'Var', (43, 63))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
43581	28894575	Previous findings have unequivocally shown that rearrangements of MYB is the main genomic hallmark of ACC.	('ACC', 'Disease', (102, 105))	('MYB', 'Gene', '4602', (66, 69))	('MYB', 'Gene', (66, 69))	('rearrangements', 'Var', (48, 62))
43584	28894575	Activation of MYB through gene fusion or juxtaposition of strong enhancer elements to MYB occurs in 80-90% of ACCs irrespective of anatomical localization (salivary gland, breast, skin, lacrimal gland, tracheobronchial tree, digestive tract, prostate, and female genital tract).	('breast', 'Disease', (172, 178))	('juxtaposition', 'Var', (41, 54))	('prostate', 'Disease', (242, 250))	('enhancer', 'PosReg', (65, 73))	('MYB', 'Gene', (86, 89))	('MYB', 'Gene', (14, 17))	('skin', 'Disease', (180, 184))	('salivary gland', 'Disease', (156, 170))	('ACCs', 'Gene', '84680', (110, 114))	('ACCs', 'Gene', (110, 114))	('digestive tract', 'Disease', (225, 240))	('Activation', 'PosReg', (0, 10))	('localization', 'biological_process', 'GO:0051179', ('142', '154'))	('lacrimal gland', 'Disease', (186, 200))	('gene fusion', 'Var', (26, 37))	('tracheobronchial tree', 'Disease', (202, 223))	('MYB', 'Gene', '4602', (86, 89))	('MYB', 'Gene', '4602', (14, 17))
43590	28894575	However, studies of the mutational landscape of breast and salivary gland ACCs have revealed a similar mutational profile with mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination, and canonical signaling pathway genes.	('RNA', 'MPA', (185, 188))	('cell', 'CPA', (170, 174))	('ACCs', 'Gene', '84680', (74, 78))	('canonical signaling', 'Pathway', (218, 237))	('chromatin', 'cellular_component', 'GO:0000785', ('147', '156'))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('147', '168'))	('RNA', 'cellular_component', 'GO:0005562', ('185', '188'))	('chromatin', 'MPA', (147, 156))	('signaling pathway', 'biological_process', 'GO:0007165', ('228', '245'))	('ACCs', 'Gene', (74, 78))	('mutations', 'Var', (127, 136))	('ubiquitination', 'MPA', (198, 212))	('cell adhesion', 'biological_process', 'GO:0007155', ('170', '183'))
43592	28894575	The ILC had no rearrangements of 6q, did not express the MYB-NFIB gene fusion, and showed gain of 1q21.1-qter, loss of 16q11.2-qter, and 22q12.2-q12.3 as the sole genomic imbalances.	('imbalances', 'Phenotype', 'HP:0002172', (171, 181))	('1q21.1-qter', 'Var', (98, 109))	('16q11.2-qter', 'Var', (119, 131))	('loss', 'NegReg', (111, 115))	('gain', 'PosReg', (90, 94))	('NFIB', 'Gene', (61, 65))	('MYB', 'Gene', '4602', (57, 60))	('22q12.2-q12.3', 'Var', (137, 150))	('imbalance', 'Phenotype', 'HP:0002172', (171, 180))	('NFIB', 'Gene', '4781', (61, 65))	('MYB', 'Gene', (57, 60))
43604	24587029	Outcomes of Sentinel Lymph Node Dissection Alone vs. Axillary Lymph Node Dissection in Early Stage Invasive Lobular Carcinoma: A Retrospective Study of the Surveillance, Epidemiology and End Results (SEER) Database The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in local-regional recurrence (LRR), disease-specific survival (DSS) or overall survival (OS) for sentinel lymph node dissection (SLND) and completion axillary lymph node dissection (ALND) among patients undergoing breast-conserving therapy for clinical T1-T2, N0 breast cancer with 1 or 2 positive SLNs.	('Carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('DSS', 'Chemical', '-', (374, 377))	('Lobular Carcinoma', 'Disease', 'MESH:D018275', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (581, 587))	('Lobular Carcinoma', 'Phenotype', 'HP:0030076', (108, 125))	('breast cancer', 'Disease', 'MESH:D001943', (574, 587))	('OS', 'Chemical', '-', (266, 268))	('ALND', 'Chemical', '-', (493, 497))	('patients', 'Species', '9606', (505, 513))	('OS', 'Chemical', '-', (400, 402))	('Oncology', 'Phenotype', 'HP:0002664', (248, 256))	('breast cancer', 'Disease', (574, 587))	('Lobular Carcinoma', 'Disease', (108, 125))	('T1-T2', 'Var', (564, 569))	('breast cancer', 'Phenotype', 'HP:0003002', (574, 587))
43664	24587029	The results of the ACOSOG Z0011 trial will likely lead to further reductions in the extent of surgery for early-stage invasive breast cancers; in particular, ALND can be omitted in patients undergoing BCT for clinical T1-T2, N0 breast cancer found to have 1 or 2 positive SLNs.	('OS', 'Chemical', '-', (21, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('breast cancers', 'Phenotype', 'HP:0003002', (127, 141))	('invasive breast cancers', 'Disease', (118, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('invasive breast cancers', 'Disease', 'MESH:D001943', (118, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('patients', 'Species', '9606', (181, 189))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('ALND', 'Chemical', '-', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('reductions', 'NegReg', (66, 76))	('breast cancer', 'Disease', (228, 241))	('T1-T2', 'Var', (218, 223))
43691	24587029	Nevertheless, the analyses from the SEER database showed no difference in OS or DSS in the SLND and ALND groups using the above surrogates, despite the potential survival difference caused by arbitrary subgrouping, indicating that it may be safe to perform SLND in early stage (clinical T1 and T2, N0) ILC.	('ALND', 'Chemical', '-', (100, 104))	('ILC', 'Disease', (302, 305))	('DSS', 'Chemical', '-', (80, 83))	('OS', 'Chemical', '-', (74, 76))	('clinical T1', 'Var', (278, 289))	('ER', 'Gene', '2099', (38, 40))
43703	24587029	In conclusion, the results of current study demonstrate that among patients with T1-T2 ILC and low volume nodal metastasis, there is no difference in LRR, DSS or OS for patients undergoing SLND alone compared to those undergoing ALND.	('patients', 'Species', '9606', (169, 177))	('T1-T2', 'Var', (81, 86))	('patients', 'Species', '9606', (67, 75))	('OS', 'Chemical', '-', (162, 164))	('ALND', 'Chemical', '-', (229, 233))	('DSS', 'Chemical', '-', (155, 158))	('DSS', 'Disease', (155, 158))	('LRR', 'Disease', (150, 153))
43758	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))
43877	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.	('allergies', 'Disease', 'MESH:D004342', (388, 397))	('gadolinium', 'Chemical', 'MESH:D005682', (360, 370))	('allergies', 'Phenotype', 'HP:0012393', (388, 397))	('MRI', 'Var', (262, 265))	('allergies', 'Disease', (388, 397))	('patient', 'Species', '9606', (299, 306))	('menstrual cycle', 'biological_process', 'GO:0044850', ('309', '324'))
43943	33907159	The results showed that CD5, CD3E, CD40LG, CD52, CD27, CD69 and IL7R were significantly related to the OS of patients with breast IDC (Fig.	('IL7R', 'Gene', (64, 68))	('related', 'Reg', (88, 95))	('patients', 'Species', '9606', (109, 117))	('CD69', 'Var', (55, 59))	('CD5', 'Var', (24, 27))	('CD27', 'Var', (49, 53))	('CD3E', 'Var', (29, 33))	('CD40LG', 'Var', (35, 41))	('IL7R', 'molecular_function', 'GO:0004917', ('64', '68'))	('CD52', 'Var', (43, 47))	('IL7R', 'Gene', '3575', (64, 68))	('breast IDC', 'Disease', (123, 133))
43974	33907159	With PPI network analysis and univariate/multivariate Cox regression analysis, five hub genes in the TME of breast IDC with prognostic significance were identified: CD5, CD3E, CD40LG, CD52 and CD27.	('CD5', 'Var', (165, 168))	('CD3E', 'Var', (170, 174))	('CD40LG', 'Var', (176, 182))	('hub', 'Gene', (84, 87))	('PPI', 'biological_process', 'GO:0060134', ('5', '8'))	('CD52', 'Gene', (184, 188))	('CD27', 'Gene', (193, 197))	('hub', 'Gene', '1993', (84, 87))
43980	33907159	CD40LG, also called CD154 or CD40L, is mainly expressed in activated T lymphocytes and belongs to the tumor necrosis factor family.	('tumor necrosis', 'Disease', (102, 116))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('102', '123'))	('necrosis', 'biological_process', 'GO:0001906', ('108', '116'))	('CD40LG', 'Var', (0, 6))	('CD154', 'Gene', (20, 25))	('tumor necrosis', 'Disease', 'MESH:D009336', (102, 116))	('necrosis', 'biological_process', 'GO:0070265', ('108', '116'))	('necrosis', 'biological_process', 'GO:0008219', ('108', '116'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('CD154', 'Gene', '959', (20, 25))	('necrosis', 'biological_process', 'GO:0019835', ('108', '116'))	('necrosis', 'biological_process', 'GO:0008220', ('108', '116'))
43982	33907159	Our results from PPI network analysis showed that CD40LG is closely related to many important proteins, including CD69, VCAM1 and TLR7, and its expression level is an independent prognostic factor in patients with breast IDC.	('patients', 'Species', '9606', (200, 208))	('VCAM1', 'Gene', '7412', (120, 125))	('TLR7', 'Gene', (130, 134))	('PPI', 'biological_process', 'GO:0060134', ('17', '20'))	('breast IDC', 'Disease', (214, 224))	('CD40LG', 'Var', (50, 56))	('TLR7', 'Gene', '51284', (130, 134))	('expression level', 'MPA', (144, 160))	('VCAM1', 'Gene', (120, 125))
43983	33907159	Furthermore, the expression of CD40LG is closely related to cellularity and the Claudin subtype of breast IDC, and the results of GSEA indicated that CD40LG was mainly enriched in WNT, ERBB, VEGF, MAPK and JAK signaling pathways.	('ERBB', 'Gene', '1956', (185, 189))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('VEGF', 'Gene', (191, 195))	('CD40LG', 'Gene', (31, 37))	('GSEA', 'Chemical', '-', (130, 134))	('related', 'Reg', (49, 56))	('VEGF', 'Gene', '7422', (191, 195))	('MAPK', 'molecular_function', 'GO:0004707', ('197', '201'))	('WNT', 'Pathway', (180, 183))	('JAK', 'molecular_function', 'GO:0004713', ('206', '209'))	('breast IDC', 'Disease', (99, 109))	('CD40LG', 'Var', (150, 156))	('ERBB', 'Gene', (185, 189))	('JAK signaling pathways', 'Pathway', (206, 228))
43985	33907159	In addition, high expression of CD40LG is a favorable indicator for the recurrence-free survival of patients with breast IDC.	('CD40LG', 'Var', (32, 38))	('patients', 'Species', '9606', (100, 108))	('breast IDC', 'Disease', (114, 124))
43986	33907159	Mesenchymal stem cells edited with TNF-alpha and CD40L enhanced the anti-tumor immune function of mice by promoting the function of Th1 cells and inhibiting the function of Th2 and Treg cells.	('CD40L', 'Var', (49, 54))	('function', 'MPA', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('function', 'MPA', (120, 128))	('promoting', 'PosReg', (106, 115))	('TNF-alpha', 'Gene', '21926', (35, 44))	('enhanced', 'PosReg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TNF-alpha', 'Gene', (35, 44))	('tumor', 'Disease', (73, 78))	('Th1', 'Protein', (132, 135))	('inhibiting', 'NegReg', (146, 156))	('mice', 'Species', '10090', (98, 102))
43988	33907159	found that a cell vaccine containing granulocyte macrophage-colony stimulating factor and CD40L enhanced anti-tumor ability in a mouse model of breast cancer by increasing infiltration of CD3+ lymphocytes through IL-2 and TNF-gamma activation.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('CD40L', 'Var', (90, 95))	('IL-2', 'Gene', (213, 217))	('enhanced', 'PosReg', (96, 104))	('breast cancer', 'Disease', (144, 157))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('granulocyte macrophage-colony stimulating factor', 'Gene', (37, 85))	('tumor', 'Disease', (110, 115))	('IL-2', 'Gene', '16183', (213, 217))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('increasing', 'PosReg', (161, 171))	('granulocyte macrophage-colony stimulating factor', 'molecular_function', 'GO:0005129', ('37', '85'))	('IL-2', 'molecular_function', 'GO:0005134', ('213', '217'))	('mouse', 'Species', '10090', (129, 134))	('granulocyte macrophage-colony stimulating factor', 'Gene', '12981', (37, 85))	('infiltration', 'CPA', (172, 184))
43989	33907159	Studies on non-solid tumors have shown that CD40LG and IL4 promote tumor cell proliferation and chemotherapy resistance by activating STAT3, NF-kappaB, ERK and AKT signaling pathways.	('tumor', 'Disease', (21, 26))	('NF-kappaB', 'Pathway', (141, 150))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('STAT3', 'Gene', (134, 139))	('AKT', 'Gene', '207', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('STAT3', 'Gene', '6774', (134, 139))	('CD40LG', 'Var', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('AKT signaling', 'biological_process', 'GO:0043491', ('160', '173'))	('ERK', 'molecular_function', 'GO:0004707', ('152', '155'))	('chemotherapy resistance', 'CPA', (96, 119))	('ERK', 'Gene', (152, 155))	('tumors', 'Disease', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('IL4', 'molecular_function', 'GO:0005136', ('55', '58'))	('ERK', 'Gene', '2048', (152, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('activating', 'PosReg', (123, 133))	('IL4', 'Gene', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('IL4', 'Gene', '3565', (55, 58))	('promote', 'PosReg', (59, 66))	('AKT', 'Gene', (160, 163))
43991	33907159	A recent study found that the use of function-blocking anti-CD5 monoclonal antibody or the knockout of CD5 inhibits tumor growth in a breast cancer mouse model by enhancing the capability of CD8+ T cells.	('antibody', 'cellular_component', 'GO:0019815', ('75', '83'))	('CD8', 'Gene', '925', (191, 194))	('breast cancer', 'Disease', (134, 147))	('knockout', 'Var', (91, 99))	('antibody', 'cellular_component', 'GO:0019814', ('75', '83'))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CD5', 'Gene', (103, 106))	('mouse', 'Species', '10090', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('inhibits', 'NegReg', (107, 115))	('antibody', 'molecular_function', 'GO:0003823', ('75', '83'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('enhancing', 'PosReg', (163, 172))	('CD8', 'Gene', (191, 194))	('tumor', 'Disease', (116, 121))	('antibody', 'cellular_component', 'GO:0042571', ('75', '83'))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
43997	33907159	demonstrated that agonistic anti-CD27 antibodies inhibited the growth and metastasis of melanoma in vivo by enhancing the function of tumor-specific CD8+ T cells.	('anti-CD27', 'Gene', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('function', 'MPA', (122, 130))	('metastasis of melanoma', 'Disease', 'MESH:D009362', (74, 96))	('antibodies', 'Var', (38, 48))	('anti-CD27', 'Protein', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('CD8', 'Gene', (149, 152))	('metastasis of melanoma', 'Disease', (74, 96))	('CD8', 'Gene', '925', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('enhancing', 'PosReg', (108, 117))	('inhibited', 'NegReg', (49, 58))	('tumor', 'Disease', (134, 139))
44019	32168782	These results show that a high NR2F2 is associated with better survival of a specific subset of patients, namely those with luminal A breast cancer.	('high', 'Var', (26, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('better', 'PosReg', (56, 62))	('luminal A breast cancer', 'Disease', 'MESH:D001943', (124, 147))	('patients', 'Species', '9606', (96, 104))	('NR2F2', 'Gene', (31, 36))	('survival', 'MPA', (63, 71))	('luminal A breast cancer', 'Disease', (124, 147))
44024	32168782	The presence of estrogen receptor alpha (ERalpha) in cancerous cells has a crucial role in the treatments, which associates with better survival and is the key target of endocrine therapy.	('better', 'PosReg', (129, 135))	('estrogen receptor alpha', 'Gene', (16, 39))	('estrogen receptor alpha', 'Gene', '2099', (16, 39))	('ERalpha', 'Gene', (41, 48))	('cancerous', 'Disease', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('presence', 'Var', (4, 12))	('cancerous', 'Disease', 'MESH:D009369', (53, 62))
44029	32168782	reported that a decreased NR2F2 expression correlates with antiestrogen resistance, i.e., if NR2F2 was knocked out of tamoxifen-sensitive MCF-7 cells, the effect of tamoxifen ended, but if NR2F2 was made to overexpress in tamoxifen-resistant cells, sensitivity to tamoxifen was reestablished.	('tamoxifen', 'Chemical', 'MESH:D013629', (118, 127))	('tamoxifen', 'Chemical', 'MESH:D013629', (222, 231))	('MCF-7', 'CellLine', 'CVCL:0031', (138, 143))	('NR2F2', 'Gene', (26, 31))	('tamoxifen', 'Chemical', 'MESH:D013629', (165, 174))	('antiestrogen resistance', 'Disease', (59, 82))	('tamoxifen', 'Chemical', 'MESH:D013629', (264, 273))	('NR2F2', 'Gene', (93, 98))	('expression', 'MPA', (32, 42))	('knocked', 'Var', (103, 110))	('decreased', 'NegReg', (16, 25))
44046	32168782	We have found that patients with luminal A breast cancer and a high expression of NR2F2 have better disease-free survival (logrank p < 0.0001, Mantel-Cox test) than those with a low NR2F2 level.	('luminal A breast cancer', 'Disease', (33, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('patients', 'Species', '9606', (19, 27))	('NR2F2', 'Gene', (82, 87))	('high expression', 'Var', (63, 78))	('luminal A breast cancer', 'Disease', 'MESH:D001943', (33, 56))	('disease-free survival', 'CPA', (100, 121))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('better', 'PosReg', (93, 99))
44050	32168782	MCF-7 cells are cancerous and contain copy number variations that are overrepresented or underrepresented during peak calling.	('MCF-7', 'CellLine', 'CVCL:0031', (0, 5))	('cancerous', 'Disease', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('copy number variations', 'Var', (38, 60))	('cancerous', 'Disease', 'MESH:D009369', (16, 25))
44072	32168782	Downregulated genes after NR2F2 depletion are associated with DREAM (dimerization partner, RB-like, E2F and multi-vulval class B) complex target genes.	('depletion', 'Var', (32, 41))	('NR2F2', 'Gene', (26, 31))	('DREAM', 'Gene', (62, 67))	('RB', 'Disease', 'MESH:D012175', (91, 93))	('Downregulated', 'NegReg', (0, 13))	('DREAM', 'Gene', '30818', (62, 67))
44078	32168782	In our paper, we demonstrated that breast cancer patients with the luminal A subtype who have a high NR2F2 expression show better survival.	('better', 'PosReg', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('survival', 'CPA', (130, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('expression', 'MPA', (107, 117))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('luminal', 'Chemical', 'MESH:D010634', (67, 74))	('high', 'Var', (96, 100))	('breast cancer', 'Disease', (35, 48))	('patients', 'Species', '9606', (49, 57))	('NR2F2', 'Gene', (101, 106))
44084	32168782	However, Zhang has found the opposite, claiming that the high expression of NR2F2 shows better overall and disease-free survival in breast cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('overall', 'CPA', (95, 102))	('breast cancer', 'Disease', (132, 145))	('disease-free survival', 'CPA', (107, 128))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('better', 'PosReg', (88, 94))	('patients', 'Species', '9606', (146, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('high expression', 'Var', (57, 72))	('NR2F2', 'Gene', (76, 81))
44086	32168782	Our results correlate with those of Zhang, in that the high expression of NR2F2 shows better survival; however, we have found that this is true only in ER-positive breast cancer patients, and in the case of ER-negative patients there is no difference in survival between the high and low expressions of NR2F2.	('NR2F2', 'Gene', (74, 79))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('patients', 'Species', '9606', (178, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('better', 'PosReg', (86, 92))	('breast cancer', 'Disease', (164, 177))	('survival', 'CPA', (93, 101))	('high', 'Var', (55, 59))	('patients', 'Species', '9606', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
44101	32168782	Further investigations are needed to study the contribution of direct NR2F2:DNA binding to the modulation of ERalpha-dependent transcription in breast cancer cells, such as generating breast cancer cells with mutant DNA-binding domain of NR2F2 and the assessment of the transcriptional effect of such NR2F2 mutants.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('DNA', 'cellular_component', 'GO:0005574', ('216', '219'))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('DNA binding', 'molecular_function', 'GO:0003677', ('76', '87'))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('DNA-binding', 'molecular_function', 'GO:0003677', ('216', '227'))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('transcription', 'biological_process', 'GO:0006351', ('127', '140'))	('breast cancer', 'Disease', (184, 197))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('mutant', 'Var', (209, 215))	('NR2F2', 'Gene', (238, 243))
44115	32168782	Data is available with the following numbers: ENCSR752UOD (H3K27ac), ENCSR985MIB (H3K4me3), ENCSR493NBY (H3K4me1), ENCSR000EWS (GATA3), ENCSR000AHD (CTCF), GSM2137769 (FOXA1) and ENCSR000BZZ (processed ERalpha ChIA-PET).	('FOXA1', 'Gene', (168, 173))	('ENCSR493NBY', 'CellLine', 'CVCL:6783', (92, 103))	('H3K27ac', 'Var', (59, 66))	('GATA3', 'Gene', (128, 133))	('H3K4me3', 'Var', (82, 89))	('FOXA1', 'Gene', '3169', (168, 173))	('H3K4me1', 'Var', (105, 112))	('GATA3', 'Gene', '2625', (128, 133))	('CTCF', 'Gene', (149, 153))	('ENCSR493NBY (H3K4me1', 'Var', (92, 112))	('CTCF', 'Gene', '10664', (149, 153))
44119	32168782	Our results showed that high NR2F2 expression is correlated with better survival in luminal A breast cancer patients only.	('luminal A breast cancer', 'Disease', 'MESH:D001943', (84, 107))	('survival', 'MPA', (72, 80))	('luminal A breast cancer', 'Disease', (84, 107))	('expression', 'MPA', (35, 45))	('better', 'PosReg', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (108, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('NR2F2', 'Gene', (29, 34))
44130	27602491	ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively.	('ERBB2', 'Gene', (177, 182))	('invasive breast cancers', 'Disease', (262, 285))	('ERBB2', 'Gene', (0, 5))	('breast carcinomas', 'Phenotype', 'HP:0003002', (77, 94))	('mutations', 'Var', (136, 145))	('associated', 'Reg', (16, 26))	('ERBB3', 'Gene', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('ERBB2', 'Gene', '2064', (177, 182))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', (95, 100))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('mutations', 'Var', (6, 15))	('ERBB2', 'Gene', '2064', (95, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (271, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('ERBB3', 'Gene', '2065', (105, 110))	('invasive lobular breast carcinomas', 'Disease', 'MESH:D018275', (60, 94))	('breast cancers', 'Phenotype', 'HP:0003002', (271, 285))	('gain-of-function', 'PosReg', (119, 135))	('invasive lobular breast carcinomas', 'Disease', (60, 94))	('invasive breast cancers', 'Disease', 'MESH:D001943', (262, 285))
44133	27602491	Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutation', 'Var', (112, 120))	('ILC', 'Disease', (36, 39))	('tumors', 'Disease', (45, 51))	('ERBB2', 'Gene', '2064', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('ERBB2', 'Gene', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('ERBB2', 'Gene', '2064', (21, 26))	('ERBB2', 'Gene', (21, 26))
44136	27602491	ERBB2 mutations were statistically associated with solid ILC features (p=0.01).	('ERBB2', 'Gene', '2064', (0, 5))	('associated', 'Reg', (35, 45))	('ERBB2', 'Gene', (0, 5))	('solid ILC features', 'Disease', (51, 69))	('mutations', 'Var', (6, 15))
44137	27602491	Survival analyses showed no significant prognostic impact of ERBB2 mutations.	('ERBB2', 'Gene', '2064', (61, 66))	('ERBB2', 'Gene', (61, 66))	('mutations', 'Var', (67, 76))
44138	27602491	Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening.	('ERBB2', 'Gene', '2064', (39, 44))	('ILC', 'Disease', (54, 57))	('mutations', 'Var', (92, 101))	('ERBB2', 'Gene', '2064', (86, 91))	('ERBB2', 'Gene', (86, 91))	('ERBB2', 'Gene', (39, 44))
44140	27602491	However, ERBB2 has no known ligand and its intracellular kinase activity is exclusively activated by homo- or heterodimerization.	('heterodimerization', 'MPA', (110, 128))	('intracellular', 'cellular_component', 'GO:0005622', ('43', '56'))	('activated', 'PosReg', (88, 97))	('ligand', 'molecular_function', 'GO:0005488', ('28', '34'))	('homo-', 'Var', (101, 106))	('ERBB2', 'Gene', (9, 14))	('kinase activity', 'molecular_function', 'GO:0016301', ('57', '72'))	('ERBB2', 'Gene', '2064', (9, 14))	('intracellular kinase activity', 'MPA', (43, 72))
44142	27602491	The key oncogenic role of ERBB2 amplification in a subset of breast cancer has been described in the late 80's.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', '2064', (26, 31))	('amplification', 'Var', (32, 45))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
44149	27602491	With the advent of massively parallel sequencing, mutations in the sequence of the ERBB2 gene were found in a limited fraction (<1%) of breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancers', 'Disease', 'MESH:D001943', (136, 150))	('breast cancers', 'Disease', (136, 150))	('mutations in', 'Var', (50, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('ERBB2', 'Gene', (83, 88))	('found', 'Reg', (99, 104))	('ERBB2', 'Gene', '2064', (83, 88))	('breast cancers', 'Phenotype', 'HP:0003002', (136, 150))
44150	27602491	In vitro functional characterization of these mutations demonstrated that some of them had oncogenic properties and promoted cancer cells growth, invasion and survival.	('mutations', 'Var', (46, 55))	('promoted', 'PosReg', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('survival', 'CPA', (159, 167))	('cancer', 'Disease', (125, 131))	('oncogenic properties', 'CPA', (91, 111))	('invasion', 'CPA', (146, 154))
44151	27602491	Moreover, ERBB2 activating mutations conferred in vitro sensibility to anti-ERBB2 drugs, particularly but not exclusively to the second generation tyrosine kinase inhibitor neratinib, even in the absence of any ERBB2 amplification.	('mutations', 'Var', (27, 36))	('neratinib', 'Chemical', 'MESH:C487932', (173, 182))	('ERBB2', 'Gene', (211, 216))	('ERBB2', 'Gene', '2064', (211, 216))	('ERBB2', 'Gene', (10, 15))	('ERBB2', 'Gene', '2064', (10, 15))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('156', '172'))	('ERBB2', 'Gene', (76, 81))	('activating', 'PosReg', (16, 26))	('ERBB2', 'Gene', '2064', (76, 81))	('sensibility', 'MPA', (56, 67))
44152	27602491	Following this seminal report, several other ERBB2 mutations were reported, together with their in vitro or in patient sensitivity to ERBB2-targeted therapy.	('mutations', 'Var', (51, 60))	('ERBB2', 'Gene', '2064', (134, 139))	('ERBB2', 'Gene', (134, 139))	('ERBB2', 'Gene', '2064', (45, 50))	('patient', 'Species', '9606', (111, 118))	('ERBB2', 'Gene', (45, 50))
44153	27602491	Similarly, activating point mutations of ERBB3 have been described in 2013 and were found in vitro to display oncogenic activities in breast cancer cells.	('point mutations', 'Var', (22, 37))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('activating', 'PosReg', (11, 21))	('ERBB3', 'Gene', (41, 46))	('ERBB3', 'Gene', '2065', (41, 46))	('oncogenic activities', 'CPA', (110, 130))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
44154	27602491	ERBB3 being unable to initiate an intracellular signal on its own, Jaiswal and colleagues demonstrated that ERBB3 mutants signal through heterodimerization with ERBB2, and that anti-ERBB2 therapies efficiently blocked ERBB3-initiated oncogenic signaling in cell lines.	('oncogenic signaling', 'CPA', (234, 253))	('intracellular', 'cellular_component', 'GO:0005622', ('34', '47'))	('ERBB3', 'Gene', (0, 5))	('ERBB3', 'Gene', '2065', (0, 5))	('ERBB2', 'Gene', '2064', (161, 166))	('signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('signal through', 'Reg', (122, 136))	('ERBB2', 'Gene', (161, 166))	('ERBB3', 'Gene', '2065', (108, 113))	('mutants', 'Var', (114, 121))	('ERBB2', 'Gene', '2064', (182, 187))	('heterodimerization', 'MPA', (137, 155))	('ERBB2', 'Gene', (182, 187))	('ERBB3', 'Gene', (108, 113))	('ERBB3', 'Gene', '2065', (218, 223))	('blocked', 'NegReg', (210, 217))	('ERBB3', 'Gene', (218, 223))
44155	27602491	Our group reported a few months ago the first case of a patient who was treated by trastuzumab and lapatinib as third line regimen for ERBB2-negative metastatic breast cancer on the basis of an activating ERBB3 mutation retrieved by all-exome sequencing in both the primary tumor and liver metastases.	('ERBB3', 'Gene', (205, 210))	('lapatinib', 'Chemical', 'MESH:D000077341', (99, 108))	('ERBB3', 'Gene', '2065', (205, 210))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('liver metastases', 'Disease', 'MESH:D009362', (284, 300))	('patient', 'Species', '9606', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (161, 174))	('trastuzumab', 'Chemical', 'MESH:D000068878', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('activating', 'PosReg', (194, 204))	('ERBB2', 'Gene', '2064', (135, 140))	('primary tumor', 'Disease', (266, 279))	('liver metastases', 'Disease', (284, 300))	('ERBB2', 'Gene', (135, 140))	('mutation', 'Var', (211, 219))	('primary tumor', 'Disease', 'MESH:D009369', (266, 279))
44157	27602491	In light of the above-mentioned preclinical and clinical results, ERBB2 and ERBB3 activating mutations are now considered as "targetable" by anti-ERBB2 drugs, but further clinical evidences are needed.	('mutations', 'Var', (93, 102))	('activating', 'PosReg', (82, 92))	('ERBB2', 'Gene', '2064', (66, 71))	('ERBB2', 'Gene', '2064', (146, 151))	('ERBB3', 'Gene', '2065', (76, 81))	('ERBB2', 'Gene', (146, 151))	('ERBB2', 'Gene', (66, 71))	('ERBB3', 'Gene', (76, 81))
44160	27602491	Previous reports suggested that ERBB2 mutations might be enriched in a specific histological subtype, invasive lobular carcinoma (ILC), which account for 5-15 % of invasive breast tumors.	('breast tumor', 'Phenotype', 'HP:0100013', (173, 185))	('ERBB2', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (32, 37))	('enriched', 'Reg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('invasive breast tumors', 'Disease', (164, 186))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (111, 128))	('invasive lobular carcinoma', 'Disease', (102, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('invasive breast tumors', 'Disease', 'MESH:D001943', (164, 186))	('mutations', 'Var', (38, 47))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (102, 128))	('breast tumors', 'Phenotype', 'HP:0100013', (173, 186))
44162	27602491	We therefore hypothesized that ERBB2 and ERBB3 activating mutations might be over-represented in ILC harboring atypical features such as high tumor grade or ERBB2 amplification.	('ILC', 'Disease', (97, 100))	('high tumor', 'Disease', 'MESH:D009369', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('amplification', 'Var', (163, 176))	('ERBB2', 'Gene', (157, 162))	('ERBB2', 'Gene', '2064', (157, 162))	('ERBB3', 'Gene', (41, 46))	('ERBB3', 'Gene', '2065', (41, 46))	('ERBB2', 'Gene', '2064', (31, 36))	('over-represented', 'PosReg', (77, 93))	('ERBB2', 'Gene', (31, 36))	('high tumor', 'Disease', (137, 147))	('activating', 'PosReg', (47, 57))
44163	27602491	The aim of our study was to report the detection rate of ERBB2 and ERBB3 mutations in a consecutive series of high grade or ERBB2-positive ILC.	('ERBB2', 'Gene', '2064', (57, 62))	('ERBB2', 'Gene', (57, 62))	('mutations', 'Var', (73, 82))	('ERBB3', 'Gene', '2065', (67, 72))	('ERBB2', 'Gene', '2064', (124, 129))	('ERBB2', 'Gene', (124, 129))	('ERBB3', 'Gene', (67, 72))
44171	27602491	Among the 55 ILC subjected to sequencing, six (11%, 95%CI[3; 19]) were found to have at least one ERBB2 missense somatic mutation.	('ERBB2', 'Gene', '2064', (98, 103))	('missense', 'Var', (104, 112))	('ERBB2', 'Gene', (98, 103))
44173	27602491	Four tumors displayed the p.L755S (c.2264T>C) missense mutation, whereas two tumors had two mutations, p.L755S and p.S310Y (c.929C>A) for one and p.I767M (c.2301C>G) and p.S310Y for the other (Figure 2a).	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('c.2264T>C', 'Mutation', 'rs121913470', (35, 44))	('p.S310Y', 'Mutation', 'rs1057519816', (170, 177))	('p.S310Y', 'Mutation', 'rs1057519816', (115, 122))	('p.L755S', 'Var', (103, 110))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('p.S310Y', 'Var', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('p.L755S', 'Mutation', 'rs121913470', (26, 33))	('p.L755S (c.2264T>C', 'Var', (26, 44))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('tumors', 'Disease', (77, 83))	('p.S310Y (c.929C>A', 'Var', (115, 132))	('c.2301C>G', 'Var', (155, 164))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Disease', (5, 11))	('c.2301C>G', 'Mutation', 'c.2301C>G', (155, 164))	('p.L755S', 'Mutation', 'rs121913470', (103, 110))	('p.I767M (c.2301C>G', 'Var', (146, 164))	('c.929C>A', 'Mutation', 'rs1057519816', (124, 132))	('p.I767M', 'Mutation', 'p.I767M', (146, 153))
44174	27602491	Thus, we identified six mutations in the kinase domain (p.L755S (five out of eight mutations; 63%) and p.I767M) and two mutations in the extracellular domain of the receptor (p.S310Y) (Figure 2b).	('p.S310Y', 'Mutation', 'rs1057519816', (175, 182))	('p.L755S', 'Mutation', 'rs121913470', (56, 63))	('extracellular', 'cellular_component', 'GO:0005576', ('137', '150'))	('p.L755S', 'Var', (56, 63))	('p.I767M', 'Mutation', 'p.I767M', (103, 110))	('p.I767M', 'Var', (103, 110))	('p.S310Y', 'Var', (175, 182))
44176	27602491	The validity of the ERBB3 sequencing method was successfully checked by sequencing the ERBB3-mutated breast cancer case (G284R) mentioned in the introduction and used as a positive control.	('ERBB3', 'Gene', '2065', (20, 25))	('ERBB3', 'Gene', (20, 25))	('G284R', 'Mutation', 'rs1057519803', (121, 126))	('G284R', 'Var', (121, 126))	('ERBB3', 'Gene', '2065', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ERBB3', 'Gene', (87, 92))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
44178	27602491	The solid subtype of ILC was significantly associated with ERBB2 mutation (Fisher's exact test; p = 0.01).	('solid subtype', 'Disease', (4, 17))	('ERBB2', 'Gene', (59, 64))	('ERBB2', 'Gene', '2064', (59, 64))	('mutation', 'Var', (65, 73))	('associated', 'Reg', (43, 53))	('ILC', 'Disease', (21, 24))
44179	27602491	Solid subtype was observed in 50% (3/6) of mutant ERBB2 tumors versus 6% (3/49) of wild type ERBB2 tumors (Fisher's exact test; p = 0.01).	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('type ERBB2 tumors', 'Disease', (88, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ERBB2', 'Gene', (50, 55))	('ERBB2', 'Gene', '2064', (50, 55))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('mutant', 'Var', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('ERBB2', 'Gene', (93, 98))	('ERBB2', 'Gene', '2064', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('type ERBB2 tumors', 'Disease', 'MESH:D009369', (88, 105))	('tumors', 'Disease', (99, 105))
44180	27602491	No significant correlation was found between the mutant ERBB2 status and other classical clinicopathological parameters such as age, Elston-Ellis tumor grade, mitotic index, presence of lymphovascular invasion, macroscopic tumor size, lymph node status, ER, PR and E-cadherin expression.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mutant', 'Var', (49, 55))	('ER', 'Gene', '2099', (254, 256))	('ER', 'Gene', '2099', (56, 58))	('tumor', 'Disease', (146, 151))	('Elston-Ellis tumor', 'Disease', (133, 151))	('ERBB2', 'Gene', '2064', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('Elston-Ellis tumor', 'Disease', 'MESH:D004613', (133, 151))	('cadherin', 'molecular_function', 'GO:0008014', ('267', '275'))	('ERBB2', 'Gene', (56, 61))	('mitotic index', 'CPA', (159, 172))	('E-cadherin', 'Gene', (265, 275))	('E-cadherin', 'Gene', '999', (265, 275))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
44181	27602491	Four mutated ILC expressed ER and PR, one expressed only ER and the last one was triple negative.	('expressed', 'Reg', (17, 26))	('ER', 'Gene', '2099', (27, 29))	('ILC', 'Gene', (13, 16))	('ER', 'Gene', '2099', (57, 59))	('mutated', 'Var', (5, 12))
44182	27602491	All mutated ILC were E-cadherin-negative by immunohistochemistry.	('mutated', 'Var', (4, 11))	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))	('ILC', 'Gene', (12, 15))
44183	27602491	We observed that all ERBB2 mutations were found in ERBB2-negative samples, although this possible mutual exclusion did not reach statistical significance (Fisher's exact test p = 0.2).	('mutations', 'Var', (27, 36))	('ERBB2', 'Gene', '2064', (21, 26))	('ERBB2', 'Gene', '2064', (51, 56))	('ERBB2', 'Gene', (21, 26))	('ERBB2', 'Gene', (51, 56))
44184	27602491	We therefore report a 15.4% (6/39, 95%CI[4%; 27%]) ERBB2 mutations rate in grade 3 ERBB2-negative ILC versus 0% (0/16) in grade 3 ERBB2-positive ILC.	('ERBB2', 'Gene', '2064', (130, 135))	('ERBB2', 'Gene', (130, 135))	('ILC', 'Disease', (98, 101))	('ERBB2', 'Gene', (83, 88))	('mutations', 'Var', (57, 66))	('ERBB2', 'Gene', '2064', (83, 88))	('ERBB2', 'Gene', '2064', (51, 56))	('ERBB2', 'Gene', (51, 56))
44187	27602491	This exploratory analysis showed no significant prognostic impact of ERBB2 mutation on breast cancer-free interval and breast cancer specific survival (p = 0.82 and 0.35 respectively, Figure 3).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer-free interval', 'Disease', 'MESH:D001943', (87, 114))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('mutation', 'Var', (75, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ERBB2', 'Gene', '2064', (69, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('ERBB2', 'Gene', (69, 74))	('breast cancer-free interval', 'Disease', (87, 114))
44189	27602491	Based on a large consecutive series, our study demonstrates that activating ERBB2 mutations are particularly enriched (15.4% detection rate, 95%CI[4;27]) in grade 3 ERBB2-negative ILC.	('ILC', 'Disease', (180, 183))	('ERBB2', 'Gene', '2064', (165, 170))	('activating', 'PosReg', (65, 75))	('ERBB2', 'Gene', (165, 170))	('mutations', 'Var', (82, 91))	('ERBB2', 'Gene', (76, 81))	('ERBB2', 'Gene', '2064', (76, 81))
44191	27602491	Interestingly, a similar rate of ERBB2 mutations was previously reported in a smaller series by Lien and colleagues, who identified ERBB2 mutations in five out of 24 (21%) invasive and in-situ pleomorphic lobular carcinomas.	('ERBB2', 'Gene', '2064', (33, 38))	('ERBB2', 'Gene', (132, 137))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (205, 223))	('situ pleomorphic lobular carcinomas', 'Disease', 'MESH:D000071960', (188, 223))	('situ pleomorphic lobular carcinomas', 'Disease', (188, 223))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (205, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('carcinomas', 'Phenotype', 'HP:0030731', (213, 223))	('ERBB2', 'Gene', '2064', (132, 137))	('ERBB2', 'Gene', (33, 38))	('mutations', 'Var', (138, 147))
44193	27602491	This composition of our series did not allow identifying any significant correlation between ERBB2 mutations and E-cadherin loss of expression by immunohistochemistry.	('cadherin', 'molecular_function', 'GO:0008014', ('115', '123'))	('loss of expression', 'NegReg', (124, 142))	('E-cadherin', 'Gene', (113, 123))	('mutations', 'Var', (99, 108))	('E-cadherin', 'Gene', '999', (113, 123))	('ERBB2', 'Gene', (93, 98))	('ERBB2', 'Gene', '2064', (93, 98))
44194	27602491	Interestingly enough, using the cBioportal, we found that the 9 ERBB2 mutated ILC cases of TCGA 2015 were CDH1 mutated with a significant correlation with a Fisher's exact test (p = 0.02) calculated among breast carcinomas of other histological subtypes.	('carcinomas', 'Phenotype', 'HP:0030731', (212, 222))	('breast carcinomas', 'Phenotype', 'HP:0003002', (205, 222))	('CDH1', 'Gene', '999', (106, 110))	('mutated', 'Var', (111, 118))	('ERBB2', 'Gene', (64, 69))	('ERBB2', 'Gene', '2064', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('breast carcinomas', 'Disease', 'MESH:D001943', (205, 222))	('breast carcinomas', 'Disease', (205, 222))	('CDH1', 'Gene', (106, 110))	('mutated', 'Var', (70, 77))
44195	27602491	In our study, the solid subtype of ILC appears as frequently mutated, as half of the six solid ILC had at least one ERBB2 mutation.	('ERBB2', 'Gene', (116, 121))	('mutation', 'Var', (122, 130))	('ERBB2', 'Gene', '2064', (116, 121))
44196	27602491	This link between an ILC subtype and more frequent ERBB2 mutations has been also suggested by Desmedt et al.	('ILC', 'Disease', (21, 24))	('mutations', 'Var', (57, 66))	('ERBB2', 'Gene', (51, 56))	('ERBB2', 'Gene', '2064', (51, 56))
44197	27602491	However, the first TCGA study identified ERBB2 mutations in grade 2 and 3 classic ILC (Supplementary Table 1).	('ERBB2', 'Gene', '2064', (41, 46))	('mutations', 'Var', (47, 56))	('ERBB2', 'Gene', (41, 46))
44198	27602491	Additional series are needed to confirm the preferential association on the one hand between ERBB2 mutations and solid subtype of ILC and on the other hand between ERBB2 mutations and CDH1 mutations.	('solid subtype', 'Disease', (113, 126))	('mutations', 'Var', (170, 179))	('CDH1', 'Gene', (184, 188))	('ERBB2', 'Gene', '2064', (164, 169))	('ERBB2', 'Gene', (164, 169))	('mutations', 'Var', (99, 108))	('ILC', 'Disease', (130, 133))	('ERBB2', 'Gene', (93, 98))	('CDH1', 'Gene', '999', (184, 188))	('ERBB2', 'Gene', '2064', (93, 98))
44199	27602491	In contrast to Lien et al, apocrine differentiation was not associated with ERBB2 mutations.	('mutations', 'Var', (82, 91))	('ERBB2', 'Gene', (76, 81))	('ERBB2', 'Gene', '2064', (76, 81))	('apocrine differentiation', 'Disease', (27, 51))
44200	27602491	Also, our result suggests that ERBB2 mutation and amplification are two mutually exclusive oncogenic events in ILC.	('amplification', 'Var', (50, 63))	('mutation', 'Var', (37, 45))	('ILC', 'Disease', (111, 114))	('ERBB2', 'Gene', '2064', (31, 36))	('ERBB2', 'Gene', (31, 36))
44201	27602491	However, a few breast cancers with coexisting ERBB2 mutation and homogeneous or heterogeneous amplification have been already reported.	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('breast cancers', 'Phenotype', 'HP:0003002', (15, 29))	('mutation', 'Var', (52, 60))	('ERBB2', 'Gene', '2064', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancers', 'Disease', 'MESH:D001943', (15, 29))	('breast cancers', 'Disease', (15, 29))	('ERBB2', 'Gene', (46, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
44202	27602491	Regarding mutation distribution, the p.L755S mutation represented five of the eight (63%) ERBB2 mutations identified in this study.	('p.L755S', 'Mutation', 'rs121913470', (37, 44))	('p.L755S', 'Var', (37, 44))	('ERBB2', 'Gene', (90, 95))	('ERBB2', 'Gene', '2064', (90, 95))
44203	27602491	The L755 residue has been previously reported by Bose et al as the most frequent mutation hotspot in the ERBB2 gene.	('ERBB2', 'Gene', (105, 110))	('L755', 'Var', (4, 8))	('ERBB2', 'Gene', '2064', (105, 110))
44204	27602491	Although the oncogenic activity of the L755 mutations was not demonstrated, Bose et al reported that mutated L755 breast cancer cell lines were less sensitive to the reversible dual EGFR/ERBB2 inhibitor lapatinib but may be sensitive to irreversible dual EGFR/ERBB2 inhibitors such as neratinib.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('EGFR', 'Gene', (255, 259))	('EGFR', 'molecular_function', 'GO:0005006', ('182', '186'))	('EGFR', 'Gene', '1956', (182, 186))	('lapatinib', 'Chemical', 'MESH:D000077341', (203, 212))	('L755', 'Var', (109, 113))	('less', 'NegReg', (144, 148))	('sensitive', 'MPA', (149, 158))	('ERBB2', 'Gene', (260, 265))	('EGFR', 'molecular_function', 'GO:0005006', ('255', '259'))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('ERBB2', 'Gene', (187, 192))	('EGFR', 'Gene', '1956', (255, 259))	('EGFR', 'Gene', (182, 186))	('ERBB2', 'Gene', '2064', (260, 265))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('ERBB2', 'Gene', '2064', (187, 192))	('neratinib', 'Chemical', 'MESH:C487932', (285, 294))	('breast cancer', 'Disease', (114, 127))
44205	27602491	Regarding the other mutations found in our series, the p.I767M mutation was also not functionally characterized as oncogenic, but appeared sensitive to conventional anti-ERBB2 drugs (trastuzumab, lapatinib, neratinib); the p.S310Y mutation has been functionally characterized as activating mutations that sensitize cancer cells to ERBB2 inhibitors.	('p.S310Y', 'Var', (223, 230))	('ERBB2', 'Gene', (170, 175))	('lapatinib', 'Chemical', 'MESH:D000077341', (196, 205))	('neratinib', 'Chemical', 'MESH:C487932', (207, 216))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('p.S310Y', 'Mutation', 'rs1057519816', (223, 230))	('cancer', 'Disease', (315, 321))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('trastuzumab', 'Chemical', 'MESH:D000068878', (183, 194))	('ERBB2', 'Gene', (331, 336))	('p.I767M', 'Mutation', 'p.I767M', (55, 62))	('ERBB2', 'Gene', '2064', (331, 336))	('ERBB2', 'Gene', '2064', (170, 175))
44207	27602491	Notably, a case-report described the spectacular response to lapatinib for a metastatic ILC patient harboring a rare ERBB2 mutation (p.L869Q).	('p.L869Q', 'Mutation', 'p.L869Q', (133, 140))	('patient', 'Species', '9606', (92, 99))	('ERBB2', 'Gene', (117, 122))	('p.L869Q', 'Var', (133, 140))	('ERBB2', 'Gene', '2064', (117, 122))	('response to lapatinib', 'biological_process', 'GO:0036274', ('49', '70'))	('lapatinib', 'Chemical', 'MESH:D000077341', (61, 70))
44208	27602491	Altogether these results demonstrate the interest of ERBB2 mutations screening in clinical practice.	('ERBB2', 'Gene', '2064', (53, 58))	('mutations', 'Var', (59, 68))	('ERBB2', 'Gene', (53, 58))
44209	27602491	Their study included 127 ILC of any grade and reported five ERBB2 mutations (4% mutation rate).	('mutations', 'Var', (66, 75))	('ERBB2', 'Gene', (60, 65))	('ERBB2', 'Gene', '2064', (60, 65))
44211	27602491	It might therefore be possible that the large and very exhaustive analysis published by Ciriello et al had not enough power to detect the association between ERBB2 mutations and high grade ILC.	('ERBB2', 'Gene', (158, 163))	('mutations', 'Var', (164, 173))	('high grade ILC', 'Disease', (178, 192))	('ERBB2', 'Gene', '2064', (158, 163))
44213	27602491	ERBB2 mutations were found in 4% of ILC, in line with a number of previous studies.	('ERBB2', 'Gene', '2064', (0, 5))	('ILC', 'Disease', (36, 39))	('ERBB2', 'Gene', (0, 5))	('found', 'Reg', (21, 26))	('mutations', 'Var', (6, 15))
44214	27602491	that reported a 3.6% (15/413) mutation of ERBB3 in ILC, we did not find any ERBB3 activating mutation among the 55 tested ILC.	('ERBB3', 'Gene', '2065', (42, 47))	('ERBB3', 'Gene', (42, 47))	('mutation', 'Var', (30, 38))	('ERBB3', 'Gene', '2065', (76, 81))	('ERBB3', 'Gene', (76, 81))
44216	27602491	Our results suggest that ERBB3 mutations are not enriched in grade 3 ILC, and may rather be found in ILC of lower grade.	('ERBB3', 'Gene', (25, 30))	('ERBB3', 'Gene', '2065', (25, 30))	('mutations', 'Var', (31, 40))
44217	27602491	did not find a link between ERBB3 mutations and high grade ILC.	('mutations', 'Var', (34, 43))	('ERBB3', 'Gene', (28, 33))	('ERBB3', 'Gene', '2065', (28, 33))	('high grade ILC', 'Disease', (48, 62))
44218	27602491	ICGC data showed that, among breast cancers, ERBB3 activating mutations are predominantly found in ILC and / or triple negative breast carcinomas but remain a rare event in breast carcinomas.	('breast carcinomas', 'Phenotype', 'HP:0003002', (173, 190))	('breast cancers', 'Phenotype', 'HP:0003002', (29, 43))	('breast carcinomas', 'Disease', 'MESH:D001943', (128, 145))	('breast carcinomas', 'Disease', (128, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('ERBB3', 'Gene', '2065', (45, 50))	('breast carcinomas', 'Phenotype', 'HP:0003002', (128, 145))	('mutations', 'Var', (62, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('ILC', 'Disease', (99, 102))	('breast carcinomas', 'Disease', 'MESH:D001943', (173, 190))	('breast carcinomas', 'Disease', (173, 190))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('ERBB3', 'Gene', (45, 50))	('activating', 'PosReg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancers', 'Disease', 'MESH:D001943', (29, 43))	('breast cancers', 'Disease', (29, 43))
44219	27602491	A last interesting finding is that, although of limited size, our cohort had a long clinical follow-up after surgery; this allowed performing an exploratory survival analysis which showed no major prognostic impact of ERBB2 mutations.	('mutations', 'Var', (224, 233))	('ERBB2', 'Gene', (218, 223))	('ERBB2', 'Gene', '2064', (218, 223))
44220	27602491	To conclude, our study demonstrates that, in the era of personalized therapy, rare targetable activating mutations can be significantly enriched in specific breast tumor subtypes.	('breast tumor', 'Phenotype', 'HP:0100013', (157, 169))	('breast tumor', 'Disease', 'MESH:D001943', (157, 169))	('mutations', 'Var', (105, 114))	('activating', 'PosReg', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('breast tumor', 'Disease', (157, 169))
44221	27602491	With a very high ERBB2 mutation rate of 15.4%, patients with ERBB2-negative ILC should be screened and grade 3 addressed to personalized therapeutic trials whenever possible.	('ILC', 'Disease', (76, 79))	('ERBB2', 'Gene', (61, 66))	('mutation', 'Var', (23, 31))	('ERBB2', 'Gene', '2064', (61, 66))	('patients', 'Species', '9606', (47, 55))	('ERBB2', 'Gene', '2064', (17, 22))	('ERBB2', 'Gene', (17, 22))
44240	27602491	They were designed to allow identification of most prevalent ERBB2 and ERBB3 mutations, including S310F/Y, R678Q, L755M/P/S/W, V777A/L/M and V842I mutations in ERBB2 and M91I, V104M/L, N126K, H228Q/R, A232V/T, G284R/G, D297N/V/Y mutations in ERBB3.	('V842I', 'Var', (141, 146))	('D297N', 'Var', (219, 224))	('G284R', 'Var', (210, 215))	('H228Q', 'Var', (192, 197))	('V777A', 'SUBSTITUTION', 'None', (127, 132))	('L755M', 'SUBSTITUTION', 'None', (114, 119))	('M91I', 'Var', (170, 174))	('V104M', 'Var', (176, 181))	('ERBB2', 'Gene', (160, 165))	('G284R', 'SUBSTITUTION', 'None', (210, 215))	('H228Q', 'SUBSTITUTION', 'None', (192, 197))	('R678Q', 'Mutation', 'rs1057519862', (107, 112))	('R678Q', 'Var', (107, 112))	('ERBB3', 'Gene', '2065', (242, 247))	('V104M', 'SUBSTITUTION', 'None', (176, 181))	('A232V', 'SUBSTITUTION', 'None', (201, 206))	('M91I', 'Mutation', 'p.M91I', (170, 174))	('ERBB3', 'Gene', (71, 76))	('ERBB2', 'Gene', '2064', (160, 165))	('ERBB2', 'Gene', (61, 66))	('S310F', 'Var', (98, 103))	('N126K', 'Mutation', 'p.N126K', (185, 190))	('S310F', 'SUBSTITUTION', 'None', (98, 103))	('A232V', 'Var', (201, 206))	('N126K', 'Var', (185, 190))	('L755M', 'Var', (114, 119))	('D297N', 'SUBSTITUTION', 'None', (219, 224))	('ERBB2', 'Gene', '2064', (61, 66))	('V777A', 'Var', (127, 132))	('V842I', 'Mutation', 'rs1057519738', (141, 146))	('ERBB3', 'Gene', '2065', (71, 76))	('ERBB3', 'Gene', (242, 247))
44346	26294295	18F-FDG PET/CT was more likely to reveal unsuspected distant metastases in stage III IDC patients than in stage III ILC patients.	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('stage III IDC', 'Disease', (75, 88))	('metastases', 'Disease', (61, 71))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (120, 128))	('metastases', 'Disease', 'MESH:D009362', (61, 71))	('18F-FDG', 'Var', (0, 7))
44347	26294295	In addition, some ILC patients were upstaged by non-18F-FDG-avid lesions visible only on the CT images.	('upstaged', 'PosReg', (36, 44))	('patients', 'Species', '9606', (22, 30))	('non-18F-FDG-avid', 'Var', (48, 64))	('18F-FDG', 'Chemical', 'MESH:D019788', (52, 59))	('ILC', 'Disease', (18, 21))
44442	26294295	In addition to PET/CT detecting unsuspected distant metastases in 20 (22%) of 89 patients with stage III IDC, 6 (30%) of the 20 were upstaged by the 18F-FDG PET component of the PET/CT study, without corresponding suggestive findings on CT or bone scanning.	('metastases', 'Disease', (52, 62))	('metastases', 'Disease', 'MESH:D009362', (52, 62))	('patients', 'Species', '9606', (81, 89))	('upstaged', 'PosReg', (133, 141))	('18F-FDG', 'Chemical', 'MESH:D019788', (149, 156))	('18F-FDG PET', 'Var', (149, 160))
44445	26294295	99mTc-MDP is a radiotracer that accumulates at sites of osteoblastic remodeling; thus, 99mTc-MDP detects the osseous response to tumor rather than the tumor itself.	('MDP', 'molecular_function', 'GO:0004237', ('6', '9'))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('osteoblastic remodeling', 'Disease', 'MESH:D020257', (56, 79))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (151, 156))	('-MDP', 'Chemical', 'MESH:D000119', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('osseous response', 'CPA', (109, 125))	('99mTc-MDP', 'Var', (87, 96))	('MDP', 'molecular_function', 'GO:0004237', ('93', '96'))	('tumor', 'Disease', (129, 134))	('osteoblastic remodeling', 'Disease', (56, 79))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('-MDP', 'Chemical', 'MESH:D000119', (92, 96))
44450	26294295	Although the detection of unsuspected local extraaxillary nodal disease does not have the same impact on patient care as the detection of distant metastases, detection of such nodal disease may still increase the patient's stage, affect prognosis, and lead to changes in a patient's treatment plan, such as additional surgery or radiotherapy.	('nodal disease', 'Disease', (58, 71))	('patient', 'Species', '9606', (105, 112))	('affect', 'Reg', (230, 236))	('metastases', 'Disease', (146, 156))	('stage', 'CPA', (223, 228))	('patient', 'Species', '9606', (273, 280))	('patient', 'Species', '9606', (213, 220))	('increase', 'PosReg', (200, 208))	('nodal disease', 'Disease', (176, 189))	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('radiotherapy', 'Disease', (329, 341))	('detection', 'Var', (158, 167))	('prognosis', 'CPA', (237, 246))	('lead to changes', 'Reg', (252, 267))	('nodal disease', 'Disease', 'MESH:D013611', (58, 71))	('nodal disease', 'Disease', 'MESH:D013611', (176, 189))
44471	27811364	ERBB2 mutation is associated with a worse prognosis in patients with CDH1 altered invasive lobular cancer of the breast E-cadherin (CDH1) is a glycoprotein that mediates adhesion between epithelial cells and also suppresses cancer invasion.	('CDH1 altered invasive lobular cancer', 'Disease', 'MESH:D013274', (69, 105))	('CDH1 altered invasive lobular cancer', 'Disease', (69, 105))	('ERBB2', 'Gene', (0, 5))	('CDH1', 'Gene', '999', (69, 73))	('CDH1', 'Gene', '999', (132, 136))	('cancer of the breast', 'Phenotype', 'HP:0100013', (99, 119))	('cancer', 'Disease', (224, 230))	('CDH1', 'Gene', (69, 73))	('CDH1', 'Gene', (132, 136))	('ERBB2', 'Gene', '2064', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('adhesion', 'Interaction', (170, 178))	('cadherin', 'molecular_function', 'GO:0008014', ('122', '130'))	('suppresses', 'NegReg', (213, 223))	('lobular cancer', 'Phenotype', 'HP:0030076', (91, 105))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('mutation', 'Var', (6, 14))	('cancer', 'Disease', (99, 105))	('patients', 'Species', '9606', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
44472	27811364	Mutation or deletion of the CDH1 gene has been reported in 30-60% cases of invasive lobular carcinoma (ILC).	('deletion', 'Var', (12, 20))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (84, 101))	('CDH1', 'Gene', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('Mutation', 'Var', (0, 8))	('invasive lobular carcinoma', 'Disease', (75, 101))	('CDH1', 'Gene', '999', (28, 32))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (75, 101))	('reported', 'Reg', (47, 55))
44473	27811364	However, little is known about genomic differences between ILC with and without a CDH1 alteration.	('CDH1', 'Gene', (82, 86))	('alteration', 'Var', (87, 97))	('ILC', 'Disease', (59, 62))	('CDH1', 'Gene', '999', (82, 86))
44477	27811364	Seven recurrent mutations (PTEN, MUC16, ERBB2, FAT4, PCDHGA2, HERC1 and FLNC) and four chromosomal changes with recurrent copy number variation (CNV) (11q13, 17q12-21, 8p11 and 8q11) were found in ILC, which correlated with a positive or negative CDH1 alteration status, respectively.	('FLNC', 'Gene', (72, 76))	('CDH1', 'Gene', '999', (247, 251))	('PCDHGA2', 'Gene', (53, 60))	('ERBB2', 'Gene', '2064', (40, 45))	('ILC', 'Disease', (197, 200))	('ERBB2', 'Gene', (40, 45))	('MUC16', 'Gene', (33, 38))	('PCDHGA2', 'Gene', '56113', (53, 60))	('11q13', 'Var', (151, 156))	('FLNC', 'Gene', '2318', (72, 76))	('FAT4', 'Gene', (47, 51))	('HERC1', 'Gene', '8925', (62, 67))	('FAT4', 'Gene', '79633', (47, 51))	('MUC16', 'Gene', '94025', (33, 38))	('HERC1', 'Gene', (62, 67))	('PTEN', 'Gene', (27, 31))	('CDH1', 'Gene', (247, 251))
44478	27811364	The prevalence of the most common breast cancer driver abnormalities including TP53 and PIK3CA mutations and MYC and ERBB2 amplifications showed no difference between the two groups.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TP53', 'Gene', '7157', (79, 83))	('PIK3CA', 'Gene', '5290', (88, 94))	('TP53', 'Gene', (79, 83))	('MYC', 'Gene', '4609', (109, 112))	('breast cancer driver abnormalities', 'Disease', 'MESH:D001943', (34, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('ERBB2', 'Gene', (117, 122))	('breast cancer driver abnormalities', 'Disease', (34, 68))	('ERBB2', 'Gene', '2064', (117, 122))	('mutations', 'Var', (95, 104))	('PIK3CA', 'Gene', (88, 94))	('MYC', 'Gene', (109, 112))
44479	27811364	However, CDH1-altered ILC with an ERBB2 mutation shows a significantly worse prognosis compared to its counterparts without such a mutation.	('mutation', 'Var', (40, 48))	('ILC', 'Disease', (22, 25))	('ERBB2', 'Gene', (34, 39))	('ERBB2', 'Gene', '2064', (34, 39))	('CDH1', 'Gene', (9, 13))	('CDH1', 'Gene', '999', (9, 13))
44480	27811364	Our study suggests that CDH1-altered ILC patients with ERBB2 mutations may represent an actionable group of patients who could benefit from targeted breast cancer therapy.	('CDH1', 'Gene', (24, 28))	('CDH1', 'Gene', '999', (24, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('mutations', 'Var', (61, 70))	('ILC', 'Disease', (37, 40))	('patients', 'Species', '9606', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('ERBB2', 'Gene', (55, 60))	('patients', 'Species', '9606', (108, 116))	('ERBB2', 'Gene', '2064', (55, 60))	('breast cancer', 'Disease', (149, 162))
44484	27811364	The ILC tumor cells are typically estrogen receptor (ER) positive and epidermal growth factor receptor 2 (HER2) negative, and often have a lost or aberrant epithelial cadherin (E-cadherin, CDH1) protein expression.	('estrogen receptor', 'Gene', '2099', (34, 51))	('CDH1', 'Gene', '999', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cadherin', 'molecular_function', 'GO:0008014', ('179', '187'))	('CDH1', 'Gene', (189, 193))	('epithelial cadherin', 'Gene', (156, 175))	('HER2', 'Gene', (106, 110))	('ER', 'Gene', '2099', (53, 55))	('estrogen receptor', 'Gene', (34, 51))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('70', '93'))	('ER', 'Gene', '2099', (107, 109))	('epidermal growth factor receptor 2', 'Gene', '2064', (70, 104))	('tumor', 'Disease', (8, 13))	('ILC', 'Disease', (4, 7))	('epithelial cadherin', 'Gene', '999', (156, 175))	('lost', 'NegReg', (139, 143))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('aberrant', 'Var', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('expression', 'MPA', (203, 213))	('epidermal growth factor receptor 2', 'Gene', (70, 104))	('HER2', 'Gene', '2064', (106, 110))	('cadherin', 'molecular_function', 'GO:0008014', ('167', '175'))
44490	27811364	Although mutation or deletion of CDH1 gene has been well recognized to be responsible for loss of E-cadherin protein expression in lobular neoplasms, molecular mechanisms underlying ILC with and without a CDH1 alteration are not well studied.	('mutation', 'Var', (9, 17))	('lobular neoplasms', 'Disease', (131, 148))	('neoplasms', 'Phenotype', 'HP:0002664', (139, 148))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('loss', 'NegReg', (90, 94))	('CDH1', 'Gene', (205, 209))	('expression', 'MPA', (117, 127))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('deletion', 'Var', (21, 29))	('CDH1', 'Gene', (33, 37))	('ILC', 'Disease', (182, 185))	('CDH1', 'Gene', '999', (205, 209))	('E-cadherin protein', 'Protein', (98, 116))	('CDH1', 'Gene', '999', (33, 37))	('lobular neoplasms', 'Disease', 'MESH:D018275', (131, 148))
44491	27811364	The data from the COSMIC database shows that only 35% of ILC (83/235) carry a CDH1 mutation, while three recent, large scale genome sequencing studies have shown that 43% to 65% of the ILC had a CDH1 gene mutation or deletion.	('CDH1', 'Gene', '999', (195, 199))	('mutation', 'Var', (83, 91))	('deletion', 'Var', (217, 225))	('CDH1', 'Gene', (78, 82))	('CDH1', 'Gene', '999', (78, 82))	('CDH1', 'Gene', (195, 199))
44492	27811364	The study based on TCGA breast cancer sequencing data had also demonstrated that most of the remaining ILC without a CDH1 mutation also harbor various E-cadherin gene abnormalities in their transcriptional and/or translational pathways.	('transcriptional and/or', 'Pathway', (190, 212))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('mutation', 'Var', (122, 130))	('CDH1', 'Gene', (117, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('breast cancer', 'Disease', (24, 37))	('CDH1', 'Gene', '999', (117, 121))	('abnormalities', 'Var', (167, 180))	('cadherin', 'molecular_function', 'GO:0008014', ('153', '161'))	('E-cadherin', 'Protein', (151, 161))
44493	27811364	However, it remained unknown as to whether there were any differences in clinical, pathological and genetic characteristics between ILC with and without a CDH1 alteration.	('CDH1', 'Gene', (155, 159))	('CDH1', 'Gene', '999', (155, 159))	('alteration', 'Var', (160, 170))	('ILC', 'Disease', (132, 135))
44495	27811364	We also previously reported that ILC generally has fewer genomic abnormalities including a lower burden of gene mutations and copy number variations (CNV) compared to IDC.	('lower', 'NegReg', (91, 96))	('ILC', 'Disease', (33, 36))	('copy number variations', 'Var', (126, 148))	('genomic abnormalities', 'Disease', (57, 78))	('genomic abnormalities', 'Disease', 'MESH:D042822', (57, 78))
44496	27811364	In this study, we have further demonstrated that ILC with and without CDH1 alterations are strikingly similar clinically, pathologically, and even genetically.	('ILC', 'Disease', (49, 52))	('CDH1', 'Gene', '999', (70, 74))	('alterations', 'Var', (75, 86))	('CDH1', 'Gene', (70, 74))
44497	27811364	However, an ERBB2 mutation was co-occurred with CDH1 mutation and associated with a worse prognosis.	('ERBB2', 'Gene', (12, 17))	('ERBB2', 'Gene', '2064', (12, 17))	('mutation', 'Var', (53, 61))	('CDH1', 'Gene', (48, 52))	('associated', 'Reg', (66, 76))	('CDH1', 'Gene', '999', (48, 52))	('mutation', 'Var', (18, 26))
44501	27811364	Since both CDH1 gene mutation and deletion lead to an abnormal or loss of E-cadherin function, we combined CDH1 mutations and deletions into a CDH1 "altered" group in this analysis.	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('loss', 'NegReg', (66, 70))	('CDH1', 'Gene', (11, 15))	('CDH1', 'Gene', (107, 111))	('deletions', 'Var', (126, 135))	('mutation', 'Var', (21, 29))	('mutations', 'Var', (112, 121))	('CDH1', 'Gene', '999', (11, 15))	('CDH1', 'Gene', '999', (107, 111))	('deletion', 'Var', (34, 42))	('E-cadherin', 'Protein', (74, 84))	('CDH1', 'Gene', (143, 147))	('CDH1', 'Gene', '999', (143, 147))
44502	27811364	Together, 59.2% of the TCGA ILC tumors (100/169) had a CDH1 alteration and the remaining 40.8% (69/169) had a normal CDH1 genetic status.	('CDH1', 'Gene', (55, 59))	('alteration', 'Var', (60, 70))	('ILC tumors', 'Disease', 'MESH:D009369', (28, 38))	('CDH1', 'Gene', (117, 121))	('CDH1', 'Gene', '999', (55, 59))	('CDH1', 'Gene', '999', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ILC tumors', 'Disease', (28, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
44503	27811364	In contrast, IDC and ICDL had a significantly lower prevalence of CDH1 gene alterations (2.6%, 18/690 and 16.7%, 6/36, respectively).	('ICDL', 'Disease', (21, 25))	('alterations', 'Var', (76, 87))	('CDH1', 'Gene', (66, 70))	('CDH1', 'Gene', '999', (66, 70))	('lower', 'NegReg', (46, 51))	('IDC', 'Disease', (13, 16))
44510	27811364	Interestingly, although both are associated with low grade tumors, the presence of a PIK3CA mutation is not associated with a CDH1 mutation and occurs in a similarly high prevalence in ILC with and without a CDH1 mutation (Figure 2).	('CDH1', 'Gene', (126, 130))	('CDH1', 'Gene', '999', (126, 130))	('mutation', 'Var', (92, 100))	('PIK3CA', 'Gene', '5290', (85, 91))	('CDH1', 'Gene', (208, 212))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('ILC', 'Disease', (185, 188))	('CDH1', 'Gene', '999', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('PIK3CA', 'Gene', (85, 91))
44512	27811364	Both TP53 mutation and MYC amplification are also not correlated with a CDH1 mutation (Figure 2).	('mutation', 'Var', (77, 85))	('CDH1', 'Gene', (72, 76))	('MYC', 'Gene', '4609', (23, 26))	('TP53', 'Gene', '7157', (5, 9))	('CDH1', 'Gene', '999', (72, 76))	('MYC', 'Gene', (23, 26))	('TP53', 'Gene', (5, 9))
44513	27811364	These data suggests that the ILC with and without a CDH1 alteration share a common oncogenic mechanism similar to low to intermediate grade IDC during cancer initiation and progression.	('alteration', 'Var', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('CDH1', 'Gene', (52, 56))	('ILC', 'Disease', (29, 32))	('CDH1', 'Gene', '999', (52, 56))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('low to intermediate grade IDC', 'Disease', (114, 143))
44514	27811364	While there is no significant clinical or pathological difference between the ILC with and without a CDH1 alteration (Table 1), the number of significant genomic changes associated with a CDH1 gene alteration appears to be also limited.	('alteration', 'Var', (198, 208))	('CDH1', 'Gene', (101, 105))	('alteration', 'Var', (106, 116))	('CDH1', 'Gene', '999', (101, 105))	('CDH1', 'Gene', (188, 192))	('CDH1', 'Gene', '999', (188, 192))
44515	27811364	Among 47 genes with recurrent mutations and 176 chromosomal loci with recurrent gene amplifications in a prevalence >= 2%, seven recurrent gene mutations involving PTEN, MUC16, ERBB2, FAT4, PCDHGA2, HERC1 and FLNC genes (Figure 3A) and four chromosomal loci with recurrent copy number variation (11q13, 17q12-21, 8p11 and 8q11, Figure 3B) were identified to be significantly different between the two groups.	('HERC1', 'Gene', '8925', (199, 204))	('FLNC', 'Gene', '2318', (209, 213))	('PCDHGA2', 'Gene', (190, 197))	('ERBB2', 'Gene', (177, 182))	('MUC16', 'Gene', (170, 175))	('ERBB2', 'Gene', '2064', (177, 182))	('FAT4', 'Gene', (184, 188))	('PCDHGA2', 'Gene', '56113', (190, 197))	('FAT4', 'Gene', '79633', (184, 188))	('HERC1', 'Gene', (199, 204))	('mutations', 'Var', (30, 39))	('FLNC', 'Gene', (209, 213))	('MUC16', 'Gene', '94025', (170, 175))	('PTEN', 'Gene', (164, 168))	('mutations', 'Var', (144, 153))
44516	27811364	Interestingly, these seven significant mutations were mostly observed in ILC with a CDH1 alteration, in contrast, all the significant CNVs were more often seen in the ILC without a CDH1 alteration.	('ILC', 'Disease', (73, 76))	('CDH1', 'Gene', '999', (181, 185))	('alteration', 'Var', (89, 99))	('observed', 'Reg', (61, 69))	('CDH1', 'Gene', (84, 88))	('CDH1', 'Gene', '999', (84, 88))	('CDH1', 'Gene', (181, 185))
44518	27811364	Among those significant mutations and CNVs associated with a CDH1 alteration, ERBB2 was the most well-known oncogene associated with high grade breast cancer.	('ERBB2', 'Gene', '2064', (78, 83))	('CDH1', 'Gene', '999', (61, 65))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('ERBB2', 'Gene', (78, 83))	('associated', 'Reg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('alteration', 'Var', (66, 76))	('CDH1', 'Gene', (61, 65))	('mutations', 'Var', (24, 33))
44520	27811364	In contrast, all ERBB2 mutations were identified in the ILC with a CDH1 alteration.	('ERBB2', 'Gene', '2064', (17, 22))	('mutations', 'Var', (23, 32))	('alteration', 'Var', (72, 82))	('ERBB2', 'Gene', (17, 22))	('CDH1', 'Gene', (67, 71))	('CDH1', 'Gene', '999', (67, 71))
44521	27811364	While ERBB2 amplification is not associated with prognosis in ILC patients irrespective of CDH1 alteration status, the CDH1-altered ILC patients with an ERBB2 mutation showed a significantly worse prognosis as compared to their counterparts without an ERBB2 mutation (Figure 4C and 4D).	('CDH1', 'Gene', '999', (91, 95))	('CDH1', 'Gene', '999', (119, 123))	('ERBB2', 'Gene', '2064', (252, 257))	('ERBB2', 'Gene', '2064', (6, 11))	('ERBB2', 'Gene', (252, 257))	('ERBB2', 'Gene', (6, 11))	('worse', 'Reg', (191, 196))	('mutation', 'Var', (159, 167))	('patients', 'Species', '9606', (136, 144))	('CDH1', 'Gene', (119, 123))	('ERBB2', 'Gene', '2064', (153, 158))	('CDH1', 'Gene', (91, 95))	('patients', 'Species', '9606', (66, 74))	('ERBB2', 'Gene', (153, 158))
44522	27811364	No other recurrent mutation was found to have a significant effect on either overall or disease-free survival in the CDH1-altered ILC, including the PTEN mutation, which was recently reported to be associated with AKT pathway activation in ILC.	('PTEN', 'Gene', (149, 153))	('CDH1', 'Gene', (117, 121))	('mutation', 'Var', (154, 162))	('AKT', 'Gene', '207', (214, 217))	('CDH1', 'Gene', '999', (117, 121))	('ILC', 'Disease', (130, 133))	('AKT', 'Gene', (214, 217))	('activation', 'PosReg', (226, 236))
44523	27811364	For those known breast cancer driver genes such as mutations in TP53, PIK3CA, FOXA1 and amplifications in MYC, ERBB2 and CCND1, again no survival difference was observed to be associated with the presence of such genetic abnormalities.	('mutations', 'Var', (51, 60))	('FOXA1', 'Gene', '3169', (78, 83))	('CCND1', 'Gene', '595', (121, 126))	('TP53', 'Gene', '7157', (64, 68))	('ERBB2', 'Gene', (111, 116))	('FOXA1', 'Gene', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('CCND1', 'Gene', (121, 126))	('MYC', 'Gene', (106, 109))	('breast cancer', 'Disease', (16, 29))	('genetic abnormalities', 'Disease', 'MESH:D030342', (213, 234))	('genetic abnormalities', 'Disease', (213, 234))	('ERBB2', 'Gene', '2064', (111, 116))	('PIK3CA', 'Gene', '5290', (70, 76))	('MYC', 'Gene', '4609', (106, 109))	('TP53', 'Gene', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('PIK3CA', 'Gene', (70, 76))	('amplifications', 'Var', (88, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
44524	27811364	ERBB2 mutations were found in six of the 100 CDH1-altered ILC (Figure 3).	('ERBB2', 'Gene', '2064', (0, 5))	('CDH1', 'Gene', '999', (45, 49))	('ERBB2', 'Gene', (0, 5))	('ILC', 'Disease', (58, 61))	('mutations', 'Var', (6, 15))	('CDH1', 'Gene', (45, 49))
44525	27811364	The vast majority of these tumors (5/6) carried mutations in the tyrosine kinase domain of the ERBB2 protein.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ERBB2', 'Gene', '2064', (95, 100))	('tumors', 'Disease', (27, 33))	('ERBB2', 'Gene', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mutations in the', 'Var', (48, 64))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))
44527	27811364	Four of these mutations were known to be oncogenic and could be treated by Neratinib, a second-generation HER2/EGFR tyrosine kinase inhibitor.	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('HER2', 'Gene', (106, 110))	('HER2', 'Gene', '2064', (106, 110))	('Neratinib', 'Chemical', 'MESH:C487932', (75, 84))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('125', '141'))	('mutations', 'Var', (14, 23))
44528	27811364	Notably, one tumor carried three mutations, R678Q, L755W and L755M.	('tumor', 'Disease', (13, 18))	('R678Q', 'Mutation', 'rs1057519862', (44, 49))	('L755W', 'Mutation', 'rs121913470', (51, 56))	('L755M', 'Var', (61, 66))	('L755W', 'Var', (51, 56))	('R678Q', 'Var', (44, 49))	('L755M', 'Mutation', 'rs1057519890', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
44529	27811364	One rare mutation in the ERBB2 furin-like domain, S305C, was also identified, which was reported only once in the COSMIC database.	('ERBB2', 'Gene', (25, 30))	('S305C', 'Var', (50, 55))	('ERBB2', 'Gene', '2064', (25, 30))	('S305C', 'Mutation', 'p.S305C', (50, 55))
44533	27811364	However, according to recent genome sequencing studies, only 30-60% of the ILC tumors carry a CDH1 gene mutation or deletion (COSMIC data, 9-11).	('ILC tumors', 'Disease', (75, 85))	('CDH1', 'Gene', (94, 98))	('deletion', 'Var', (116, 124))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('CDH1', 'Gene', '999', (94, 98))	('mutation', 'Var', (104, 112))	('ILC tumors', 'Disease', 'MESH:D009369', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
44535	27811364	The causes could be an abnormal or lost CDH1 gene or protein expression as well as abnormalities of other components of the E-cadherin signaling pathway, such as alpha, beta, gamma and p120 catenins.	('abnormalities', 'Var', (83, 96))	('alpha', 'Protein', (162, 167))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('CDH1', 'Gene', (40, 44))	('p120', 'Gene', '1500', (185, 189))	('beta', 'Protein', (169, 173))	('signaling pathway', 'biological_process', 'GO:0007165', ('135', '152'))	('lost', 'NegReg', (35, 39))	('cadherin', 'molecular_function', 'GO:0008014', ('126', '134'))	('protein', 'Protein', (53, 60))	('CDH1', 'Gene', '999', (40, 44))	('gamma', 'Protein', (175, 180))	('p120', 'Gene', (185, 189))	('expression', 'MPA', (61, 71))
44536	27811364	In this study, we compared the clinical, pathological and genomic differences of ILC with and without a CDH1 alteration in 169 cases of ILC patients from TCGA.	('CDH1', 'Gene', (104, 108))	('alteration', 'Var', (109, 119))	('ILC', 'Disease', (81, 84))	('CDH1', 'Gene', '999', (104, 108))	('patients', 'Species', '9606', (140, 148))
44537	27811364	Surprisingly, no significant difference was identified in any of clinical or pathological features between the ILC with and without a CDH1 alteration.	('alteration', 'Var', (139, 149))	('CDH1', 'Gene', '999', (134, 138))	('CDH1', 'Gene', (134, 138))
44538	27811364	All the driver genomic abnormalities identified in IDC, including mutations in TP53 and PIK3CA genes and amplifications in MYC and ERBB2, are not associated with CDH1 alteration status.	('mutations', 'Var', (66, 75))	('PIK3CA', 'Gene', (88, 94))	('IDC', 'Disease', (51, 54))	('CDH1', 'Gene', (162, 166))	('TP53', 'Gene', (79, 83))	('TP53', 'Gene', '7157', (79, 83))	('PIK3CA', 'Gene', '5290', (88, 94))	('MYC', 'Gene', '4609', (123, 126))	('CDH1', 'Gene', '999', (162, 166))	('genomic abnormalities', 'Disease', (15, 36))	('genomic abnormalities', 'Disease', 'MESH:D042822', (15, 36))	('ERBB2', 'Gene', (131, 136))	('ERBB2', 'Gene', '2064', (131, 136))	('MYC', 'Gene', (123, 126))
44540	27811364	This view is also supported by a recent TCGA ILC study which revealed that up to 95% of TCGA ILC cases carry genetic changes in the CDH1 gene, including somatic mutations, copy-number losses, and alterations in mRNA and protein expression.	('copy-number losses', 'Var', (172, 190))	('TCGA ILC', 'Disease', (88, 96))	('CDH1', 'Gene', (132, 136))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('CDH1', 'Gene', '999', (132, 136))	('mutations', 'Var', (161, 170))	('genetic changes', 'Var', (109, 124))	('alterations', 'Reg', (196, 207))
44542	27811364	Interestingly, our study has shown that the most significant recurrent gene mutations that correlated with CDH1 mutational status occurred only in those ILC with a CDH1 alteration, and are absent in the ILC without a CDH1 alteration.	('mutations', 'Var', (76, 85))	('CDH1', 'Gene', (217, 221))	('CDH1', 'Gene', (107, 111))	('CDH1', 'Gene', '999', (217, 221))	('CDH1', 'Gene', '999', (164, 168))	('CDH1', 'Gene', '999', (107, 111))	('CDH1', 'Gene', (164, 168))	('alteration', 'Var', (169, 179))
44543	27811364	In contrast, the most recurrent significant CNVs that correlated with CDH1 mutational status were often identified in the ILC without a CDH1 alteration, but are rare in the ILC with a CDH1 alteration.	('CDH1', 'Gene', '999', (136, 140))	('CDH1', 'Gene', (184, 188))	('CDH1', 'Gene', (70, 74))	('CDH1', 'Gene', '999', (70, 74))	('CDH1', 'Gene', '999', (184, 188))	('mutational status', 'Var', (75, 92))	('CDH1', 'Gene', (136, 140))
44546	27811364	This study revealed two top tumor classes with distinct types of genomic aberrations at the first partition of the pan-cancer data analysis by hierarchical clustering, the mutation (M) class and the altered copy number (C) class.	('altered copy number', 'Var', (199, 218))	('tumor', 'Disease', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('mutation', 'Var', (172, 180))	('cancer', 'Disease', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
44547	27811364	In ILC, a CDH1 mutation was found to be clustered with a group of significant gene mutations and appears to be mutually exclusive to any significant CNV.	('mutations', 'Var', (83, 92))	('CDH1', 'Gene', (10, 14))	('mutation', 'Var', (15, 23))	('CDH1', 'Gene', '999', (10, 14))	('ILC', 'Disease', (3, 6))
44548	27811364	Our data suggests that although a CDH1 alteration is the diagnostic hallmark of ILC and is the genetic basis of the lobular phenotype of most ILC, a CDH1 alteration itself (and its associated genomic changes) may not be as important in determining the prognosis of this most common non-ductal variant of breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (304, 317))	('alteration', 'Var', (39, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (304, 317))	('ILC', 'Disease', (80, 83))	('alteration', 'Var', (154, 164))	('CDH1', 'Gene', (34, 38))	('CDH1', 'Gene', '999', (34, 38))	('CDH1', 'Gene', (149, 153))	('non-ductal variant', 'Disease', (282, 300))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('CDH1', 'Gene', '999', (149, 153))	('breast cancer', 'Disease', (304, 317))
44551	27811364	A PTEN mutation and a FOXA1 mutation were recently found to be associated with activation of the AKT pathway and increased ER activity, respectively, in ILC.	('AKT', 'Gene', '207', (97, 100))	('FOXA1', 'Gene', '3169', (22, 27))	('ILC', 'Disease', (153, 156))	('AKT', 'Gene', (97, 100))	('mutation', 'Var', (28, 36))	('PTEN', 'Gene', (2, 6))	('mutation', 'Var', (7, 15))	('increased', 'PosReg', (113, 122))	('activation', 'PosReg', (79, 89))	('FOXA1', 'Gene', (22, 27))	('ER', 'Gene', '2099', (123, 125))
44552	27811364	have also showed that disruption of PTEN in the mouse mammary gland lacking E-cadherin expression using CRISPR/Cas9 gene editing lead to efficient development of ILC in the mouse model.	('Cas', 'cellular_component', 'GO:0005650', ('111', '114'))	('lead to', 'Reg', (129, 136))	('mouse', 'Species', '10090', (48, 53))	('disruption', 'Var', (22, 32))	('PTEN', 'Gene', (36, 40))	('cadherin', 'molecular_function', 'GO:0008014', ('78', '86'))	('development', 'CPA', (147, 158))	('mouse', 'Species', '10090', (173, 178))	('mammary gland lacking', 'Phenotype', 'HP:0100783', (54, 75))
44553	27811364	In TCGA ILC cohort, PTEN mutation occurs more frequently in CDH1-altered ILC (6 of 100 or 6% vs 0/69, respectively, p < 0.05).	('ILC', 'Disease', (73, 76))	('mutation', 'Var', (25, 33))	('CDH1', 'Gene', (60, 64))	('CDH1', 'Gene', '999', (60, 64))	('PTEN', 'Gene', (20, 24))
44555	27811364	ERBB2 amplification is a known oncologic driver in breast cancer, however, the role of ERBB2 mutation is not well defined.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB2', 'Gene', (0, 5))	('ERBB2', 'Gene', (87, 92))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('ERBB2', 'Gene', '2064', (87, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('amplification', 'Var', (6, 19))	('breast cancer', 'Disease', (51, 64))
44556	27811364	While no synergistic effect is observed between CDH1 mutation and ERBB2 amplification, the CDH1-altered ILC with an ERBB2 mutation shows a significantly worse prognosis compared to its CDH1-unaltered counterparts.	('CDH1', 'Gene', '999', (91, 95))	('CDH1', 'Gene', (185, 189))	('ERBB2', 'Gene', '2064', (116, 121))	('CDH1', 'Gene', (48, 52))	('ERBB2', 'Gene', (116, 121))	('mutation', 'Var', (122, 130))	('CDH1', 'Gene', '999', (185, 189))	('CDH1', 'Gene', '999', (48, 52))	('ERBB2', 'Gene', '2064', (66, 71))	('ERBB2', 'Gene', (66, 71))	('CDH1', 'Gene', (91, 95))
44557	27811364	Our observation is in line with a recent genomic study which showed that the relapsed classic E-cadherin mutated ILC had a high frequency of ERBB2 gene mutation (4/22, 18%).	('ILC', 'Disease', (113, 116))	('mutated', 'Var', (105, 112))	('ERBB2', 'Gene', '2064', (141, 146))	('cadherin', 'molecular_function', 'GO:0008014', ('96', '104'))	('mutation', 'Var', (152, 160))	('ERBB2', 'Gene', (141, 146))
44558	27811364	CDH1 mutations were also found enriched in ERBB2 mutated metastatic breast cancer and associated with its recurrence.	('mutated', 'Var', (49, 56))	('ERBB2', 'Gene', '2064', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('ERBB2', 'Gene', (43, 48))	('CDH1', 'Gene', '999', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('associated', 'Reg', (86, 96))	('breast cancer', 'Disease', (68, 81))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CDH1', 'Gene', (0, 4))
44559	27811364	Significantly, our finding has been further validated using the data from another large cohort of ILC sequencing study, in which 18 ERBB2 mutations were found in 270 cases of ILC with a CDH1 alteration while only three ERBB2 mutations were present in their CDH1-unaltered counterparts.	('CDH1', 'Gene', (257, 261))	('ERBB2', 'Gene', (132, 137))	('CDH1', 'Gene', '999', (257, 261))	('alteration', 'Var', (191, 201))	('found', 'Reg', (153, 158))	('ERBB2', 'Gene', (219, 224))	('CDH1', 'Gene', (186, 190))	('ERBB2', 'Gene', '2064', (219, 224))	('ILC', 'Disease', (175, 178))	('CDH1', 'Gene', '999', (186, 190))	('ERBB2', 'Gene', '2064', (132, 137))	('mutations', 'Var', (138, 147))
44560	27811364	Interestingly, in this study, a survival analysis shows that the CDH1-mutated ILC patients with an ERBB2 mutation had a worse 5-year survival (p < 0.05), but a similar 10 years survival as compared to their counterparts without an ERBB2 mutation (p > 0.05, data not shown).	('mutation', 'Var', (105, 113))	('CDH1', 'Gene', (65, 69))	('ERBB2', 'Gene', (99, 104))	('patients', 'Species', '9606', (82, 90))	('ERBB2', 'Gene', '2064', (99, 104))	('CDH1', 'Gene', '999', (65, 69))	('ILC', 'Disease', (78, 81))	('ERBB2', 'Gene', '2064', (231, 236))	('worse', 'NegReg', (120, 125))	('ERBB2', 'Gene', (231, 236))
44561	27811364	While the causes of this controversy could be multifactorial, including limited cases studied and heterogeneity in tumor genetics and patient treatment, our finding is clinically significant since most ERBB2 mutations are known to be oncogenic and were identified in a significantly high percentage of recurrent ILC patients.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('mutations', 'Var', (208, 217))	('ILC', 'Disease', (312, 315))	('ERBB2', 'Gene', '2064', (202, 207))	('patient', 'Species', '9606', (316, 323))	('ERBB2', 'Gene', (202, 207))	('patient', 'Species', '9606', (134, 141))	('patients', 'Species', '9606', (316, 324))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
44562	27811364	Importantly, cancers with ERBB2 mutations could be treated by Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, which is currently in late-phase clinical development.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('ERBB2', 'Gene', (26, 31))	('Neratinib', 'Chemical', 'MESH:C487932', (62, 71))	('ERBB2', 'Gene', '2064', (26, 31))	('ER', 'Gene', '2099', (94, 96))	('mutations', 'Var', (32, 41))	('cancers', 'Disease', (13, 20))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('ER', 'Gene', '2099', (26, 28))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('106', '122'))
44563	27811364	Therefore, ERBB2 mutation is an actionable genetic abnormality and identification of ERBB2 mutation in CDH1-altered ILC patients may be an important step towards targeted therapy of this group of ILC patients.	('mutation', 'Var', (91, 99))	('CDH1', 'Gene', (103, 107))	('patients', 'Species', '9606', (200, 208))	('ERBB2', 'Gene', (85, 90))	('genetic abnormality', 'Disease', (43, 62))	('ERBB2', 'Gene', '2064', (85, 90))	('genetic abnormality', 'Disease', 'MESH:D030342', (43, 62))	('CDH1', 'Gene', '999', (103, 107))	('ERBB2', 'Gene', (11, 16))	('ILC', 'Disease', (116, 119))	('patients', 'Species', '9606', (120, 128))	('ERBB2', 'Gene', '2064', (11, 16))
44565	27811364	Furthermore, ILC patients with tumors carrying both CDH1 and ERBB2 mutations have a worse prognosis, but represent an actionable group who may benefit from targeted breast cancer therapy.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('ERBB2', 'Gene', (61, 66))	('breast cancer', 'Disease', (165, 178))	('ERBB2', 'Gene', '2064', (61, 66))	('CDH1', 'Gene', (52, 56))	('tumors', 'Disease', (31, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('CDH1', 'Gene', '999', (52, 56))	('mutations', 'Var', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('ILC', 'Disease', (13, 16))	('patients', 'Species', '9606', (17, 25))
44567	27811364	This data set, as of July 1, 2016, contains the genomic sequencing data encompassing gene mutations, copy number alterations (CNA), mRNA and protein expression as well as clinical and pathological data including patient survival, pathology reports and digitized tumor slides from 1105 samples from 1098 patients with invasive breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (326, 339))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('mutations', 'Var', (90, 99))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('invasive breast cancer', 'Disease', (317, 339))	('tumor', 'Disease', (262, 267))	('patient', 'Species', '9606', (212, 219))	('copy number alterations', 'Var', (101, 124))	('mRNA and', 'MPA', (132, 140))	('patient', 'Species', '9606', (303, 310))	('invasive breast cancer', 'Disease', 'MESH:D001943', (317, 339))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('patients', 'Species', '9606', (303, 311))
44569	32852708	Impact of fibroblast growth factor receptor 1 (FGFR1) amplification on the prognosis of breast cancer patients Various aberrations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3 are found in different cancers, including breast cancer (BC).	('cancers', 'Disease', (225, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('10', '34'))	('aberrations', 'Var', (119, 130))	('FGFR2', 'Gene', (185, 190))	('FGFR1', 'Gene', (47, 52))	('breast cancer', 'Disease', 'MESH:D001943', (244, 257))	('breast cancer', 'Disease', (244, 257))	('FGFR3', 'Gene', (196, 201))	('FGFR1', 'Gene', '2260', (178, 183))	('FGFR', 'molecular_function', 'GO:0005007', ('196', '200'))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('FGFR2', 'Gene', '2263', (185, 190))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('FGFR3', 'Gene', '2261', (196, 201))	('BC', 'Phenotype', 'HP:0003002', (259, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('178', '182'))	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGFR', 'molecular_function', 'GO:0005007', ('185', '189'))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('fibroblast growth factor receptor 1', 'Gene', '2260', (10, 45))	('FGFR1', 'Gene', (178, 183))	('FGFR1', 'Gene', '2260', (47, 52))	('fibroblast growth factor receptor 1', 'Gene', (10, 45))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('138', '162'))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
44574	32852708	Increased FGFR2 copy numbers were seen in 0.9% (n = 4); only one patient had FGFR3 amplification (0.2%).	('FGFR3', 'Gene', (77, 82))	('FGFR2', 'Gene', '2263', (10, 15))	('FGFR', 'molecular_function', 'GO:0005007', ('77', '81'))	('FGFR', 'molecular_function', 'GO:0005007', ('10', '14'))	('patient', 'Species', '9606', (65, 72))	('FGFR3', 'Gene', '2261', (77, 82))	('FGFR2', 'Gene', (10, 15))	('copy numbers', 'Var', (16, 28))
44575	32852708	Most patients with FGFR1 amplification had luminal B-like tumors (69.7%, n = 23); only 32.6% (n = 153) of patients without FGFR1 amplification had luminal B-like BC.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('luminal', 'Chemical', 'MESH:D010634', (147, 154))	('patients', 'Species', '9606', (5, 13))	('tumors', 'Disease', (58, 64))	('FGFR1', 'Gene', '2260', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))	('FGFR1', 'Gene', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('patients', 'Species', '9606', (106, 114))	('FGFR1', 'Gene', '2260', (123, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('luminal', 'Chemical', 'MESH:D010634', (43, 50))	('amplification', 'Var', (25, 38))	('BC', 'Phenotype', 'HP:0003002', (162, 164))	('FGFR1', 'Gene', (19, 24))
44577	32852708	Observed outcome differences between BC patients with and without FGFR1 amplification did not achieve statistical significance; however, there was a trend toward poorer distant metastasis-free survival in BC patients with FGFR1 amplification (HR = 2.08; 95% CI 0.98 to 4.39, P = 0.05).	('BC', 'Phenotype', 'HP:0003002', (205, 207))	('patients', 'Species', '9606', (208, 216))	('FGFR1', 'Gene', (222, 227))	('FGFR1', 'Gene', '2260', (222, 227))	('amplification', 'Var', (228, 241))	('patients', 'Species', '9606', (40, 48))	('FGFR1', 'Gene', (66, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('poorer', 'NegReg', (162, 168))	('FGFR1', 'Gene', '2260', (66, 71))	('distant metastasis-free survival', 'CPA', (169, 201))	('FGFR', 'molecular_function', 'GO:0005007', ('222', '226'))	('BC', 'Phenotype', 'HP:0003002', (37, 39))
44578	32852708	FGFR1 amplification occurs most frequently in patients with luminal B-like BC.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('patients', 'Species', '9606', (46, 54))	('BC', 'Phenotype', 'HP:0003002', (75, 77))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('luminal', 'Chemical', 'MESH:D010634', (60, 67))	('amplification', 'Var', (6, 19))	('luminal B-like BC', 'Disease', (60, 77))
44579	32852708	Further research is therefore needed to address the role of FGFR1 amplifications in early BC patients.	('FGFR1', 'Gene', (60, 65))	('FGFR1', 'Gene', '2260', (60, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('amplifications', 'Var', (66, 80))	('early BC', 'Disease', (84, 92))	('BC', 'Phenotype', 'HP:0003002', (90, 92))	('patients', 'Species', '9606', (93, 101))
44580	32852708	FGFR2 and FGFR3 amplifications are rare in patients with primary BC.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR3', 'Gene', '2261', (10, 15))	('patients', 'Species', '9606', (43, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('10', '14'))	('FGFR3', 'Gene', (10, 15))	('BC', 'Phenotype', 'HP:0003002', (65, 67))	('primary BC', 'Disease', (57, 67))	('FGFR2', 'Gene', (0, 5))	('amplifications', 'Var', (16, 30))	('FGFR2', 'Gene', '2263', (0, 5))
44585	32852708	In the era of personalized medicine, more and more genetic aberrations in potentially targetable oncogenic driver genes, such as copy number variations of CCND1 and PIK3CA mutations, are now being investigated.	('PIK3CA', 'Gene', (165, 171))	('CCND1', 'Gene', '595', (155, 160))	('copy number variations', 'Var', (129, 151))	('PIK3CA', 'Gene', '5290', (165, 171))	('CCND1', 'Gene', (155, 160))
44589	32852708	Amplification of FGFR1 is found in several types of cancer (e.g., nonsmall cell lung carcinoma, head and neck tumors, breast cancer, ovarian cancer, bladder cancer, and rhabdomyosarcoma), with a frequency of up to 10% in breast cancer.	('neck tumors', 'Disease', 'MESH:D006258', (105, 116))	('FGFR1', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian cancer', 'Disease', (133, 147))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('breast cancer', 'Disease', (221, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (169, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (169, 185))	('found', 'Reg', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('head and neck tumors', 'Phenotype', 'HP:0012288', (96, 116))	('cancer', 'Disease', (125, 131))	('breast cancer', 'Disease', (118, 131))	('cancer', 'Disease', (141, 147))	('bladder cancer', 'Disease', 'MESH:D001749', (149, 163))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('cancer', 'Disease', (228, 234))	('bladder cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('nonsmall cell lung carcinoma', 'Disease', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cancer', 'Disease', (157, 163))	('FGFR1', 'Gene', '2260', (17, 22))	('neck tumors', 'Disease', (105, 116))	('cancer', 'Disease', (52, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (149, 163))	('neck', 'cellular_component', 'GO:0044326', ('105', '109'))	('nonsmall cell lung carcinoma', 'Disease', 'MESH:D002289', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (133, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rhabdomyosarcoma', 'Disease', (169, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
44590	32852708	Chromosomal aberration has been found to be associated with FGFR1 overexpression, luminal B subtype (16-27%), negative PR expression, and high Ki-67 protein expression.	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('PR', 'Gene', '5241', (119, 121))	('Chromosomal aberration', 'Phenotype', 'HP:0040012', (0, 22))	('FGFR1', 'Gene', (60, 65))	('FGFR1', 'Gene', '2260', (60, 65))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('Chromosomal aberration', 'Var', (0, 22))	('luminal B subtype', 'Disease', (82, 99))	('negative', 'NegReg', (110, 118))	('luminal', 'Chemical', 'MESH:D010634', (82, 89))	('overexpression', 'PosReg', (66, 80))	('high', 'Var', (138, 142))
44591	32852708	In addition, breast cancer cell lines with FGFR1 amplification harbor endocrine resistance that can be reversed by RNA silencing, and FGFR1-amplified breast cancers have been reported to be associated with a poorer prognosis.	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('harbor', 'Reg', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('FGFR1', 'Gene', (134, 139))	('FGFR1', 'Gene', '2260', (43, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Disease', (13, 26))	('endocrine resistance', 'MPA', (70, 90))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('amplification', 'Var', (49, 62))	('breast cancers', 'Disease', 'MESH:D001943', (150, 164))	('FGFR1', 'Gene', (43, 48))	('breast cancers', 'Disease', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('FGFR1', 'Gene', '2260', (134, 139))	('breast cancers', 'Phenotype', 'HP:0003002', (150, 164))
44593	32852708	Single-nucleotide polymorphisms (SNPs) in FGFR2 locus 10q26 have been reported to have the strongest association with breast cancer risk in genome-wide association studies.	('FGFR2', 'Gene', (42, 47))	('FGFR2', 'Gene', '2263', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('association', 'Interaction', (101, 112))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
44596	32852708	The authors also carried out an analysis of the METABRIC (Molecular Taxonomy of Breast Cancer) dataset and found a 1.8% rate of FGFR2 amplification in breast cancer, associated with a poorer prognosis and resistance to endocrine therapy.	('METABRIC', 'Gene', (48, 56))	('Breast Cancer', 'Disease', 'MESH:D001943', (80, 93))	('Breast Cancer', 'Phenotype', 'HP:0003002', (80, 93))	('FGFR2', 'Gene', (128, 133))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('amplification', 'Var', (134, 147))	('METABRIC', 'Gene', '5205', (48, 56))	('breast cancer', 'Disease', (151, 164))	('FGFR2', 'Gene', '2263', (128, 133))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('Breast Cancer', 'Disease', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))
44598	32852708	Since fibroblast growth factor receptor (FGFR) alterations are found in a variety of cancers, several FGFR inhibitors:both pan-FGFR and also selective FGFR inhibitors:have been developed and tested in clinical trials.	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('6', '30'))	('alterations', 'Var', (47, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('FGFR', 'molecular_function', 'GO:0005007', ('151', '155'))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('FGFR', 'Gene', (41, 45))	('cancers', 'Disease', (85, 92))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('found', 'Reg', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
44600	32852708	However, assuming that there is an association between FGFR1 amplification and prognostically unfavorable luminal B breast cancer, it may be hypothesized that FGFR inhibitors may improve the prognosis, particularly in patients who are suffering from highly proliferative, hormone receptor-positive breast cancer with FGFR1 amplification.	('FGFR1', 'Gene', '2260', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('hormone receptor', 'Gene', (272, 288))	('amplification', 'Var', (61, 74))	('FGFR1', 'Gene', (317, 322))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('317', '321'))	('FGFR1', 'Gene', (55, 60))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('luminal', 'Chemical', 'MESH:D010634', (106, 113))	('breast cancer', 'Disease', (116, 129))	('patients', 'Species', '9606', (218, 226))	('hormone receptor', 'Gene', '3164', (272, 288))	('improve', 'PosReg', (179, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (298, 311))	('association', 'Interaction', (35, 46))	('FGFR1', 'Gene', '2260', (317, 322))	('breast cancer', 'Disease', 'MESH:D001943', (298, 311))	('breast cancer', 'Disease', (298, 311))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('amplification', 'Var', (323, 336))
44627	32852708	In this final cohort, amplification of the FGFR1 gene was observed in 6.6% (33 of 503).	('amplification', 'Var', (22, 35))	('FGFR1', 'Gene', (43, 48))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR1', 'Gene', '2260', (43, 48))
44628	32852708	1, one breast cancer case with FGFR1 amplification as well as one tumor without amplification but normal FGFR1 gene status are illustrated.	('one breast', 'Phenotype', 'HP:0012813', (3, 13))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('FGFR1', 'Gene', (105, 110))	('tumor', 'Disease', (66, 71))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('amplification', 'Var', (37, 50))	('FGFR1', 'Gene', '2260', (105, 110))	('breast cancer', 'Disease', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('FGFR1', 'Gene', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('FGFR1', 'Gene', '2260', (31, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
44633	32852708	Most breast cancer patients with FGFR1 amplification showed moderate differentiation (G2, 69.7%) and a luminal subtype with positive hormone receptor status and predominantly HER2- negative status (ER+, 90.9%; PR+, 78.8%; HER2+, 9.1%).	('ER', 'Gene', '2099', (223, 225))	('HER2', 'Gene', '2064', (175, 179))	('FGFR', 'molecular_function', 'GO:0005007', ('33', '37'))	('breast cancer', 'Phenotype', 'HP:0003002', (5, 18))	('HER2', 'Gene', '2064', (222, 226))	('breast cancer', 'Disease', 'MESH:D001943', (5, 18))	('hormone receptor', 'Gene', (133, 149))	('ER', 'Gene', '2099', (198, 200))	('breast cancer', 'Disease', (5, 18))	('patients', 'Species', '9606', (19, 27))	('FGFR1', 'Gene', '2260', (33, 38))	('HER2', 'Gene', (175, 179))	('PR', 'Gene', '5241', (210, 212))	('ER', 'Gene', '2099', (176, 178))	('amplification', 'Var', (39, 52))	('luminal', 'Chemical', 'MESH:D010634', (103, 110))	('HER2', 'Gene', (222, 226))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('hormone receptor', 'Gene', '3164', (133, 149))	('FGFR1', 'Gene', (33, 38))
44635	32852708	Patients with breast cancer who had normal FGFR1 copy numbers showed lower expression rate measurements (IHC) for the estrogen receptor (median, 70%; IQR, 10% to 80%) than patients with FGFR1 amplification (median, 80%; IQR, 60% to 90%; Fig.	('FGFR1', 'Gene', '2260', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('FGFR1', 'Gene', (43, 48))	('FGFR1', 'Gene', '2260', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('lower', 'NegReg', (69, 74))	('Patients', 'Species', '9606', (0, 8))	('expression rate measurements', 'MPA', (75, 103))	('breast cancer', 'Disease', (14, 27))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('estrogen receptor', 'Gene', (118, 135))	('patients', 'Species', '9606', (172, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('copy numbers', 'Var', (49, 61))	('estrogen receptor', 'Gene', '2099', (118, 135))	('FGFR', 'molecular_function', 'GO:0005007', ('186', '190'))	('FGFR1', 'Gene', (186, 191))
44639	32852708	The median follow-up period for the primary study aim of DFS was 10.0 years for patients both with and without FGFR1 amplification.	('FGFR1', 'Gene', '2260', (111, 116))	('patients', 'Species', '9606', (80, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('FGFR1', 'Gene', (111, 116))	('amplification', 'Var', (117, 130))
44640	32852708	No significant differences were observed between breast cancer patients with and without FGFR1 amplification in relation to DFS.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('FGFR1', 'Gene', (89, 94))	('FGFR1', 'Gene', '2260', (89, 94))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('amplification', 'Var', (95, 108))	('breast cancer', 'Disease', (49, 62))	('patients', 'Species', '9606', (63, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
44641	32852708	Breast cancer patients with FGFR1 amplification had a poorer DMFS than patients without amplification (P = 0.04, unadjusted analysis); however, this difference in DMFS outcome did not achieve significance in the adjusted analysis (P = 0.05).	('poorer', 'NegReg', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('DMFS', 'Disease', (61, 65))	('DMFS', 'Disease', 'None', (61, 65))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('patients', 'Species', '9606', (71, 79))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR1', 'Gene', (28, 33))	('DMFS', 'Disease', (163, 167))	('DMFS', 'Disease', 'None', (163, 167))	('FGFR1', 'Gene', '2260', (28, 33))	('amplification', 'Var', (34, 47))	('Breast cancer', 'Disease', (0, 13))	('patients', 'Species', '9606', (14, 22))
44642	32852708	No significant impact of FGFR1 amplification on the other secondary outcomes, OS and LRFS, was observed.	('FGFR', 'molecular_function', 'GO:0005007', ('25', '29'))	('RFS', 'Disease', (86, 89))	('FGFR1', 'Gene', (25, 30))	('RFS', 'Disease', 'MESH:D005198', (86, 89))	('FGFR1', 'Gene', '2260', (25, 30))	('amplification', 'Var', (31, 44))
44647	32852708	In view of the very small numbers of FGFR2-amplified and FGFR3-amplified cases, the analyses were on outcomes in patients with FGFR1 amplification.	('FGFR3', 'Gene', (57, 62))	('patients', 'Species', '9606', (113, 121))	('FGFR2', 'Gene', (37, 42))	('amplification', 'Var', (133, 146))	('FGFR1', 'Gene', (127, 132))	('FGFR1', 'Gene', '2260', (127, 132))	('FGFR', 'molecular_function', 'GO:0005007', ('127', '131'))	('FGFR3', 'Gene', '2261', (57, 62))	('FGFR2', 'Gene', '2263', (37, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('37', '41'))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))
44648	32852708	Amplification of FGFR1 was seen in 6.6% of assessable BC cases.	('Amplification', 'Var', (0, 13))	('BC', 'Phenotype', 'HP:0003002', (54, 56))	('FGFR1', 'Gene', (17, 22))	('FGFR1', 'Gene', '2260', (17, 22))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))
44650	32852708	The fact that the frequency of FGFR1 amplification in the present study was lower might be due to different methods of evaluating gene status (e.g., multiplex ligation-dependent probe amplification), a different composition of the cohort (e.g., varying distribution of intrinsic subtypes), and the fact that the FGFR1 gene was not always included in the amplification unit in the earlier studies.	('FGFR1', 'Gene', (312, 317))	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('FGFR1', 'Gene', '2260', (312, 317))	('FGFR', 'molecular_function', 'GO:0005007', ('312', '316'))	('amplification', 'Var', (37, 50))	('lower', 'NegReg', (76, 81))	('FGFR1', 'Gene', (31, 36))	('FGFR1', 'Gene', '2260', (31, 36))
44652	32852708	In this study, BC patients with FGFR1 amplification showed a trend toward poorer outcomes, especially DMFS and LRFS.	('DMFS', 'Disease', (102, 106))	('DMFS', 'Disease', 'None', (102, 106))	('FGFR1', 'Gene', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('RFS', 'Disease', (112, 115))	('BC', 'Phenotype', 'HP:0003002', (15, 17))	('RFS', 'Disease', 'MESH:D005198', (112, 115))	('FGFR1', 'Gene', '2260', (32, 37))	('patients', 'Species', '9606', (18, 26))	('amplification', 'Var', (38, 51))
44653	32852708	FGFR1 amplification was not an independent predictor of shorter DFS or OS.	('amplification', 'Var', (6, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))
44654	32852708	Thus, the study does not fully confirm the findings of an earlier report that FGFR1-amplified BC was associated with poorer OS in the overall cohort and that FGFR1 amplification was predictive of poor DFS, OS, and DMFS in ER-positive patients with BC.	('FGFR1', 'Gene', (78, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('FGFR1', 'Gene', '2260', (78, 83))	('poorer', 'NegReg', (117, 123))	('FGFR1', 'Gene', (158, 163))	('FGFR', 'molecular_function', 'GO:0005007', ('158', '162'))	('DFS', 'Disease', (201, 204))	('FGFR1', 'Gene', '2260', (158, 163))	('ER', 'Gene', '2099', (222, 224))	('patients', 'Species', '9606', (234, 242))	('amplification', 'Var', (164, 177))	('BC', 'Phenotype', 'HP:0003002', (248, 250))	('BC', 'Phenotype', 'HP:0003002', (94, 96))	('DMFS', 'Disease', (214, 218))	('DMFS', 'Disease', 'None', (214, 218))
44656	32852708	Intriguingly, co-amplification of FGFR1 and the cyclin D1 gene (CCND1) showed even poorer DFS than increased FGFR1 copy numbers without CCND1 amplification.	('cyclin D1', 'Gene', (48, 57))	('FGFR1', 'Gene', (109, 114))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('FGFR1', 'Gene', (34, 39))	('poorer', 'NegReg', (83, 89))	('FGFR1', 'Gene', '2260', (109, 114))	('increased FGFR1', 'Phenotype', 'HP:0030269', (99, 114))	('cyclin', 'molecular_function', 'GO:0016538', ('48', '54'))	('CCND1', 'Gene', (136, 141))	('CCND1', 'Gene', (64, 69))	('DFS', 'MPA', (90, 93))	('FGFR1', 'Gene', '2260', (34, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('co-amplification', 'Var', (14, 30))	('cyclin D1', 'Gene', '595', (48, 57))	('CCND1', 'Gene', '595', (136, 141))	('CCND1', 'Gene', '595', (64, 69))
44658	32852708	In another study, FGFR1 amplification was not associated with relapse-free survival (RFS) or BC-specific survival.	('BC', 'Phenotype', 'HP:0003002', (93, 95))	('RFS', 'Disease', (85, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('18', '22'))	('RFS', 'Disease', 'MESH:D005198', (85, 88))	('FGFR1', 'Gene', (18, 23))	('amplification', 'Var', (24, 37))	('associated', 'Reg', (46, 56))	('FGFR1', 'Gene', '2260', (18, 23))	('relapse-free survival', 'Disease', (62, 83))
44661	32852708	Estrogen receptor-positive BC and luminal B BC have been reported to show the highest frequency of FGFR1 amplifications.	('amplifications', 'Var', (105, 119))	('Estrogen receptor', 'Gene', '2099', (0, 17))	('luminal', 'Chemical', 'MESH:D010634', (34, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('BC', 'Phenotype', 'HP:0003002', (44, 46))	('FGFR1', 'Gene', (99, 104))	('Estrogen receptor', 'Gene', (0, 17))	('FGFR1', 'Gene', '2260', (99, 104))	('BC', 'Phenotype', 'HP:0003002', (27, 29))	('luminal B BC', 'Disease', (34, 46))
44663	32852708	Interestingly, luminal A BC that expressed high levels of FGFR1 has been found to behave more aggressively, with a prognosis similar to that in luminal B tumors.	('high levels', 'Var', (43, 54))	('luminal', 'Chemical', 'MESH:D010634', (144, 151))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('58', '62'))	('BC', 'Phenotype', 'HP:0003002', (25, 27))	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', '2260', (58, 63))	('luminal', 'Chemical', 'MESH:D010634', (15, 22))	('luminal B tumors', 'Disease', (144, 160))	('luminal B tumors', 'Disease', 'MESH:D006509', (144, 160))
44665	32852708	The present study showed that 69.7% of BCs with FGFR1 amplification harbored a luminal B phenotype, whereas the other intrinsic subtypes were only found at lower frequencies, up to 15.2%.	('harbored', 'Reg', (68, 76))	('amplification', 'Var', (54, 67))	('luminal', 'Chemical', 'MESH:D010634', (79, 86))	('FGFR1', 'Gene', (48, 53))	('FGFR1', 'Gene', '2260', (48, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('luminal B phenotype', 'MPA', (79, 98))	('BC', 'Phenotype', 'HP:0003002', (39, 41))
44667	32852708	Inhibition of FGFR1 has been regarded as a potential therapeutic target.	('Inhibition', 'Var', (0, 10))	('FGFR1', 'Gene', '2260', (14, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('FGFR1', 'Gene', (14, 19))
44669	32852708	Multikinase inhibitors (TKIs), such as lucitanib (E-3810, NCT01283945), dovitinib (TKI258), nintedanib, and ponatinib, and selective FGFR inhibitors, such as AZD4547 (NCT00979134, NCT01202591), BGJ398 (NCT01004224), LY2874455 (NCT01212107), and JNJ-42756493 (NCT01703481), have been tested in several phase I and II trials in cancers with FGFR1 aberrations.	('FGFR', 'molecular_function', 'GO:0005007', ('339', '343'))	('NCT01004224', 'Var', (202, 213))	('NCT00979134', 'Var', (167, 178))	('aberrations', 'Var', (345, 356))	('cancers', 'Disease', 'MESH:D009369', (326, 333))	('cancers', 'Phenotype', 'HP:0002664', (326, 333))	('LY2874455', 'Var', (216, 225))	('FGFR1', 'Gene', (339, 344))	('cancers', 'Disease', (326, 333))	('FGFR1', 'Gene', '2260', (339, 344))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('dovitinib', 'Chemical', 'MESH:C500007', (72, 81))	('ponatinib', 'Chemical', 'MESH:C545373', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
44671	32852708	Administration of multi-TKIs was accompanied by asthenia, gastrointestinal symptoms, hypertension, and lymphopenia, whereas selective FGFR inhibitors led to hyperphosphatemia, gastrointestinal symptoms, nail toxicity, and stomatitis.	('hypertension', 'Disease', 'MESH:D006973', (85, 97))	('lymphopenia', 'Phenotype', 'HP:0001888', (103, 114))	('hypertension', 'Disease', (85, 97))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (58, 83))	('asthenia', 'Disease', 'MESH:D001247', (48, 56))	('toxicity', 'Disease', (208, 216))	('asthenia', 'Phenotype', 'HP:0025406', (48, 56))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (176, 201))	('stomatitis', 'Phenotype', 'HP:0010280', (222, 232))	('hyperphosphatemia', 'Disease', (157, 174))	('stomatitis', 'Disease', (222, 232))	('FGFR', 'Gene', (134, 138))	('lymphopenia', 'Disease', 'MESH:D008231', (103, 114))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (157, 174))	('hypertension', 'Phenotype', 'HP:0000822', (85, 97))	('led to', 'Reg', (150, 156))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))	('gastrointestinal symptoms', 'Disease', (58, 83))	('gastrointestinal symptoms', 'Disease', (176, 201))	('asthenia', 'Disease', (48, 56))	('multi-TKIs', 'Var', (18, 28))	('stomatitis', 'Disease', 'MESH:D013280', (222, 232))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (157, 174))	('toxicity', 'Disease', 'MESH:D064420', (208, 216))	('lymphopenia', 'Disease', (103, 114))
44672	32852708	Amplification of FGFR1 was seen in up to 43% of patients with invasive lobular cancer (ILC) of the breast, and it was associated with expression.	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('invasive lobular cancer', 'Disease', (62, 85))	('FGFR1', 'Gene', (17, 22))	('lobular cancer', 'Phenotype', 'HP:0030076', (71, 85))	('invasive lobular cancer', 'Disease', 'MESH:D013274', (62, 85))	('FGFR1', 'Gene', '2260', (17, 22))	('associated', 'Reg', (118, 128))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('patients', 'Species', '9606', (48, 56))
44673	32852708	FGFR1 inhibition has been found to reduce the viability of the BC cell line MDA-MB-134, which has similarities to ILC in relation to some copy number variations (including FGFR1) and protein expression.	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', (172, 177))	('viability', 'CPA', (46, 55))	('inhibition', 'Var', (6, 16))	('BC', 'Phenotype', 'HP:0003002', (63, 65))	('reduce', 'NegReg', (35, 41))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (76, 86))	('FGFR1', 'Gene', '2260', (172, 177))	('FGFR', 'molecular_function', 'GO:0005007', ('172', '176'))
44677	32852708	ODM-203 acts as a selective dual blockade of FGFR and VEGFR, but may cause hyperphosphatemia and bilirubinemia.	('bilirubinemia', 'Disease', (97, 110))	('bilirubinemia', 'Disease', 'MESH:D006932', (97, 110))	('ODM-203', 'Var', (0, 7))	('VEGFR', 'Gene', (54, 59))	('hyperphosphatemia', 'Phenotype', 'HP:0002905', (75, 92))	('hyperphosphatemia', 'Disease', 'MESH:D054559', (75, 92))	('cause', 'Reg', (69, 74))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('VEGFR', 'Gene', '3791', (54, 59))	('hyperphosphatemia', 'Disease', (75, 92))
44681	32852708	FGFR1 amplification is associated with increased expression.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('expression', 'MPA', (49, 59))	('increased', 'PosReg', (39, 48))	('amplification', 'Var', (6, 19))
44682	32852708	However, it needs to be borne in mind that increased copy numbers may not always predict high levels of FGFR1 protein expression, so that inhibition might fail if treatment were to be selected on the basis of FGFR1 amplification.	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('copy numbers', 'Var', (53, 65))	('FGFR1', 'Gene', (209, 214))	('FGFR1', 'Gene', '2260', (209, 214))	('FGFR', 'molecular_function', 'GO:0005007', ('104', '108'))	('FGFR', 'molecular_function', 'GO:0005007', ('209', '213'))	('FGFR1', 'Gene', (104, 109))	('FGFR1', 'Gene', '2260', (104, 109))
44684	32852708	One limitation of our study is that, up to date, we did not analyze the association between FGFR1 amplification and protein expression of FGFR1.	('FGFR1', 'Gene', (92, 97))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('FGFR1', 'Gene', '2260', (92, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGFR1', 'Gene', (138, 143))	('amplification', 'Var', (98, 111))	('FGFR1', 'Gene', '2260', (138, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('138', '142'))
44685	32852708	Further investigations have to show whether the copy number gain of the gene lead to increased expression of this growth factor receptor in our breast cancer cohort and whether FGFR1 overexpression might predict prognosis.	('copy number gain', 'Var', (48, 64))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('FGFR1', 'Gene', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('FGFR1', 'Gene', '2260', (177, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('predict', 'Reg', (204, 211))	('increased', 'PosReg', (85, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('177', '181'))	('expression', 'MPA', (95, 105))
44689	32852708	In addition to FGFR1 copy number aberrations, an FGFR1 SNP (rs17182023) has been investigated and was found to be associated with a reduced risk of BC and lower FGFR1 expression.	('FGFR1', 'Gene', '2260', (15, 20))	('FGFR1', 'Gene', (161, 166))	('BC', 'Phenotype', 'HP:0003002', (148, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('reduced', 'NegReg', (132, 139))	('FGFR1', 'Gene', '2260', (161, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('rs17182023', 'Var', (60, 70))	('lower', 'NegReg', (155, 160))	('FGFR1', 'Gene', (49, 54))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('FGFR1', 'Gene', (15, 20))	('expression', 'MPA', (167, 177))	('rs17182023', 'Mutation', 'rs17182023', (60, 70))	('FGFR1', 'Gene', '2260', (49, 54))
44690	32852708	By contrast, high levels of FGFR1 were associated with a poor outcome.	('high levels', 'Var', (13, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('FGFR1', 'Gene', (28, 33))	('associated', 'Reg', (39, 49))	('FGFR1', 'Gene', '2260', (28, 33))
44692	32852708	Rather than increased gene copy numbers, SNPs in the FGFR2 risk locus appear to be associated with the development of BC.	('BC', 'Phenotype', 'HP:0003002', (118, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('associated with', 'Reg', (83, 98))	('FGFR2', 'Gene', (53, 58))	('FGFR2', 'Gene', '2263', (53, 58))	('SNPs', 'Var', (41, 45))
44693	32852708	reported reduced FGFR2 expression and consequently:due to less influence of FGFR2 on the estrogen regulon:increased responsiveness to estrogen if one of three FGFR2 variants existed.	('FGFR2', 'Gene', (17, 22))	('FGFR2', 'Gene', '2263', (17, 22))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('variants', 'Var', (165, 173))	('FGFR2', 'Gene', (159, 164))	('FGFR2', 'Gene', (76, 81))	('FGFR2', 'Gene', '2263', (159, 164))	('FGFR2', 'Gene', '2263', (76, 81))	('responsiveness to estrogen', 'MPA', (116, 142))	('reduced', 'NegReg', (9, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))	('FGFR', 'molecular_function', 'GO:0005007', ('17', '21'))	('increased', 'PosReg', (106, 115))	('expression', 'MPA', (23, 33))
44695	32852708	reported FGFR2 amplification in 4.0% of triple-negative BCs, but not in any other subtype.	('amplification', 'Var', (15, 28))	('BCs', 'Disease', (56, 59))	('triple-negative BCs', 'Disease', (40, 59))	('FGFR2', 'Gene', '2263', (9, 14))	('FGFR2', 'Gene', (9, 14))	('BC', 'Phenotype', 'HP:0003002', (56, 58))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))
44700	32852708	Mutations, rearrangements, post-transcriptional regulation, and isoform switching/alternative splicing, as well as stimulation via fibroblast growth factors from tumor or stromal cells, can also have an impact on the system.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('isoform', 'Var', (64, 71))	('tumor', 'Disease', (162, 167))	('rearrangements', 'Var', (11, 25))	('splicing', 'biological_process', 'GO:0045292', ('94', '102'))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
44702	32852708	In conclusion, fibroblast growth factor receptor alterations (e.g., FGFR1 copy number variations and FGFR2 SNPs) influence the risk and prognosis in patients with breast cancer.	('patients', 'Species', '9606', (149, 157))	('FGFR2', 'Gene', (101, 106))	('FGFR1', 'Gene', (68, 73))	('FGFR2', 'Gene', '2263', (101, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('copy number variations', 'Var', (74, 96))	('influence', 'Reg', (113, 122))	('FGFR1', 'Gene', '2260', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('15', '39'))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('SNPs', 'Var', (107, 111))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('breast cancer', 'Disease', (163, 176))
44712	28935545	We show that TAM has several distinct effects on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy.	('LCCTam', 'Chemical', '-', (70, 76))	('effects', 'Reg', (38, 45))	('improves', 'PosReg', (301, 309))	('mutations', 'Var', (156, 165))	('glutamate', 'Chemical', 'MESH:D018698', (204, 213))	('alterations', 'Var', (140, 151))	('TAM', 'Chemical', 'MESH:D013629', (13, 16))	('growth-inhibitory actions of endocrine therapy', 'MPA', (326, 372))	('MAPK', 'molecular_function', 'GO:0004707', ('182', '186'))	('restores', 'PosReg', (313, 321))	('impinge', 'Reg', (171, 178))	('signaling', 'biological_process', 'GO:0023052', ('235', '244'))	('transcriptome', 'MPA', (53, 66))
44718	28935545	The most common genetic lesion in ILC is mutation of CDH1 leading to loss of E-cadherin expression, which is thought to underlie ILC's unusual metastatic pattern as well as its tendency to be multifocal and affect the contralateral breast.	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('loss', 'NegReg', (69, 73))	('common', 'Reg', (9, 15))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('affect', 'Reg', (207, 213))	('mutation', 'Var', (41, 49))	('ILC', 'Disease', (129, 132))	('CDH1', 'Gene', (53, 57))	('genetic lesion', 'Disease', (16, 30))	('expression', 'MPA', (88, 98))	('CDH1', 'Gene', '999', (53, 57))	('genetic lesion', 'Disease', 'MESH:D020022', (16, 30))
44719	28935545	Recent studies have performed genomic, transcriptomic, and proteomic characterization of ILC clinical specimens to identify additional events that are enriched in ILC vs. IDC; these include higher rates of PTEN loss, FOXA1 mutation, and AKT phosphorylation.	('AKT', 'Gene', (237, 240))	('PTEN loss', 'Disease', 'MESH:D006223', (206, 215))	('ILC', 'Disease', (163, 166))	('FOXA1', 'Gene', (217, 222))	('phosphorylation', 'CPA', (241, 256))	('PTEN loss', 'Disease', (206, 215))	('mutation', 'Var', (223, 231))	('FOXA1', 'Gene', '3169', (217, 222))	('AKT', 'Gene', '207', (237, 240))	('phosphorylation', 'biological_process', 'GO:0016310', ('241', '256'))	('higher', 'PosReg', (190, 196))
44726	28935545	We find that 4-hydroxytamoxifen (4HT) has a distinct effect on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and specific gene mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy.	('restores', 'PosReg', (341, 349))	('4HT', 'Chemical', '-', (33, 36))	('LCCTam', 'Chemical', '-', (84, 90))	('growth-inhibitory actions of endocrine therapy', 'MPA', (354, 400))	('mutations', 'Var', (184, 193))	('effect', 'Reg', (53, 59))	('improves', 'PosReg', (329, 337))	('MAPK', 'molecular_function', 'GO:0004707', ('210', '214'))	('signaling', 'biological_process', 'GO:0023052', ('263', '272'))	('glutamate', 'Chemical', 'MESH:D018698', (232, 241))	('impinge', 'Reg', (199, 206))	('4-hydroxytamoxifen', 'Chemical', '-', (13, 31))	('transcriptome', 'MPA', (67, 80))
44735	28935545	The final database included patients from GSE2990, GSE3494, GSE6532, GSE12093, GSE9195, GSE16391, GSE17705, GSE19615, GSE26971, and GSE45255.	('GSE17705', 'Var', (98, 106))	('GSE2990', 'Var', (42, 49))	('GSE16391', 'Var', (88, 96))	('GSE2990', 'Chemical', '-', (42, 49))	('GSE9195', 'Chemical', '-', (79, 86))	('GSE6532', 'Chemical', '-', (60, 67))	('GSE26971', 'Var', (118, 126))	('GSE9195', 'Var', (79, 86))	('GSE45255', 'Var', (132, 140))	('GSE3494', 'Chemical', '-', (51, 58))	('GSE12093', 'Var', (69, 77))	('GSE19615', 'Var', (108, 116))	('patients', 'Species', '9606', (28, 36))	('GSE6532', 'Var', (60, 67))	('GSE3494', 'Var', (51, 58))
44746	28935545	Briefly, equal amounts of cell line and reference DNA were directly labeled with Cy3 and Cy5, respectively, using the SureTag Labeling Kit (Agilent Technologies) and hybridized in the presence of human Cot1-DNA (Life Technologies) to the array for 40 hours.	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('Cy5', 'Var', (89, 92))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('human', 'Species', '9606', (196, 201))	('Cy3', 'Chemical', '-', (81, 84))	('Cy5', 'Chemical', 'MESH:C085321', (89, 92))	('Cy3', 'Var', (81, 84))
44760	28935545	Membranes were blocked in 5% nonfat dry milk in TBST buffer, then probed overnight with the following primary antibodies: phospho-MAPK (1:500-1:1000) and total MAPK (1:500-1:1000) from Cell Signaling (Danvers, MA); phospho-Serine 118 ERalpha (1:500) from EMD Millipore (Billerica, MA); and total ERalpha (clone 6F11, 1:500-1:1000) from Vector Labs (Burlingame, CA).	('MAPK', 'molecular_function', 'GO:0004707', ('160', '164'))	('EMD', 'Disease', 'None', (255, 258))	('ERalpha', 'Gene', (296, 303))	('ERalpha', 'Gene', '2099', (234, 241))	('ERalpha', 'Gene', (234, 241))	('ERalpha', 'Gene', '2099', (296, 303))	('MAPK', 'molecular_function', 'GO:0004707', ('130', '134'))	('1:500-1:1000', 'Var', (166, 178))	('Signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('Serine', 'Chemical', 'MESH:D012694', (223, 229))	('EMD', 'Disease', (255, 258))	('TBST', 'Chemical', '-', (48, 52))
44776	28935545	Relative index (RI) calculations were used to test the nature of the interaction between U0126 and 4HT, or Riluzole (RIL) and Fulvestrant (ICI).	('Riluzole', 'Chemical', 'MESH:D019782', (107, 115))	('RIL', 'Chemical', 'MESH:D019782', (117, 120))	('4HT', 'Gene', (99, 102))	('4HT', 'Chemical', '-', (99, 102))	('interaction', 'Interaction', (69, 80))	('U0126', 'Var', (89, 94))	('Fulvestrant', 'Chemical', 'MESH:D000077267', (126, 137))	('test', 'Reg', (46, 50))	('ICI', 'Chemical', '-', (139, 142))	('U0126', 'Chemical', 'MESH:C113580', (89, 94))
44785	28935545	These data support the relevance of the SUM44/LCCTam model system as a platform to identify additional alterations in gene expression, as well as copy number and mutations, in ILC that are associated with poor response to TAM.	('mutations', 'Var', (162, 171))	('expression', 'MPA', (123, 133))	('alterations', 'Reg', (103, 114))	('LCCTam', 'Chemical', '-', (46, 52))	('TAM', 'Chemical', 'MESH:D013629', (222, 225))	('copy number', 'Var', (146, 157))	('gene expression', 'biological_process', 'GO:0010467', ('118', '133'))	('ILC', 'Gene', (176, 179))
44787	28935545	We previously reported that, in conjunction with ESRRG, aberrant activating protein 1 (AP1) activity plays a key functional role in the TAM-resistant phenotype of LCCTam cells, and identified candidate AP1-regulated genes whose expression is increased in LCCTam cells.	('LCCTam', 'Chemical', '-', (163, 169))	('ESRRG', 'Gene', (49, 54))	('AP1', 'Gene', '3727', (202, 205))	('ESRRG', 'Gene', '2104', (49, 54))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('AP1', 'Gene', (202, 205))	('AP1', 'cellular_component', 'GO:0005907', ('202', '205'))	('aberrant', 'Var', (56, 64))	('AP1', 'Gene', (87, 90))	('AP1', 'Gene', '3727', (87, 90))	('increased', 'PosReg', (242, 251))	('AP1', 'cellular_component', 'GO:0005907', ('87', '90'))	('LCCTam', 'Disease', (163, 169))	('TAM', 'Chemical', 'MESH:D013629', (136, 139))	('activity', 'MPA', (92, 100))	('expression', 'MPA', (228, 238))	('LCCTam', 'Chemical', '-', (255, 261))
44795	28935545	PIK3CA mutation is enriched in Luminal A ILC and a likely driver of ILC endocrine resistance that could be targeted with PI3K inhibitors.	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))	('PI3K', 'molecular_function', 'GO:0016303', ('121', '125'))	('PIK3CA', 'Gene', (0, 6))
44805	28935545	By array comparative genomic hybridization (aCGH) we confirm that the parental SUM44 cell line has many of these features, including broad gain of chromosome 1q, losses on the p arm of chromosome 10 that encompass PTEN, and focal amplification of fibroblast growth factor receptor 1 (FGFR1) and cyclin D1 (CCND1) (Figure 3A and).	('CCND1', 'Gene', (306, 311))	('chromosome', 'cellular_component', 'GO:0005694', ('185', '195'))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('247', '271'))	('FGFR1', 'Gene', '2260', (284, 289))	('PTEN', 'Gene', '5728', (214, 218))	('gain', 'PosReg', (139, 143))	('FGFR', 'molecular_function', 'GO:0005007', ('284', '288'))	('cyclin D1', 'Gene', (295, 304))	('losses', 'NegReg', (162, 168))	('focal amplification', 'Var', (224, 243))	('cyclin D1', 'Gene', '595', (295, 304))	('chromosome', 'cellular_component', 'GO:0005694', ('147', '157'))	('FGFR1', 'Gene', (284, 289))	('cyclin', 'molecular_function', 'GO:0016538', ('295', '301'))	('CGH', 'Gene', '3342', (45, 48))	('fibroblast growth factor receptor 1', 'Gene', '2260', (247, 282))	('PTEN', 'Gene', (214, 218))	('CCND1', 'Gene', '595', (306, 311))	('fibroblast growth factor receptor 1', 'Gene', (247, 282))	('CGH', 'Gene', (45, 48))
44810	28935545	All three of these genes have been previously implicated in altered response to endocrine therapy or ER signaling in ER+ breast cancer, while FOXA1 mutation is significantly enriched in Luminal A ILCs from TCGA.	('ER', 'Gene', '2099', (117, 119))	('response to endocrine therapy', 'MPA', (68, 97))	('implicated', 'Reg', (46, 56))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('FOXA1', 'Gene', (142, 147))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('ER', 'Gene', '2099', (101, 103))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('mutation', 'Var', (148, 156))	('FOXA1', 'Gene', '3169', (142, 147))
44812	28935545	It has been recently shown that FOXA1 is amplified in TAM-resistant MCF7 cells and copy-number gain exists in 20% of TCGA breast tumors, especially in the Luminal B subtype.	('breast tumors', 'Phenotype', 'HP:0100013', (122, 135))	('FOXA1', 'Gene', '3169', (32, 37))	('TCGA', 'Gene', (117, 121))	('copy-number gain', 'Var', (83, 99))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('breast tumors', 'Disease', 'MESH:D001943', (122, 135))	('TAM', 'Chemical', 'MESH:D013629', (54, 57))	('MCF7', 'CellLine', 'CVCL:0031', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('breast tumors', 'Disease', (122, 135))	('FOXA1', 'Gene', (32, 37))
44814	28935545	Use of an insertional mutational screen in mice with Cdh1 inactivation implicated the MAPK pathway as a second hit necessary for ILC development in mouse models.	('mice', 'Species', '10090', (43, 47))	('MAPK', 'molecular_function', 'GO:0004707', ('86', '90'))	('mouse', 'Species', '10090', (148, 153))	('inactivation', 'Var', (58, 70))	('Cdh1', 'Gene', (53, 57))	('Cdh1', 'Gene', '12550', (53, 57))
44815	28935545	Serine 118 of ER is a known substrate of ERK/MAPK signaling, and ER phosphorylation at this site has been implicated in poor response to TAM, though other studies contradict this.	('Serine', 'Var', (0, 6))	('ER', 'Gene', '2099', (41, 43))	('ERK', 'molecular_function', 'GO:0004707', ('41', '44'))	('ER', 'Gene', '2099', (14, 16))	('ER', 'Gene', '2099', (65, 67))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('poor response to', 'MPA', (120, 136))	('ERK', 'Gene', '5594', (41, 44))	('MAPK signaling', 'biological_process', 'GO:0000165', ('45', '59'))	('Serine', 'Chemical', 'MESH:D012694', (0, 6))	('TAM', 'Chemical', 'MESH:D013629', (137, 140))	('implicated', 'Reg', (106, 116))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))	('ERK', 'Gene', (41, 44))
44819	28935545	Mutations in CDH1 are a hallmark of ILC, while those affecting PIK3CA and FOXA1 are overrepresented in Luminal A ILC vs. Luminal A IDC.	('CDH1', 'Gene', '999', (13, 17))	('FOXA1', 'Gene', '3169', (74, 79))	('ILC', 'Disease', (36, 39))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', '5290', (63, 69))	('FOXA1', 'Gene', (74, 79))	('CDH1', 'Gene', (13, 17))
44820	28935545	SUM44 cells have known loss of heterozygosity (LOH) and mutation of CDH1, but aside from this and LOH/mutation of TP53 (p53), the mutational status of key drivers or breast cancer-associated genes in this ILC cell line is not known.	('p53', 'Gene', '7157', (120, 123))	('TP53', 'Gene', '7157', (114, 118))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CDH1', 'Gene', (68, 72))	('breast cancer', 'Disease', (166, 179))	('TP53', 'Gene', (114, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('mutation', 'Var', (56, 64))	('p53', 'Gene', (120, 123))	('CDH1', 'Gene', '999', (68, 72))
44821	28935545	With respect to mutations that arise during progression on endocrine therapy, multiple ESR1 (ER) mutations are increasingly appreciated as drivers of clinical resistance to AIs, and are also observed in a proportion of TAM- or Fulvestrant-resistant disease.	('mutations', 'Var', (97, 106))	('observed', 'Reg', (191, 199))	('ESR1', 'Gene', (87, 91))	('ER', 'Gene', '2099', (93, 95))	('Fulvestrant', 'Chemical', 'MESH:D000077267', (227, 238))	('TAM', 'Chemical', 'MESH:D013629', (219, 222))	('ESR1', 'Gene', '2099', (87, 91))
44823	28935545	Both the parental SUM44 and resistant variant LCCTam contain wild type ESR1, ERBB2 (HER2), and FOXA1, and maintain their previously reported CDH1 and TP53 mutations (Supplementary Table 4).	('FOXA1', 'Gene', (95, 100))	('TP53', 'Gene', (150, 154))	('ERBB2', 'Gene', '2064', (77, 82))	('mutations', 'Var', (155, 164))	('CDH1', 'Gene', (141, 145))	('HER2', 'Gene', (84, 88))	('ERBB2', 'Gene', (77, 82))	('ESR1', 'Gene', '2099', (71, 75))	('variant', 'Var', (38, 45))	('HER2', 'Gene', '2064', (84, 88))	('FOXA1', 'Gene', '3169', (95, 100))	('LCCTam', 'Chemical', '-', (46, 52))	('CDH1', 'Gene', '999', (141, 145))	('LCCTam', 'Gene', (46, 52))	('ESR1', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (150, 154))
44824	28935545	Comparison of LCCTam to SUM44 cells identifies one hundred eighty (180) unique predicted protein- or splice site-altering mutations in one hundred fifty two (152) unique genes (Figure 4A).	('LCCTam', 'Chemical', '-', (14, 20))	('mutations', 'Var', (122, 131))	('protein-', 'MPA', (89, 97))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
44825	28935545	A splice-disrupting mutation is present in exon 43 of Neurofibromin 1 (NF1), a tumor suppressor that is a key negative regulator of the Ras/MAPK pathway, and while NF1 is frequently mutated in sporadic breast cancers, its role in ILC is not fully understood.	('mutated', 'Var', (182, 189))	('Neurofibromin 1', 'Gene', (54, 69))	('NF1', 'Gene', (71, 74))	('mutation', 'Var', (20, 28))	('NF1', 'Gene', '4763', (164, 167))	('NF1', 'Gene', (164, 167))	('sporadic breast cancers', 'Disease', 'MESH:D001943', (193, 216))	('Neurofibromin 1', 'Gene', '4763', (54, 69))	('breast cancers', 'Phenotype', 'HP:0003002', (202, 216))	('tumor', 'Disease', (79, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('NF1', 'Gene', '4763', (71, 74))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('sporadic breast cancers', 'Disease', (193, 216))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
44827	28935545	Phenotypically, these data are consistent with our aCGH, PCR, and Western blot results in Figure 3 (where we show that MAPK pathway activation is deregulated in LCCTam cells) and with prior studies that implicate NF1 loss or mutation with reduced efficacy of endocrine therapy or poor prognostic factors, respectively.	('activation', 'PosReg', (132, 142))	('CGH', 'Gene', (52, 55))	('deregulated', 'NegReg', (146, 157))	('CGH', 'Gene', '3342', (52, 55))	('NF1', 'Gene', (213, 216))	('MAPK pathway', 'Pathway', (119, 131))	('NF1', 'Gene', '4763', (213, 216))	('MAPK', 'molecular_function', 'GO:0004707', ('119', '123'))	('LCCTam', 'Chemical', '-', (161, 167))	('mutation', 'Var', (225, 233))	('loss', 'NegReg', (217, 221))
44828	28935545	We further identify missense mutations in two members of the GRM/mGluR family, GRM1 on chromosome 6 and GRM2 on chromosome 3 (Figure 4B).	('GRM2', 'Gene', '2912', (104, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('GRM1', 'Gene', (79, 83))	('missense mutations', 'Var', (20, 38))	('GRM2', 'Gene', (104, 108))	('GRM1', 'Gene', '2911', (79, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))
44830	28935545	The GRM1 A229E and GRM2 I315V mutations found in LCCTam cells reside in the extracellular glutamate binding regions of the receptors (Figure 4D for GRM1).	('GRM1', 'Gene', (4, 8))	('I315V', 'Mutation', 'rs143181148', (24, 29))	('glutamate binding', 'molecular_function', 'GO:0016595', ('90', '107'))	('A229E', 'Var', (9, 14))	('LCCTam', 'Chemical', '-', (49, 55))	('GRM1', 'Gene', (148, 152))	('I315V', 'Var', (24, 29))	('GRM1', 'Gene', '2911', (4, 8))	('extracellular', 'cellular_component', 'GO:0005576', ('76', '89'))	('GRM2', 'Gene', '2912', (19, 23))	('A229E', 'Mutation', 'p.A229E', (9, 14))	('glutamate', 'Chemical', 'MESH:D018698', (90, 99))	('GRM1', 'Gene', '2911', (148, 152))	('GRM2', 'Gene', (19, 23))
44831	28935545	In TCGA, GRM1 mutations occur at a greater frequency in primary Luminal A ILC tumors (3%, Figure 4D) than primary Luminal A IDC tumors (0.5%, chi2 = 0.08), while GRM2 mutations are not observed in ILC.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('GRM2', 'Gene', '2912', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('A IDC tumors', 'Disease', (122, 134))	('Luminal A ILC tumors', 'Disease', 'MESH:D009369', (64, 84))	('GRM1', 'Gene', (9, 13))	('A IDC tumors', 'Disease', 'MESH:D009369', (122, 134))	('Luminal A ILC tumors', 'Disease', (64, 84))	('GRM2', 'Gene', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutations', 'Var', (14, 23))	('GRM1', 'Gene', '2911', (9, 13))
44833	28935545	There is precedent for a functional interaction between GRM1, GRM2 and GRM4 and loss of CDH1, a hallmark of ILC.	('GRM2', 'Gene', '2912', (62, 66))	('GRM1', 'Gene', (56, 60))	('loss', 'Var', (80, 84))	('GRM2', 'Gene', (62, 66))	('GRM4', 'Gene', (71, 75))	('interaction', 'Interaction', (36, 47))	('CDH1', 'Gene', (88, 92))	('GRM4', 'Gene', '2914', (71, 75))	('GRM1', 'Gene', '2911', (56, 60))	('CDH1', 'Gene', '999', (88, 92))
44836	28935545	Finally, high expression of GRM1, GRM2, or GRM4 mRNA is each associated with poor distant-metastasis free survival in women with ER+ breast cancer treated with TAM, independent of lobular histology ( and Supplementary Figure 2).	('GRM2', 'Gene', '2912', (34, 38))	('high expression', 'Var', (9, 24))	('GRM1', 'Gene', (28, 32))	('breast cancer', 'Disease', (133, 146))	('women', 'Species', '9606', (118, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('poor', 'NegReg', (77, 81))	('distant-metastasis free survival', 'CPA', (82, 114))	('GRM2', 'Gene', (34, 38))	('TAM', 'Chemical', 'MESH:D013629', (160, 163))	('GRM4', 'Gene', (43, 47))	('ER', 'Gene', '2099', (129, 131))	('GRM1', 'Gene', '2911', (28, 32))	('GRM4', 'Gene', '2914', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
44839	28935545	Hyperactivation of the MAPK/ERK cascade is a common feature of endocrine resistance in ER+ breast cancer patients and preclinical models.	('ERK', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('ERK cascade', 'biological_process', 'GO:0070371', ('28', '39'))	('patients', 'Species', '9606', (105, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('endocrine', 'MPA', (63, 72))	('ER', 'Gene', '2099', (28, 30))	('ER', 'Gene', '2099', (87, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('Hyperactivation', 'Var', (0, 15))	('ERK', 'Gene', '5594', (28, 31))	('ERK', 'molecular_function', 'GO:0004707', ('28', '31'))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
44840	28935545	Here, we identify NF1 mutation and downregulation, MAPK1 amplification and upregulation, and increased MAPK substrate phosphorylation (ER Serine 118) in TAM-resistant ILC cells.	('mutation', 'Var', (22, 30))	('MAPK1', 'Gene', '5594', (51, 56))	('increased', 'PosReg', (93, 102))	('ER', 'Gene', '2099', (135, 137))	('MAPK', 'molecular_function', 'GO:0004707', ('103', '107'))	('upregulation', 'PosReg', (75, 87))	('TAM', 'Chemical', 'MESH:D013629', (153, 156))	('MAPK', 'molecular_function', 'GO:0004707', ('51', '55'))	('MAPK1', 'Gene', (51, 56))	('downregulation', 'NegReg', (35, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('amplification', 'PosReg', (57, 70))	('Serine', 'Chemical', 'MESH:D012694', (138, 144))	('NF1', 'Gene', (18, 21))	('NF1', 'Gene', '4763', (18, 21))
44841	28935545	Accordingly, U0126 - a potent and selective MEK inhibitor chemical probe known to enhance TAM responsiveness - suppresses MAPK/ERK phosphorylation in ILC cells (Figure 5A), and is additive or better-than-additive in combination with TAM in suppressing the growth of responsive (SUM44) or resistant (LCCTam) ILC cells, respectively (Figure 5B).	('TAM', 'Chemical', 'MESH:D013629', (90, 93))	('LCCTam', 'Chemical', '-', (299, 305))	('MAPK', 'molecular_function', 'GO:0004707', ('122', '126'))	('MEK', 'Gene', '5609', (44, 47))	('phosphorylation', 'biological_process', 'GO:0016310', ('131', '146'))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))	('ERK', 'Gene', '5594', (127, 130))	('U0126 -', 'Var', (13, 20))	('ERK', 'molecular_function', 'GO:0004707', ('127', '130'))	('ERK', 'Gene', (127, 130))	('MEK', 'Gene', (44, 47))	('TAM', 'Chemical', 'MESH:D013629', (233, 236))	('suppresses', 'NegReg', (111, 121))	('enhance', 'PosReg', (82, 89))
44846	28935545	Multiple GRMs upregulated in LCCTam cells (Figure 4G) are transducers of pro-proliferative glutamate signaling, and GRM1 mutations can lead to hyperactivation of the MAPK pathway in response to paracrine or autocrine glutamate.	('glutamate', 'Chemical', 'MESH:D018698', (91, 100))	('mutations', 'Var', (121, 130))	('glutamate', 'Chemical', 'MESH:D018698', (217, 226))	('GRM1', 'Gene', '2911', (116, 120))	('MAPK pathway', 'Pathway', (166, 178))	('LCCTam', 'Chemical', '-', (29, 35))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('response to paracrine or autocrine glutamate', 'MPA', (182, 226))	('MAPK', 'molecular_function', 'GO:0004707', ('166', '170'))	('GRM1', 'Gene', (116, 120))	('hyperactivation', 'PosReg', (143, 158))
44851	28935545	Together these data show that perturbation of two different actionable alterations identified in this study (MAPK amplification and hyperactivation, GRM/mGluR mutation and upregulation) are effective against TAM-resistant and responsive ILC cells.	('upregulation', 'PosReg', (172, 184))	('hyperactivation', 'PosReg', (132, 147))	('TAM', 'Chemical', 'MESH:D013629', (208, 211))	('mutation', 'Var', (159, 167))	('amplification', 'PosReg', (114, 127))	('MAPK', 'molecular_function', 'GO:0004707', ('109', '113'))	('GRM/mGluR', 'Gene', (149, 158))	('MAPK', 'Gene', (109, 113))
44853	28935545	A comprehensive analysis of genetic alterations in a preclinical model of TAM-resistant ILC provides an opportunity to identify novel pathways of resistance, ultimately leading to better treatment options for patients.	('genetic alterations', 'Var', (28, 47))	('patients', 'Species', '9606', (209, 217))	('ILC', 'Disease', (88, 91))	('TAM', 'Chemical', 'MESH:D013629', (74, 77))
44856	28935545	FOXA1 mutation is a defining feature of Luminal A ILC, and in LCCTam cells we report FOXA1 gain and increased mRNA expression, although its sequence is wild type based on our WES data.	('FOXA1', 'Gene', (0, 5))	('increased', 'PosReg', (100, 109))	('LCCTam', 'Chemical', '-', (62, 68))	('mutation', 'Var', (6, 14))	('FOXA1', 'Gene', '3169', (0, 5))	('FOXA1', 'Gene', '3169', (85, 90))	('mRNA expression', 'MPA', (110, 125))	('gain', 'PosReg', (91, 95))	('FOXA1', 'Gene', (85, 90))
44861	28935545	Multiple alterations in copy number, sequence, and mRNA or protein expression acquired by LCCTam cells impinge on the MAPK/ERK signaling network, including MAPK1 amplification, upregulation, and hyperactivation, as well as NF1 mutation and downregulation.	('NF1', 'Gene', '4763', (223, 226))	('MAPK', 'molecular_function', 'GO:0004707', ('156', '160'))	('upregulation', 'PosReg', (177, 189))	('ERK', 'Gene', (123, 126))	('mutation', 'Var', (227, 235))	('NF1', 'Gene', (223, 226))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('MAPK1', 'Gene', (156, 161))	('hyperactivation', 'PosReg', (195, 210))	('amplification', 'PosReg', (162, 175))	('ERK', 'molecular_function', 'GO:0004707', ('123', '126'))	('LCCTam', 'Chemical', '-', (90, 96))	('impinge', 'Reg', (103, 110))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('mRNA or protein expression', 'MPA', (51, 77))	('ERK', 'Gene', '5594', (123, 126))	('MAPK1', 'Gene', '5594', (156, 161))	('downregulation', 'NegReg', (240, 254))	('sequence', 'MPA', (37, 45))
44862	28935545	Functional validation further shows that MEK inhibition by U0126 improves or restores TAM response in SUM44 and LCCTam cells.	('inhibition', 'NegReg', (45, 55))	('U0126', 'Chemical', 'MESH:C113580', (59, 64))	('MEK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (41, 44))	('U0126', 'Var', (59, 64))	('restores', 'PosReg', (77, 85))	('LCCTam', 'Chemical', '-', (112, 118))	('TAM response', 'MPA', (86, 98))	('improves', 'PosReg', (65, 73))	('TAM', 'Chemical', 'MESH:D013629', (86, 89))
44863	28935545	These data suggest that MAPK deregulation is a core feature of the TAM resistant phenotype of LCCTam cells, but we cannot rule out the potential contributions of other alterations detected by aCGH and/or WES.	('CGH', 'Gene', (193, 196))	('MAPK', 'molecular_function', 'GO:0004707', ('24', '28'))	('CGH', 'Gene', '3342', (193, 196))	('LCCTam', 'Chemical', '-', (94, 100))	('TAM', 'Chemical', 'MESH:D013629', (67, 70))	('MAPK', 'Gene', (24, 28))	('core', 'cellular_component', 'GO:0019013', ('47', '51'))	('deregulation', 'Var', (29, 41))
44864	28935545	For example, LCCTam cells have acquired a frameshift deletion mutation in X-box binding protein 1 (XBP1, c.333delA, K111fs).	('K111fs', 'Mutation', 'p.K111fsX', (116, 122))	('XBP1', 'Gene', (99, 103))	('X-box binding protein 1', 'Gene', '7494', (74, 97))	('X-box binding protein 1', 'Gene', (74, 97))	('c.333delA', 'Mutation', 'c.333delA', (105, 114))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('K111fs', 'Var', (116, 122))	('XBP1', 'Gene', '7494', (99, 103))	('c.333delA', 'Var', (105, 114))	('frameshift deletion', 'Var', (42, 61))	('LCCTam', 'Chemical', '-', (13, 19))
44866	28935545	Whether this mutant XBP1 may contribute to TAM resistance in LCCTam cells requires further study.	('mutant', 'Var', (13, 19))	('contribute', 'Reg', (29, 39))	('XBP1', 'Gene', (20, 24))	('TAM', 'Chemical', 'MESH:D013629', (43, 46))	('LCCTam', 'Chemical', '-', (61, 67))	('XBP1', 'Gene', '7494', (20, 24))	('TAM resistance', 'MPA', (43, 57))
44867	28935545	In the TCGA dataset GRM1 mutations are more prevalent in primary Luminal A ILC than IDC, and most somatic GRM1 mutations lead to hyperactivation of the MAPK pathway in response to glutamate et al., 2013).	('mutations', 'Var', (111, 120))	('mutations', 'Var', (25, 34))	('GRM1', 'Gene', (20, 24))	('primary Luminal A ILC', 'Disease', (57, 78))	('MAPK pathway', 'Pathway', (152, 164))	('GRM1', 'Gene', '2911', (106, 110))	('glutamate', 'Chemical', 'MESH:D018698', (180, 189))	('GRM1', 'Gene', '2911', (20, 24))	('hyperactivation', 'PosReg', (129, 144))	('response to glutamate', 'MPA', (168, 189))	('MAPK', 'molecular_function', 'GO:0004707', ('152', '156'))	('GRM1', 'Gene', (106, 110))
44868	28935545	Here, we show that multiple members of the GRM/mGluR family are mutated and/or upregulated at the mRNA and protein level in LCCTam cells.	('upregulated', 'PosReg', (79, 90))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('LCCTam', 'Chemical', '-', (124, 130))	('mutated', 'Var', (64, 71))
44872	28935545	It may be that multiple GRM/mGluR family members are required to transduce RIL's anti-proliferative effect in breast cancer, an attractive idea given that our data show multiple GRMs/mGluRs are simultaneously mutated and/or upregulated in TAM-resistant ILC cells.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutated', 'Var', (209, 216))	('RIL', 'Chemical', 'MESH:D019782', (75, 78))	('mGluRs', 'Gene', (183, 189))	('TAM', 'Chemical', 'MESH:D013629', (239, 242))	('upregulated', 'PosReg', (224, 235))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('mGluRs', 'Gene', '67417', (183, 189))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
44884	28935545	Coupled with our preclinical models and those of others in the field, these efforts should identify a number of actionable alterations that can be targeted to improve therapeutic outcomes for women with ER+ ILC ILC is an understudied breast cancer subtype with a relatively poor response to TAM In TAM-resistant ILC cells, TAM treatment is associated with activation of PIK3CA, AHR, and androgen signaling TAM-resistant ILC cells show MAPK1 amplification and hyperactivation, FOXA1 gain, and CEBPD loss TAM-resistant ILC cells are characterized by mutation of NF1 and multiple GRMs/mGluRs Inhibition of MEK or glutamate release using Riluzole improves and restores endocrine therapy response in ILC cells	('PIK3CA', 'Gene', (370, 376))	('MAPK1', 'Gene', (435, 440))	('MEK', 'Gene', '5609', (603, 606))	('FOXA1', 'Gene', '3169', (476, 481))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('mGluRs', 'Gene', (582, 588))	('glutamate release', 'MPA', (610, 627))	('CEBPD', 'Gene', '1052', (492, 497))	('women', 'Species', '9606', (192, 197))	('glutamate', 'Chemical', 'MESH:D018698', (610, 619))	('MEK', 'Gene', (603, 606))	('mGluRs', 'Gene', '67417', (582, 588))	('FOXA1', 'Gene', (476, 481))	('AHR', 'Gene', (378, 381))	('NF1', 'Gene', '4763', (560, 563))	('TAM', 'Chemical', 'MESH:D013629', (323, 326))	('signaling', 'biological_process', 'GO:0023052', ('396', '405'))	('CEBPD', 'Gene', (492, 497))	('Riluzole', 'Chemical', 'MESH:D019782', (634, 642))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('TAM', 'Chemical', 'MESH:D013629', (298, 301))	('TAM', 'Chemical', 'MESH:D013629', (291, 294))	('NF1', 'Gene', (560, 563))	('ER', 'Gene', '2099', (203, 205))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('mutation', 'Var', (548, 556))	('breast cancer', 'Disease', (234, 247))	('ILC', 'Disease', (695, 698))	('PIK3CA', 'Gene', '5290', (370, 376))	('TAM', 'Chemical', 'MESH:D013629', (503, 506))	('MAPK1', 'Gene', '5594', (435, 440))	('AHR', 'Gene', '196', (378, 381))	('improves', 'PosReg', (643, 651))	('MAPK', 'molecular_function', 'GO:0004707', ('435', '439'))	('restores', 'PosReg', (656, 664))	('endocrine therapy response', 'MPA', (665, 691))	('TAM', 'Chemical', 'MESH:D013629', (406, 409))	('gain', 'PosReg', (482, 486))
44928	27835573	The MCD in patients with Ki67 <= 14% was also significantly higher than MDC in patients with Ki67 > 14%.	('MDC', 'Gene', (72, 75))	('MCD', 'Gene', (4, 7))	('MDC', 'Gene', '6367', (72, 75))	('Ki67 <= 14%', 'Var', (25, 36))	('MCD', 'Gene', '4582', (4, 7))	('higher', 'PosReg', (60, 66))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (11, 19))
44974	27835573	The average rank of MCD in cancers with Ki67 <= 14% was significantly higher than that in cancers with Ki67 > 14% (132.8 vs. 103.4, P = 0.004) (Table 2).	('MCD', 'Gene', (20, 23))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('MCD', 'Gene', '4582', (20, 23))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('higher', 'PosReg', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('Ki67 <= 14%', 'Var', (40, 51))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancers', 'Disease', (27, 34))
44987	27835573	The expression profiles of female hormone receptors, ER and PR, was found to be independent prognostic factors for the development, progression and treatment of breast cancer, our data showed that mast cell density is higher in the ER and/or PR positive tissue, which suggests that mast cells were inversely associated with negative factors of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('mast cell density', 'CPA', (197, 214))	('higher', 'PosReg', (218, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('breast cancer', 'Disease', (161, 174))	('ER', 'Gene', '2099', (232, 234))	('ER', 'Gene', '2099', (53, 55))	('breast cancer', 'Disease', 'MESH:D001943', (344, 357))	('positive', 'Var', (245, 253))	('breast cancer', 'Disease', (344, 357))	('breast cancer', 'Phenotype', 'HP:0003002', (344, 357))
45025	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))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('women', 'Species', '9606', (182, 187))	('BRCA', 'Gene', '672', (246, 250))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('BRCA', 'Gene', (246, 250))	('cancer', 'Disease', (306, 312))
45027	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))
45028	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))
45071	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))
45077	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))
45092	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))
45118	24795533	Herein we report the case of an elderly gentleman diagnosed with the pleomorphic variant of invasive lobular carcinoma along with involvement of the ipsilateral axillary lymph nodes.	('pleomorphic', 'Var', (69, 80))	('invasive lobular carcinoma', 'Disease', (92, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (92, 118))	('men', 'Species', '9606', (137, 140))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (101, 118))
45147	24795533	A higher incidence of HER2 gene amplification and a lower frequency of hormone receptor expression are other features typical of the pleomorphic variant when compared to its invasive lobular counterpart.	('amplification', 'MPA', (32, 45))	('HER2', 'Gene', (22, 26))	('pleomorphic variant', 'Var', (133, 152))	('lower', 'NegReg', (52, 57))	('HER2', 'Gene', '2064', (22, 26))	('hormone receptor', 'Gene', (71, 87))	('hormone receptor', 'Gene', '3164', (71, 87))
45198	22031809	found that the majority of ILC lack cohesiveness due to inactivation of E-cadherin, a cell-to-cell adhesion protein.	('cell adhesion', 'biological_process', 'GO:0007155', ('94', '107'))	('cadherin', 'molecular_function', 'GO:0008014', ('74', '82'))	('lack', 'NegReg', (31, 35))	('ILC', 'Disease', (27, 30))	('inactivation', 'Var', (56, 68))	('cohesiveness', 'MPA', (36, 48))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
45201	22031809	Overexpression of HER2 receptor in breast cancer has been associated with fast growth and a poorer prognosis.	('HER2', 'Gene', '2064', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('fast', 'MPA', (74, 78))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('fast growth', 'Phenotype', 'HP:0001510', (74, 85))	('breast cancer', 'Disease', (35, 48))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('HER2', 'Gene', (18, 22))
45216	22031809	As stated previously, positivity for CK7 and negativity for CK20 suggest a metastasis, while CK7-/CK20+ profile characterizes a large bowel primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CK7', 'Gene', (37, 40))	('bowel primary tumor', 'Disease', 'MESH:D015212', (134, 153))	('CK20', 'Gene', '54474', (98, 102))	('CK7', 'Gene', '3855', (93, 96))	('large bowel primary tumor', 'Phenotype', 'HP:0100834', (128, 153))	('large bowel', 'Phenotype', 'HP:0002037', (128, 139))	('metastasis', 'CPA', (75, 85))	('bowel primary tumor', 'Disease', (134, 153))	('CK20', 'Gene', (60, 64))	('CK7', 'Gene', '3855', (37, 40))	('CK20', 'Gene', '54474', (60, 64))	('CK20', 'Gene', (98, 102))	('positivity', 'Var', (22, 32))	('CK7', 'Gene', (93, 96))
45226	29471435	In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('high', 'Var', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('TIL', 'Gene', (13, 16))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('associated', 'Reg', (29, 39))	('lymph node involvement', 'CPA', (56, 78))	('TIL', 'Gene', '7096', (13, 16))
45227	29471435	In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter.	('high', 'Var', (28, 32))	('TIL', 'Gene', (33, 36))	('TIL', 'Gene', '7096', (33, 36))
45264	29471435	In the retrospective series, we observed at the univariate level that higher TIL values were associated with ER- and PR-negative status, high proliferation status (>=20% Ki67), high grade, node-positive status, and young age at diagnosis (Figure 2A;Supplementary Table 5, available online).	('TIL', 'Gene', (77, 80))	('ER', 'Gene', '2099', (109, 111))	('TIL', 'Gene', '7096', (77, 80))	('higher', 'PosReg', (70, 76))	('node-positive', 'CPA', (189, 202))	('high proliferation', 'CPA', (137, 155))	('high grade', 'Var', (177, 187))
45267	29471435	The associations between TILs and age, as well as Ki67 in all ILC patients from BIG 02-98 (n = 204), were consistent with our results (Supplementary Figure 2 and Supplementary Table 6, available online).	('TIL', 'Gene', '7096', (25, 28))	('patients', 'Species', '9606', (66, 74))	('TIL', 'Gene', (25, 28))	('ILC', 'Disease', (62, 65))	('Ki67', 'Var', (50, 54))	('associations', 'Interaction', (4, 16))
45269	29471435	When restricting the analyses to the ER-positive/HER2-positive ILC in our cohort (n = 555), we made similar observations as in the global ILC population regarding the association with high Ki67, node-positive status, and young age at diagnosis (Figure 2A;Supplementary Table 7, available online).	('high Ki67', 'Var', (184, 193))	('ER', 'Gene', '2099', (50, 52))	('ER', 'Gene', '2099', (37, 39))	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (49, 53))
45271	29471435	TILs were positively associated with Ki67 both in IDC and ILC.	('Ki67', 'Var', (37, 41))	('TIL', 'Gene', '7096', (0, 3))	('IDC', 'Disease', (50, 53))	('associated', 'Interaction', (21, 31))	('TIL', 'Gene', (0, 3))	('ILC', 'Disease', (58, 61))
45273	29471435	We observed statistically significantly lower TIL counts in tumors harboring ERBB3 mutations and higher TIL counts in tumors presenting somatic oncogenic TP53, ARID1A, and BRCA2 mutations compared with tumors that were not mutated in those genes.	('higher', 'PosReg', (97, 103))	('TIL', 'Gene', (46, 49))	('BRCA2', 'Gene', '675', (172, 177))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('ERBB3', 'Gene', '2065', (77, 82))	('TIL', 'Gene', '7096', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Disease', (118, 124))	('ARID1A', 'Gene', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('TP53', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TIL', 'Gene', (104, 107))	('TIL', 'Gene', '7096', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('ARID1A', 'Gene', '8289', (160, 166))	('BRCA2', 'Gene', (172, 177))	('lower', 'NegReg', (40, 45))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('ERBB3', 'Gene', (77, 82))	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (202, 208))	('mutations', 'Var', (178, 187))	('TP53', 'Gene', '7157', (154, 158))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
45274	29471435	KMT2C and PIK3CA mutated tumors were associated with higher TIL, although not statistically significantly (Figure 3A;Supplementary Table 10, available online).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TIL', 'Gene', (60, 63))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PIK3CA', 'Gene', (10, 16))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('TIL', 'Gene', '7096', (60, 63))	('PIK3CA', 'Gene', '5290', (10, 16))	('mutated', 'Var', (17, 24))
45277	29471435	We observed statistically significantly higher TIL values in tumors with 8q24.23 loss (which included PTK2) and 7p21.2 gains (ETV1), but statistically significantly fewer TILs in tumors with 5q gains (Figure 3B;Supplementary Table 11, available online).	('TIL', 'Gene', '7096', (171, 174))	('higher', 'PosReg', (40, 46))	('TIL', 'Gene', (47, 50))	('ETV1', 'Gene', '2115', (126, 130))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('gains', 'PosReg', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('8q24.23', 'Var', (73, 80))	('TIL', 'Gene', (171, 174))	('PTK2', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('loss', 'NegReg', (81, 85))	('PTK2', 'Gene', '5747', (102, 106))	('TIL', 'Gene', '7096', (47, 50))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ETV1', 'Gene', (126, 130))	('tumors', 'Disease', (179, 185))	('7p21.2', 'Var', (112, 118))	('fewer', 'NegReg', (165, 170))
45291	29471435	TILs were next considered a categorical variable using the following groups, with the cut-points adapted from the interquartile range rounded to the nearest multiple of 5: low (<=5%), intermediate (>5 and <=10%), and high (>10%).	('TIL', 'Gene', (0, 3))	('>5', 'Var', (198, 200))	('TIL', 'Gene', '7096', (0, 3))
45299	29471435	The vast majority of ILC tumors (~90%) are ER-positive/HER2-negative, making our findings consistent with previous reports showing that TILs are more prevalent in triple-negative and HER2-positive breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('HER2', 'Gene', '2064', (183, 187))	('ER', 'Gene', '2099', (56, 58))	('HER2', 'Gene', '2064', (55, 59))	('ILC tumors', 'Disease', 'MESH:D009369', (21, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('ILC tumors', 'Disease', (21, 31))	('prevalent', 'Reg', (150, 159))	('triple-negative', 'Var', (163, 178))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('HER2', 'Gene', (183, 187))	('breast cancer', 'Disease', (197, 210))	('TIL', 'Gene', '7096', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('ER', 'Gene', '2099', (43, 45))	('HER2', 'Gene', (55, 59))	('ER', 'Gene', '2099', (184, 186))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('TIL', 'Gene', (136, 139))
45315	29471435	Tumors presenting ARID1A, BRCA2, and TP53 mutations, as well as 8q24.23 loss and 7p21.2 gains, were associated with higher TIL counts.	('BRCA2', 'Gene', '675', (26, 31))	('loss', 'NegReg', (72, 76))	('TIL', 'Gene', (123, 126))	('TIL', 'Gene', '7096', (123, 126))	('gains', 'PosReg', (88, 93))	('TP53', 'Gene', '7157', (37, 41))	('Tumors', 'Disease', (0, 6))	('BRCA2', 'Gene', (26, 31))	('ARID1A', 'Gene', '8289', (18, 24))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('ARID1A', 'Gene', (18, 24))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('8q24.23', 'Gene', (64, 71))	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
45316	29471435	Although we could not find previous evidence for the association of ARID1A mutations and TILs in breast cancer, a study of hepatocellular carcinoma demonstrated that hepatocyte-specific deficiency of ARID1A leads to the infiltration of innate immune cells.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('ARID1A', 'Gene', '8289', (68, 74))	('TIL', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ARID1A', 'Gene', (68, 74))	('TIL', 'Gene', '7096', (89, 92))	('leads to', 'Reg', (207, 215))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('infiltration', 'CPA', (220, 232))	('ARID1A', 'Gene', '8289', (200, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('ARID1A', 'Gene', (200, 206))	('deficiency', 'Var', (186, 196))	('hepatocellular carcinoma', 'Disease', (123, 147))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('breast cancer', 'Disease', (97, 110))
45317	29471435	Similarly, in colorectal cancer, ARID1A mutations are known to be more frequent in microsatellite-instable tumors, and these tumors are also associated with higher immune expression scores.	('immune expression scores', 'MPA', (164, 188))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('tumors', 'Disease', (107, 113))	('frequent', 'Reg', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (40, 49))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('colorectal cancer', 'Disease', (14, 31))	('higher', 'PosReg', (157, 163))	('ARID1A', 'Gene', '8289', (33, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (14, 31))	('ARID1A', 'Gene', (33, 39))
45318	29471435	It has to be noted, however, that ARID1A mutations were previously demonstrated to be enriched in ER-positive/HER2-negative ILC (~6%) compared with ER-positive/HER2-negative IDC (<2%).	('mutations', 'Var', (41, 50))	('ER', 'Gene', '2099', (98, 100))	('ER', 'Gene', '2099', (161, 163))	('ARID1A', 'Gene', '8289', (34, 40))	('HER2', 'Gene', (160, 164))	('ARID1A', 'Gene', (34, 40))	('HER2', 'Gene', '2064', (160, 164))	('ER', 'Gene', '2099', (111, 113))	('ER', 'Gene', '2099', (148, 150))	('HER2', 'Gene', (110, 114))	('HER2', 'Gene', '2064', (110, 114))	('ILC', 'Disease', (124, 127))
45320	29471435	While TP53 mutations have been shown to be associated with higher levels of TILs in ovarian cancer, lymphocytic infiltration in basal-like breast cancer has only recently been reported to be associated with the retention of wild-type TP53.	('ovarian cancer', 'Disease', (84, 98))	('mutations', 'Var', (11, 20))	('TP53', 'Gene', (6, 10))	('TIL', 'Gene', '7096', (76, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TP53', 'Gene', (234, 238))	('lymphocytic infiltration', 'Disease', (100, 124))	('retention', 'biological_process', 'GO:0051235', ('211', '220'))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('TIL', 'Gene', (76, 79))	('TP53', 'Gene', '7157', (6, 10))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', (139, 152))	('higher', 'PosReg', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('TP53', 'Gene', '7157', (234, 238))	('levels', 'MPA', (66, 72))
45325	29471435	Finally, we showed that higher TIL levels were found in association with specific mutations and copy number alterations.	('TIL', 'Gene', '7096', (31, 34))	('copy number alterations', 'Var', (96, 119))	('higher', 'PosReg', (24, 30))	('mutations', 'Var', (82, 91))	('TIL', 'Gene', (31, 34))
45360	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))
45406	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))
45426	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))
45447	26462242	Epigenetic analysis of abnormal DNA methylation has been promising in the detection of breast cancer.	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('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))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))
45448	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 suppressor', 'biological_process', 'GO:0051726', ('88', '104'))	('tumor', 'Disease', (88, 93))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('88', '104'))
45449	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))	('pathogenesis', 'biological_process', 'GO:0009405', ('241', '253'))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('DOK7', 'Gene', '285489', (71, 75))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('Docking Protein', 'molecular_function', 'GO:0005047', ('77', '92'))	('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))
45488	26462242	Overall, CT regimens based on anthracyclines and taxanes reduce breast cancer mortality by about one-third.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('reduce', 'NegReg', (57, 63))	('breast cancer', 'Disease', (64, 77))	('anthracyclines', 'Chemical', 'MESH:D018943', (30, 44))	('men', 'Species', '9606', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('taxanes', 'Chemical', 'MESH:D043823', (49, 56))	('anthracyclines', 'Var', (30, 44))
45505	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))
45560	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))
45592	26462242	NP formulation prepared with 15% PEGylated PLGA showed maximum cellular uptake due to its smallest particle size and lowest zeta potential.	('uptake', 'biological_process', 'GO:0098739', ('72', '78'))	('uptake', 'biological_process', 'GO:0098657', ('72', '78'))	('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))
45668	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))
45684	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))
45775	26163296	In a retrospective study by the same group, the authors assessed the impact of preoperative MRI on the re-excision rate in ILC and found that patients who had an MRI had significantly lower re-excision rates compared with patients without preoperative MRI (9 % versus 27 %, respectively).	('patients', 'Species', '9606', (222, 230))	('re-excision', 'CPA', (190, 201))	('ILC', 'Disease', (123, 126))	('MRI', 'Var', (162, 165))	('lower', 'NegReg', (184, 189))	('patients', 'Species', '9606', (142, 150))
45786	26163296	Thus, discriminating between malignant and benign lesions in the setting of an already diagnosed ILC is likely to increase the number of biopsies and elevate patient anxiety.	('ILC', 'Disease', (97, 100))	('anxiety', 'Disease', 'MESH:D001008', (166, 173))	('increase', 'PosReg', (114, 122))	('discriminating', 'Var', (6, 20))	('patient', 'Species', '9606', (158, 165))	('anxiety', 'Disease', (166, 173))	('anxiety', 'Phenotype', 'HP:0000739', (166, 173))	('elevate', 'PosReg', (150, 157))
45918	27102151	Compared to PMBC, MMBC had more lymph node metastasis (p = 0.043), Her2 positivity (p = 0.036), high Ki-67 index (defined as>20%, p = 0.026) and anti-Her2 targeted therapy (p = 0.016).	('PMBC', 'Chemical', '-', (12, 16))	('Her2', 'Gene', (67, 71))	('targeted', 'Reg', (155, 163))	('lymph node metastasis', 'CPA', (32, 53))	('Her2', 'Gene', '2064', (150, 154))	('Her2', 'Gene', (150, 154))	('more', 'PosReg', (27, 31))	('positivity', 'Var', (72, 82))	('MMBC', 'Chemical', '-', (18, 22))	('Her2', 'Gene', '2064', (67, 71))	('Ki-67', 'Chemical', '-', (101, 106))
45921	27102151	High Ki-67 (p = 0.020) appeared as DFS factor in PMBC, while anti-Her2 targeted therapy (p = 0.047) as the DFS predictors in MMBC.	('Ki-67', 'Chemical', '-', (5, 10))	('Her2', 'Gene', '2064', (66, 70))	('PMBC', 'Disease', (49, 53))	('Ki-67', 'Var', (5, 10))	('MMBC', 'Chemical', '-', (125, 129))	('PMBC', 'Chemical', '-', (49, 53))	('Her2', 'Gene', (66, 70))
45938	27102151	Compared to PMBC, MMBC had significantly more lymph node metastasis (p = 0.043), Her2 positivity (p = 0.036), high Ki-67 index (defined as > 20%, p = 0.026) and anti-Her2 targeted therapy (p = 0.016).	('Her2', 'Gene', (166, 170))	('PMBC', 'Chemical', '-', (12, 16))	('lymph node metastasis', 'CPA', (46, 67))	('Her2', 'Gene', '2064', (166, 170))	('positivity', 'Var', (86, 96))	('more', 'PosReg', (41, 45))	('Her2', 'Gene', (81, 85))	('MMBC', 'Chemical', '-', (18, 22))	('Her2', 'Gene', '2064', (81, 85))	('Ki-67', 'Chemical', '-', (115, 120))
46002	27659691	Indeed, excessive cell proliferation promotes accumulation of DNA damage due to insufficient timely repair and mutations.	('DNA damage', 'MPA', (62, 72))	('mutations', 'Var', (111, 120))	('insufficient timely', 'Disease', 'MESH:D000309', (80, 99))	('insufficient timely', 'Disease', (80, 99))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('cell proliferation', 'biological_process', 'GO:0008283', ('18', '36'))	('cell proliferation', 'CPA', (18, 36))
46004	27659691	Moreover, genetic and epigenetic changes in genes that regulate mammary epithelial cell proliferation and apoptosis are considered possible initiators of breast carcinogenesis.	('epigenetic changes', 'Var', (22, 40))	('breast carcinogenesis', 'Disease', (154, 175))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (154, 175))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('genetic', 'Var', (10, 17))	('initiators', 'Reg', (140, 150))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('epithelial cell proliferation', 'biological_process', 'GO:0050673', ('72', '101'))
46007	27659691	Mutations within BRCA1 and BRCA2 imply a high lifetime risk of developing carcinoma and account for most cases of familial breast cancers.	('familial breast cancers', 'Disease', 'MESH:D001943', (114, 137))	('BRCA1', 'Gene', '672', (17, 22))	('breast cancers', 'Phenotype', 'HP:0003002', (123, 137))	('BRCA2', 'Gene', '675', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('BRCA1', 'Gene', (17, 22))	('familial breast cancers', 'Disease', (114, 137))	('carcinoma', 'Disease', 'MESH:D002277', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Disease', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('BRCA2', 'Gene', (27, 32))
46024	27659691	Considering these facts, the associated immune responses to few aberrant cells in breast tissue, that may give rise to malignancies due to impaired DNA-repair mechanisms by BRCA1/2 mutations, may potentially be driving the earliest stages of cancer development.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('BRCA1/2', 'Gene', (173, 180))	('impaired', 'NegReg', (139, 147))	('DNA-repair mechanisms', 'MPA', (148, 169))	('malignancies', 'Disease', (119, 131))	('BRCA1/2', 'Gene', '672;675', (173, 180))	('mutations', 'Var', (181, 190))	('DNA-repair', 'biological_process', 'GO:0006281', ('148', '158'))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))
46029	27659691	In particular, we qualitatively analyze lobular inflammation patterns under systematic variation of model parameters, such as increased epithelial cell turnover rates influenced by different hormone levels, length of the menstrual cycle, impaired DNA-repair mechanisms due to BRCA1/2 mutations and cytotoxic immune responses.	('impaired', 'NegReg', (238, 246))	('lobular inflammation', 'Disease', 'MESH:D007249', (40, 60))	('menstrual cycle', 'biological_process', 'GO:0044850', ('221', '236'))	('inflammation', 'biological_process', 'GO:0006954', ('48', '60'))	('lobular inflammation', 'Disease', (40, 60))	('BRCA1/2', 'Gene', (276, 283))	('mutations', 'Var', (284, 293))	('DNA', 'cellular_component', 'GO:0005574', ('247', '250'))	('DNA-repair', 'MPA', (247, 257))	('DNA-repair', 'biological_process', 'GO:0006281', ('247', '257'))	('BRCA1/2', 'Gene', '672;675', (276, 283))	('increased', 'PosReg', (126, 135))
46041	27659691	We further consider a "proof-of-principle" dataset consisting of breast tissue samples obtained during surgical procedures from (i) 7 premenopausal healthy women who underwent reduction mammoplasty (RM) without clinical abnormality nor familial history of breast cancer, ages ranging from 21 to 45 years (median age 32 years), (ii) 21 premenopausal women who underwent prophylactic mastectomy (PM) due to an increased risk of hereditary breast cancer (BRCA1/2 mutations) without clinical or pathological abnormalities, ages ranging from 22 to 53 years (median age 38 years), and (iii) a cohort of 7 premenopausal women with clinically manifest breast cancer, ages ranging from 30 to 43 years (median age 41 years).	('breast cancer', 'Disease', (644, 657))	('BRCA1/2', 'Gene', '672;675', (452, 459))	('women', 'Species', '9606', (613, 618))	('breast cancer', 'Disease', (256, 269))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (426, 450))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutations', 'Var', (460, 469))	('women', 'Species', '9606', (349, 354))	('cancer', 'Phenotype', 'HP:0002664', (444, 450))	('cancer', 'Phenotype', 'HP:0002664', (651, 657))	('hereditary breast cancer', 'Disease', (426, 450))	('BRCA1/2', 'Gene', (452, 459))	('breast cancer', 'Phenotype', 'HP:0003002', (437, 450))	('breast cancer', 'Phenotype', 'HP:0003002', (644, 657))	('breast cancer', 'Phenotype', 'HP:0003002', (256, 269))	('women', 'Species', '9606', (156, 161))	('breast cancer', 'Disease', 'MESH:D001943', (437, 450))	('breast cancer', 'Disease', 'MESH:D001943', (644, 657))	('breast cancer', 'Disease', 'MESH:D001943', (256, 269))
46060	27659691	We assume that epithelial cells could become aberrantly damaged by DNA repair defects, for instance due to BRCA1/2 mutations, that result in impaired DNA-double strand break repair mechanisms.	('DNA repair', 'biological_process', 'GO:0006281', ('67', '77'))	('impaired', 'NegReg', (141, 149))	('DNA-double strand break repair mechanisms', 'MPA', (150, 191))	('mutations', 'Var', (115, 124))	('BRCA1/2', 'Gene', (107, 114))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('BRCA1/2', 'Gene', '672;675', (107, 114))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('double strand break repair', 'biological_process', 'GO:0006302', ('154', '180'))
46062	27659691	In turn, aberrantly damaged cells that are not yet cancer cells, but have the potential of malignant transformation (see hallmarks of cancer concept), are a source of chemotactic signals that attract and activate immune cells.	('attract', 'PosReg', (192, 199))	('aberrantly damaged', 'Var', (9, 27))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('malignant transformation', 'CPA', (91, 115))	('activate', 'PosReg', (204, 212))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
46103	27659691	Normalizing or shortening this phase may enhance epithelial cell damage and persistent inflammation responses, hypothetically even leading to an increased risk of developing pre-neoplastic lesions.	('inflammation', 'Disease', (87, 99))	('enhance', 'PosReg', (41, 48))	('shortening', 'Var', (15, 25))	('inflammation', 'biological_process', 'GO:0006954', ('87', '99'))	('Normalizing', 'Var', (0, 11))	('pre', 'molecular_function', 'GO:0003904', ('174', '177'))	('inflammation', 'Disease', 'MESH:D007249', (87, 99))	('epithelial cell damage', 'CPA', (49, 71))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (178, 196))
46107	27659691	As a proof of principle, we compare small cohorts of breast tissue samples from women who underwent (i) reduction mammoplasty (RM) and (ii) prophylactic mastectomy (PM) due to an increased risk for hereditary breast cancer (BRCA1/2 mutations), as well as (iii) normal lobular tissue adjacent to neoplastic tissue (NT) from women with clinically manifest breast cancer.	('women', 'Species', '9606', (80, 85))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('BRCA1/2', 'Gene', (224, 231))	('breast cancer', 'Disease', 'MESH:D001943', (354, 367))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (295, 312))	('BRCA1/2', 'Gene', '672;675', (224, 231))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (198, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('mutations', 'Var', (232, 241))	('breast cancer', 'Disease', (354, 367))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('breast cancer', 'Phenotype', 'HP:0003002', (354, 367))	('NT', 'Phenotype', 'HP:0002664', (314, 316))	('women', 'Species', '9606', (323, 328))	('hereditary breast cancer', 'Disease', (198, 222))
46115	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))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('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))
46131	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))	('cell polarity', 'biological_process', 'GO:0007163', ('89', '102'))	('human', 'Species', '9606', (7, 12))	('cell invasion', 'CPA', (104, 117))	('hyperactivation', 'Var', (23, 38))	('Rap1', 'Gene', (42, 46))	('tumor', 'Disease', (131, 136))	('mammary epithelial cell polarity', 'CPA', (70, 102))
46148	25785189	In this study, tumors positive for ER (ER+), positive or negative for PR (PR+/-), and negative for HER2 (HER2-) were classified as ER-positive.	('PR', 'Gene', '5241', (70, 72))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('HER2', 'Gene', (105, 109))	('HER2', 'Gene', '2064', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('ER (ER+', 'Var', (35, 42))	('HER2', 'Gene', (99, 103))	('HER2', 'Gene', '2064', (99, 103))	('PR', 'Gene', '5241', (74, 76))	('tumors', 'Disease', (15, 21))	('negative', 'NegReg', (57, 65))
46177	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))	('HER2', 'Gene', (33, 37))	('positivity', 'Var', (38, 48))	('Rap1', 'Gene', (68, 72))	('Vav2', 'Gene', '7410', (78, 82))	('IGF-IR', 'Gene', '3480', (60, 66))	('HER2', 'Gene', '2064', (33, 37))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('Rap1', 'Gene', '5906', (68, 72))
46187	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))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('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))
46195	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).	('DCIS /T1mic', 'Var', (109, 120))	('Vav2', 'Gene', (12, 16))	('increased', 'PosReg', (96, 105))	('Vav2', 'Gene', '7410', (12, 16))	('increased', 'PosReg', (147, 156))	('DCIS/IDC', 'Disease', (160, 168))
46199	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).	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('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))
46209	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))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('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))	('IGF-IR', 'Gene', (31, 37))	('Depletion', 'Var', (0, 9))	('IGF-IR', 'Gene', '3480', (31, 37))	('amplify', 'PosReg', (156, 163))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('repair', 'MPA', (62, 68))
46238	24080446	Previous studies investigating interactions between single nucleotide polymorphisms (SNPs) and use MHT regarding breast cancer risk predominantly pursued a candidate gene approach.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('single nucleotide polymorphisms', 'Var', (52, 83))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))
46239	24080446	The possible interaction with variants of the known genetic susceptibility loci for breast cancer in FGFR2 has not been clearly confirmed in subsequent studies.	('variants', 'Var', (30, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('breast cancer', 'Disease', (84, 97))
46257	24080446	Genotyping in NHS was part of the Cancer Genetic Markers of Susceptibility (CGEMS) project.	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer', 'Disease', (34, 40))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('NHS', 'Gene', (14, 17))	('Genotyping', 'Var', (0, 10))
46266	24080446	The strongest association was observed for rs3824418 located in and intronic region of TLE1 on 9q21.3 (Pint = 6.7x10-07.	('rs3824418', 'Var', (43, 52))	('rs3824418', 'Mutation', 'rs3824418', (43, 52))	('TLE1', 'Gene', (87, 91))	('TLE1', 'Gene', '7088', (87, 91))
46269	24080446	When analyzing the whole sample of the replication stage, the SNPs showing strongest association with current use of MHT were rs12538442, located in an intronic region of DOCK4 on chromosome 1 (P = 3.1x10-04), and rs17738984, located on chromosome 17q22 (P = 8.8x10-04).	('rs12538442', 'Mutation', 'rs12538442', (126, 136))	('chromosome', 'cellular_component', 'GO:0005694', ('180', '190'))	('chromosome', 'cellular_component', 'GO:0005694', ('237', '247'))	('rs17738984', 'Var', (214, 224))	('DOCK4', 'Gene', '9732', (171, 176))	('rs17738984', 'Mutation', 'rs17738984', (214, 224))	('DOCK4', 'Gene', (171, 176))	('association', 'Interaction', (85, 96))	('rs12538442', 'Var', (126, 136))
46270	24080446	The SNPs showing the strongest association with MHT use when restricting the sample to population-based studies were rs10924245 in KIF26B (P = 1.6x10-04) and rs2102354 in KCNN3 (P = 7.7x10-04), both located on chromosome 1.	('KCNN3', 'Gene', (171, 176))	('rs10924245', 'Var', (117, 127))	('KIF26B', 'Gene', (131, 137))	('KCNN3', 'Gene', '3782', (171, 176))	('KIF26B', 'Gene', '55083', (131, 137))	('rs2102354', 'Mutation', 'rs2102354', (158, 167))	('rs2102354', 'Var', (158, 167))	('chromosome', 'cellular_component', 'GO:0005694', ('210', '220'))	('rs10924245', 'Mutation', 'rs10924245', (117, 127))
46272	24080446	For overall breast cancer risk, two SNPs (rs9578047 and rs9579199) near POMP on chromosome 13 showed an interaction with current use of MHT with combined Pint = 7.9x10-06 and 7.6x10-06.	('breast cancer', 'Disease', (12, 25))	('rs9579199', 'Var', (56, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('rs9578047', 'Mutation', 'rs9578047', (42, 51))	('interaction', 'Interaction', (104, 115))	('rs9579199', 'Mutation', 'rs9579199', (56, 65))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('POMP', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('rs9578047', 'Var', (42, 51))	('POMP', 'Gene', '51371', (72, 76))
46273	24080446	SNPxMHT interactions with Pint of similar magnitude were also observed with rs7148646 and rs848694 in SLC25A21 on chromosome 14 (combined Pint = 1.2x10-05 and 4.6x10-05) and three SNPs (rs7192724, rs17202296, and rs4888190) in PLCG2 on chromosome 16 (combined Pint = 3.3x10-06, 2.8x10-05 and 4.5x10-05) (Table 1).	('rs7192724', 'Var', (186, 195))	('rs4888190', 'Mutation', 'rs4888190', (213, 222))	('PLCG2', 'Gene', '5336', (227, 232))	('SLC25A21', 'Gene', '89874', (102, 110))	('rs17202296', 'Mutation', 'rs17202296', (197, 207))	('rs7148646', 'Mutation', 'rs7148646', (76, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('chromosome', 'cellular_component', 'GO:0005694', ('236', '246'))	('rs7148646', 'Var', (76, 85))	('interactions', 'Interaction', (8, 20))	('rs848694', 'Var', (90, 98))	('rs4888190', 'Var', (213, 222))	('rs848694', 'Mutation', 'rs848694', (90, 98))	('SLC25A21', 'Gene', (102, 110))	('PLCG2', 'Gene', (227, 232))	('rs17202296', 'Var', (197, 207))	('rs7192724', 'Mutation', 'rs7192724', (186, 195))
46276	24080446	We combined rs7148646_G, rs9579199_G, and rs7192724_G and constructed a polygenic score to assess breast cancer risk associated with current use of MHT depending on the modifying genetic risk (number of risk modifying alleles) (Figure 2A).	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('rs7148646_G', 'Var', (12, 23))	('rs7192724', 'Mutation', 'rs7192724', (42, 51))	('rs9579199', 'Mutation', 'rs9579199', (25, 34))	('rs7148646', 'Mutation', 'rs7148646', (12, 21))	('rs9579199_G', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rs7192724_G', 'Var', (42, 53))
46279	24080446	The strongest association between current use of MHT and breast cancer risk was observed for women with a polygenic score of five or six (18.2% of women) (OR = 1.86, 95% CI 1.56 - 2.22), as expected.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('MHT', 'Gene', (49, 52))	('women', 'Species', '9606', (147, 152))	('polygenic score', 'Var', (106, 121))	('women', 'Species', '9606', (93, 98))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
46280	24080446	With respect to lobular breast cancer, the variant rs11680872 located in an intronic region of TMEFF2 on chromosome 2 showed a SNPxMHT interaction with combined Pint = 2.9x10-05 (Table 3).	('lobular breast cancer', 'Disease', (16, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lobular breast cancer', 'Disease', 'MESH:D013274', (16, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('TMEFF2', 'Gene', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (16, 37))	('rs11680872', 'Var', (51, 61))	('TMEFF2', 'Gene', '23671', (95, 101))	('rs11680872', 'Mutation', 'rs11680872', (51, 61))
46281	24080446	Also, rs7648642 in CD80 on chromosome 3 modified MHT associated lobular breast cancer risk in both case-only and case-control analysis (combined Pint = 5.1x10-06).	('rs7648642', 'Var', (6, 15))	('lobular breast cancer', 'Disease', 'MESH:D013274', (64, 85))	('lobular breast cancer', 'Disease', (64, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('27', '37'))	('MHT', 'Gene', (49, 52))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (64, 85))	('modified', 'Reg', (40, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('rs7648642', 'Mutation', 'rs7648642', (6, 15))	('CD80', 'Gene', (19, 23))
46282	24080446	The variants rs11654964, rs16970162 and rs11080292 located near TMEM132E on chromosome 17 yielded combined Pint of 2.7x10-06, 8.6x10-06 and 9.3x10-06, respectively.	('rs16970162', 'Var', (25, 35))	('TMEM132E', 'Gene', (64, 72))	('rs11080292', 'Mutation', 'rs11080292', (40, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('rs11654964', 'Mutation', 'rs11654964', (13, 23))	('rs11080292', 'Var', (40, 50))	('TMEM132E', 'Gene', '124842', (64, 72))	('rs16970162', 'Mutation', 'rs16970162', (25, 35))	('rs11654964', 'Var', (13, 23))
46283	24080446	Further SNPxMHT interactions were observed for rs6506940 and rs594334 near SLC25A52 on chromosome 18 (combined Pint = 1.2x10-05 and 3.4x10-05, respectively) (Table 1).	('SLC25A52', 'Gene', '147407', (75, 83))	('rs594334', 'Var', (61, 69))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('SLC25A52', 'Gene', (75, 83))	('rs594334', 'Mutation', 'rs594334', (61, 69))	('rs6506940', 'Mutation', 'rs6506940', (47, 56))	('rs6506940', 'Var', (47, 56))
46286	24080446	For lobular breast cancer risk, a polygenic score was constructed by combining rs11680872_A, rs7648642_C, rs11654964_A, and rs6506940_A (Figure 2B).	('rs6506940', 'Mutation', 'rs6506940', (124, 133))	('rs7648642', 'Mutation', 'rs7648642', (93, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('rs11680872_A', 'Var', (79, 91))	('rs6506940_A', 'Var', (124, 135))	('lobular breast cancer', 'Disease', (4, 25))	('rs11654964', 'Mutation', 'rs11654964', (106, 116))	('lobular breast cancer', 'Disease', 'MESH:D013274', (4, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('rs11654964_A', 'Var', (106, 118))	('rs7648642_C', 'Var', (93, 104))	('rs11680872', 'Mutation', 'rs11680872', (79, 89))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (4, 25))
46288	24080446	The association with current MHT use increased with the polygenic score and the odds ratio for lobular breast cancer was 2.20 (95% CI 1.66 - 2.92) in women with a polygenic score of six (30.9% of women) and 2.38, 95% CI 1.78 - 3.18) in those carrying seven or eight risk modifying alleles (25.8% of women).	('polygenic score', 'Var', (56, 71))	('lobular breast cancer', 'Disease', (95, 116))	('polygenic score', 'Var', (163, 178))	('association', 'Interaction', (4, 15))	('lobular breast cancer', 'Disease', 'MESH:D013274', (95, 116))	('women', 'Species', '9606', (150, 155))	('women', 'Species', '9606', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (95, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('increased', 'PosReg', (37, 46))	('women', 'Species', '9606', (299, 304))
46290	24080446	We observed three loci on chromosome 13, 14 and 16 that modified MHT associated overall breast cancer risk in both the discovery and replication stage, with combined Pint <5.0x10-05.	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('MHT', 'Gene', (65, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('associated', 'Reg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('modified', 'Var', (56, 64))
46292	24080446	When combining variants that modify the effect of current use of MHT in a polygenic score, current MHT use was associated with an 86% increased breast cancer risk among women with five to six risk modifying alleles (18.2% of all women included in the study) and was not associated with breast cancer risk among women carrying two or less (16.7% of women).	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('women', 'Species', '9606', (229, 234))	('women', 'Species', '9606', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('women', 'Species', '9606', (348, 353))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('women', 'Species', '9606', (311, 316))	('breast cancer', 'Disease', 'MESH:D001943', (286, 299))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('breast cancer', 'Phenotype', 'HP:0003002', (286, 299))	('breast cancer', 'Disease', (286, 299))	('variants', 'Var', (15, 23))	('increased', 'PosReg', (134, 143))	('MHT', 'Gene', (99, 102))
46296	24080446	The loci of the identified polymorphisms provide indication of possible biological relevance for breast carcinogenesis.	('breast carcinogenesis', 'Disease', (97, 118))	('polymorphisms', 'Var', (27, 40))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (97, 118))
46297	24080446	Two variants rs9579199 and rs9578047 close to FLT1 and POMP on chromosome 13 showed modifying effects on MHT associated breast cancer risk.	('rs9578047', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('modifying effects', 'Reg', (84, 101))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('rs9579199', 'Mutation', 'rs9579199', (13, 22))	('FLT1', 'Gene', '2321', (46, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('FLT1', 'Gene', (46, 50))	('POMP', 'Gene', (55, 59))	('rs9578047', 'Mutation', 'rs9578047', (27, 36))	('MHT associated', 'Gene', (105, 119))	('POMP', 'Gene', '51371', (55, 59))	('rs9579199', 'Var', (13, 22))
46300	24080446	The variants on chromosome 14 (rs7148646, rs848694) lie in an intronic region of SLC25A21.	('rs7148646', 'Mutation', 'rs7148646', (31, 40))	('SLC25A21', 'Gene', '89874', (81, 89))	('rs7148646', 'Var', (31, 40))	('rs848694', 'Var', (42, 50))	('rs848694', 'Mutation', 'rs848694', (42, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('16', '26'))	('SLC25A21', 'Gene', (81, 89))
46302	24080446	Interestingly, the two SNPs rs6506940 and rs594334 found to modify risk of lobular breast cancer are located near another mitochondrial carrier gene, SLC25A52, on chromosome 18.	('chromosome', 'cellular_component', 'GO:0005694', ('163', '173'))	('carrier', 'molecular_function', 'GO:0005215', ('136', '143'))	('lobular breast cancer', 'Disease', (75, 96))	('SLC25A52', 'Gene', (150, 158))	('SLC25A52', 'Gene', '147407', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lobular breast cancer', 'Disease', 'MESH:D013274', (75, 96))	('rs594334', 'Mutation', 'rs594334', (42, 50))	('rs594334', 'Var', (42, 50))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (75, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('rs6506940', 'Mutation', 'rs6506940', (28, 37))	('rs6506940', 'Var', (28, 37))
46304	24080446	The association between MHT and breast cancer was also modified by rs7192724, rs17202296 and rs4888190 located in intronic regions of PLCG2.	('breast cancer', 'Disease', (32, 45))	('rs7192724', 'Mutation', 'rs7192724', (67, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('modified', 'Reg', (55, 63))	('rs17202296', 'Var', (78, 88))	('association', 'Interaction', (4, 15))	('MHT', 'Gene', (24, 27))	('rs7192724', 'Var', (67, 76))	('rs4888190', 'Mutation', 'rs4888190', (93, 102))	('rs17202296', 'Mutation', 'rs17202296', (78, 88))	('PLCG2', 'Gene', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('rs4888190', 'Var', (93, 102))	('PLCG2', 'Gene', '5336', (134, 139))
46306	24080446	With respect to lobular breast cancer, genetic variants in two transmembrane proteins were implicated.	('lobular breast cancer', 'Disease', (16, 37))	('genetic variants', 'Var', (39, 55))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lobular breast cancer', 'Disease', 'MESH:D013274', (16, 37))	('implicated', 'Reg', (91, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (16, 37))	('two transmembrane proteins', 'Protein', (59, 85))	('transmembrane', 'cellular_component', 'GO:0044214', ('63', '76'))	('transmembrane', 'cellular_component', 'GO:0016021', ('63', '76'))
46307	24080446	rs11680872 is located in an intron of TMEFF2, whose biological function is unclear but its promoter region has been commonly found to be hypermethylated in various cancers, including breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('rs11680872', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('TMEFF2', 'Gene', (38, 44))	('TMEFF2', 'Gene', '23671', (38, 44))	('cancers', 'Disease', (164, 171))	('rs11680872', 'Mutation', 'rs11680872', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', (183, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
46308	24080446	Three variants (rs11654964, rs16970162 and rs11080292) are near (23-32kb 3') TMEM132E, another transmembrane protein.	('rs16970162', 'Var', (28, 38))	('rs11654964', 'Mutation', 'rs11654964', (16, 26))	('rs11080292', 'Mutation', 'rs11080292', (43, 53))	('TMEM132E', 'Gene', (77, 85))	('rs11080292', 'Var', (43, 53))	('rs11654964', 'Var', (16, 26))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('transmembrane', 'cellular_component', 'GO:0044214', ('95', '108'))	('transmembrane', 'cellular_component', 'GO:0016021', ('95', '108'))	('rs16970162', 'Mutation', 'rs16970162', (28, 38))	('TMEM132E', 'Gene', '124842', (77, 85))
46309	24080446	We observed also an interaction with rs7648642, which lies in an intron of CD80 on chromosome 3.	('CD80', 'Gene', (75, 79))	('interaction', 'Interaction', (20, 31))	('rs7648642', 'Mutation', 'rs7648642', (37, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('rs7648642', 'Var', (37, 46))
46314	24080446	One exception is with respect to variants in FGFR2, since it is also a know breast cancer susceptibility loci.	('FGFR2', 'Gene', '2263', (45, 50))	('FGFR2', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('FGFR', 'molecular_function', 'GO:0005007', ('45', '49'))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('variants', 'Var', (33, 41))
46315	24080446	reported that the association between combined estrogen-progestogen therapy and breast cancer risk was modified by rs1219648 in postmenopausal women of European descent (Pint = 0.010).	('modified', 'Reg', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('association', 'Interaction', (18, 29))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('rs1219648', 'Mutation', 'rs1219648', (115, 124))	('rs1219648', 'Var', (115, 124))	('breast cancer', 'Disease', (80, 93))	('women', 'Species', '9606', (143, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
46316	24080446	A study conducted in participants of the Women's Health Initiative trial could not replicate this finding (Pint = 0.661) but observed an interaction with rs3750817 in FGFR2 (Pint = 0.033).	('rs3750817', 'Mutation', 'rs3750817', (154, 163))	('participants', 'Species', '9606', (21, 33))	('Women', 'Species', '9606', (41, 46))	('rs3750817', 'Var', (154, 163))	('FGFR2', 'Gene', '2263', (167, 172))	('FGFR2', 'Gene', (167, 172))	('FGFR', 'molecular_function', 'GO:0005007', ('167', '171'))
46317	24080446	The variants rs1219648 and rs3750817 are in moderate LD (r2 = 0.44, D' = 1.00).	('rs1219648', 'Var', (13, 22))	('rs3750817', 'Mutation', 'rs3750817', (27, 36))	('rs3750817', 'Var', (27, 36))	('rs1219648', 'Mutation', 'rs1219648', (13, 22))
46318	24080446	However, we did not observe an interaction regarding breast cancer risk with current use of any MHT and rs1219648 (Pint = 0.15) or rs3750817 (Pint = 0.23) in the genome-wide association study and the variants were not followed up in the replication stage.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('MHT', 'Gene', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('rs1219648', 'Mutation', 'rs1219648', (104, 113))	('rs3750817', 'Mutation', 'rs3750817', (131, 140))	('rs1219648', 'Var', (104, 113))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('breast cancer', 'Disease', (53, 66))	('rs3750817', 'Var', (131, 140))
46319	24080446	In conclusion, the association between current use of MHT and risk of overall and lobular breast cancer is potentially modified by genetic variants in genes related to mitochondrial solute carriers, transmembrane signaling as well as immune cell activation.	('lobular breast cancer', 'Disease', (82, 103))	('signaling', 'biological_process', 'GO:0023052', ('213', '222'))	('lobular breast cancer', 'Disease', 'MESH:D013274', (82, 103))	('transmembrane', 'cellular_component', 'GO:0016021', ('199', '212'))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (82, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('MHT', 'Gene', (54, 57))	('overall', 'Disease', (70, 77))	('variants', 'Var', (139, 147))	('modified', 'Reg', (119, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('immune cell activation', 'biological_process', 'GO:0045321', ('234', '256'))	('transmembrane', 'cellular_component', 'GO:0044214', ('199', '212'))
46338	23227243	The YKL-40 gene consists of 10 exons located within 8 kb of DNA on human chromosome 1q32.1, and encodes a protein of 383 amino acids with an N terminal sequence of Tyr-Lys-Leu (YKL), hence the name, YKL-40.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('Tyr-Lys-Leu', 'Var', (164, 175))	('Leu', 'Chemical', 'MESH:D007930', (172, 175))	('YKL-40', 'Gene', '1116', (199, 205))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('YKL-40', 'Gene', '1116', (4, 10))	('YKL-40', 'Gene', (199, 205))	('Tyr', 'Chemical', 'MESH:D014443', (164, 167))	('human', 'Species', '9606', (67, 72))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('YKL-40', 'Gene', (4, 10))	('Lys', 'Chemical', 'MESH:D008239', (168, 171))
46341	23227243	High YKL-40 expression is associated with high grade ovarian cancer, and with poor prognosis of endometrial cancer, small cell lung cancer, glioma, colorectal cancer, hepatocellular carcinoma, gastric cancer, and breast cancer.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('endometrial cancer', 'Disease', (96, 114))	('ovarian cancer', 'Disease', (53, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('endometrial cancer', 'Disease', 'MESH:D016889', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('hepatocellular carcinoma', 'Disease', (167, 191))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('High', 'Var', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('YKL-40', 'Gene', (5, 11))	('small cell lung cancer', 'Disease', 'MESH:D055752', (116, 138))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', (213, 226))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('small cell lung cancer', 'Disease', (116, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('colorectal cancer', 'Disease', (148, 165))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (167, 191))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('YKL-40', 'Gene', '1116', (5, 11))	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('gastric cancer', 'Disease', (193, 207))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('endometrial cancer', 'Phenotype', 'HP:0012114', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('glioma', 'Disease', (140, 146))	('expression', 'MPA', (12, 22))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (167, 191))	('associated', 'Reg', (26, 36))
46344	23227243	Several independent studies demonstrated that high YKL-40 serum concentrations were associated with poor prognosis of breast cancer patients.	('high', 'Var', (46, 50))	('serum concentrations', 'MPA', (58, 78))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('YKL-40', 'Gene', '1116', (51, 57))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('associated', 'Reg', (84, 94))	('YKL-40', 'Gene', (51, 57))	('breast cancer', 'Disease', (118, 131))	('patients', 'Species', '9606', (132, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
46345	23227243	High YKL-40 serum concentrations were significantly associated with visceral metastases, shorter overall survival and recurrence-free survival, as well as aggressiveness of metastases.	('recurrence-free survival', 'CPA', (118, 142))	('visceral metastases', 'Disease', (68, 87))	('High', 'Var', (0, 4))	('YKL-40', 'Gene', (5, 11))	('overall survival', 'CPA', (97, 113))	('associated', 'Reg', (52, 62))	('serum concentrations', 'MPA', (12, 32))	('aggressiveness of metastases', 'Disease', (155, 183))	('visceral metastases', 'Disease', 'MESH:D009362', (68, 87))	('aggressiveness of metastases', 'Disease', 'MESH:D009362', (155, 183))	('YKL-40', 'Gene', '1116', (5, 11))	('shorter', 'NegReg', (89, 96))	('aggressiveness', 'Phenotype', 'HP:0000718', (155, 169))
46413	23227243	The estimated mean survival time of patients with positive YKL-40 intratumoral expression was 55.13 months (95% CI: 49.69 to 60.58 months) whereas that of patients with negative tumor tissue was significantly longer at 65.78 months (95% CI: 60.17 to 71.40 months; P = 0.017 as determined by the Log-rank test) (Figure 3).	('tumor', 'Disease', (178, 183))	('patients', 'Species', '9606', (36, 44))	('longer', 'PosReg', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('YKL-40', 'Gene', '1116', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('patients', 'Species', '9606', (155, 163))	('YKL-40', 'Gene', (59, 65))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('positive', 'Var', (50, 58))
46414	23227243	Similarly, the Kaplan-Meier analysis and the Log-rank test showed that the disease-free survival time was significantly shorter in patients with YKL-40 positive intratumoral staining (36 months [95% CI: 28.95 to 43.05 months]) than those with YKL-40 negative intratumoral staining (49 months [95% CI: 38.23 to 59.77 months]; P = 0.001) (Figure 4).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('patients', 'Species', '9606', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('shorter', 'NegReg', (120, 127))	('YKL-40', 'Gene', '1116', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (264, 269))	('YKL-40', 'Gene', (243, 249))	('tumor', 'Disease', (166, 171))	('YKL-40', 'Gene', '1116', (145, 151))	('positive', 'Var', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('disease-free survival time', 'CPA', (75, 101))	('YKL-40', 'Gene', (145, 151))
46420	23227243	In our study, high YKL-40 intratumoral expression was also significantly more prevalent breast cancer patients with metastases compared with patients who did not have metastatic disease, which agrees with the studies of Johansen et al, and Jensen et al..	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('YKL-40', 'Gene', (19, 25))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Disease', (31, 36))	('patients', 'Species', '9606', (141, 149))	('YKL-40', 'Gene', '1116', (19, 25))	('high', 'Var', (14, 18))	('more', 'PosReg', (73, 77))	('metastases', 'Disease', (116, 126))	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
46424	23227243	High YKL-40 serum concentrations were significantly associated with invasive lobular carcinoma, TMN stage III, lymph node metastases, and death in our study.	('TMN', 'Disease', (96, 99))	('TMN', 'Disease', 'MESH:C562476', (96, 99))	('High', 'Var', (0, 4))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (77, 94))	('YKL-40', 'Gene', (5, 11))	('death', 'Disease', 'MESH:D003643', (138, 143))	('death', 'Disease', (138, 143))	('serum concentrations', 'MPA', (12, 32))	('metastases', 'Disease', (122, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('associated with', 'Reg', (52, 67))	('invasive lobular carcinoma', 'Disease', (68, 94))	('YKL-40', 'Gene', '1116', (5, 11))	('metastases', 'Disease', 'MESH:D009362', (122, 132))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (68, 94))
46425	23227243	Similarly, Yamac et al found high YKL-40 serum concentrations were associated with early death.	('high', 'Var', (29, 33))	('serum concentrations', 'MPA', (41, 61))	('YKL-40', 'Gene', '1116', (34, 40))	('death', 'Disease', 'MESH:D003643', (89, 94))	('early', 'Disease', (83, 88))	('death', 'Disease', (89, 94))	('YKL-40', 'Gene', (34, 40))	('associated with', 'Reg', (67, 82))
46426	23227243	A significant association was observed between metastases-positive breast cancer and high YKL-40 serum concentrations in several studies including ours but not in node-positive breast cancer in the study of Yamac et al.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('breast cancer', 'Disease', (177, 190))	('metastases-positive breast cancer', 'Disease', 'MESH:D009362', (47, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('high', 'Var', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('serum concentrations', 'MPA', (97, 117))	('YKL-40', 'Gene', '1116', (90, 96))	('metastases-positive breast cancer', 'Disease', (47, 80))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('YKL-40', 'Gene', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
46433	23227243	As shown in our study, at early and intermediate stages of follow-up, the YKL-40 positive tumor group had a shorter overall survival and disease-free survival than the YKL-40 negative tumor group.	('YKL-40', 'Gene', '1116', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('YKL-40', 'Gene', '1116', (168, 174))	('disease-free survival', 'CPA', (137, 158))	('positive', 'Var', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('shorter', 'NegReg', (108, 115))	('YKL-40', 'Gene', (74, 80))	('tumor', 'Disease', (184, 189))	('YKL-40', 'Gene', (168, 174))	('overall survival', 'CPA', (116, 132))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
46458	26557763	Because the response rate to hormonal treatment in breast cancer is associated with the presence of ER and PR, assessment of receptor expression profile allows clinicians to predict breast cancer response to hormonal treatment.	('associated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ER', 'Gene', '2099', (100, 102))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancer', 'Disease', (182, 195))	('presence', 'Var', (88, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))
46492	26557763	Analysing the pre-operative staging of studied cancers, it was found that the largest group among the IDC tumours were those described as stage T1c (38%) and T2 (46%) (T1c - larger than 1 cm, up to 2 cm in diameter, T2 - tumour larger than 2 cm but not exceeding 5 cm in diameter).	('IDC tumours', 'Disease', 'MESH:D009369', (102, 113))	('tumour', 'Disease', (221, 227))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('IDC tumours', 'Disease', (102, 113))	('cancers', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('tumour', 'Disease', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('pre', 'molecular_function', 'GO:0003904', ('14', '17'))	('T2 -', 'Var', (216, 220))
46565	26557763	On the basis of a number of studies, researchers speculate that the presence of beta receptors in tumour cells may prove to be a beneficial prognostic factor.	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('beta receptors', 'Protein', (80, 94))	('tumour', 'Disease', (98, 104))	('presence', 'Var', (68, 76))	('beneficial', 'PosReg', (129, 139))
46575	26147197	A previous study showed that altered expression of mRNA in cancer tissue may play an oncogenic role and promote tumor development; therefore, in the present findings, we focus only on the overexpression of VGCCs in different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('altered', 'Var', (29, 36))	('promote', 'PosReg', (104, 111))	('tumor', 'Disease', (112, 117))	('expression', 'MPA', (37, 47))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
46589	26147197	For instance, slight variations in Ca2+ could regulate specific cell functions, whereas a substantial alteration of Ca2+ could be responsible for cell proliferation and motility or even cell apoptosis.	('regulate', 'Reg', (46, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('191', '200'))	('apoptosis', 'biological_process', 'GO:0006915', ('191', '200'))	('responsible', 'Reg', (130, 141))	('variations', 'Var', (21, 31))	('specific cell functions', 'CPA', (55, 78))	('motility', 'CPA', (169, 177))	('Ca2+', 'Chemical', 'MESH:D000069285', (35, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('146', '164'))	('cell proliferation', 'CPA', (146, 164))	('Ca2+', 'Chemical', 'MESH:D000069285', (116, 120))
46591	26147197	The L-type, N-Type, P-type, T-type and R-type calcium channels that constitute the VGCC family are involved in the development of various types of cancer (Table 1).	('P-type', 'Var', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('calcium', 'Chemical', 'MESH:D002118', (46, 53))	('involved', 'Reg', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
46596	26147197	A previous study showed that altered gene expression in cancer tissue may play an oncogenic role and promote tumor development; therefore, in the present findings, we focus only on the overexpression of VGCCs in different types of cancer.	('promote', 'PosReg', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('gene expression', 'biological_process', 'GO:0010467', ('37', '52'))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('altered', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', (109, 114))
46622	26147197	Several calcium channel blockers, such as verapamil, nifedipine, TH-1177, 2-APB, and SK&F 96365, have been confirmed to inhibit receptor-gated calcium channels, but the particular subtypes of calcium channel have not been investigated.	('nifedipine', 'Chemical', 'MESH:D009543', (53, 63))	('calcium', 'Chemical', 'MESH:D002118', (8, 15))	('inhibit receptor-gated calcium', 'MPA', (120, 150))	('APB', 'Gene', (76, 79))	('verapamil', 'Chemical', 'MESH:D014700', (42, 51))	('calcium', 'Chemical', 'MESH:D002118', (192, 199))	('APB', 'Gene', '6051', (76, 79))	('calcium', 'Chemical', 'MESH:D002118', (143, 150))	('TH-1177', 'Chemical', 'MESH:C405269', (65, 72))	('SK&', 'Var', (85, 88))
46627	26147197	Ca2+ channel activity also triggers oxidative phosphorylation, programmed cell death, and alterations in the apoptosis signaling pathway.	('alterations', 'Reg', (90, 101))	('Ca2+ channel activity', 'Var', (0, 21))	('Ca2+', 'Chemical', 'MESH:D000069285', (0, 4))	('oxidative phosphorylation', 'MPA', (36, 61))	('apoptosis signaling', 'biological_process', 'GO:0006915', ('109', '128'))	('triggers', 'Reg', (27, 35))	('signaling pathway', 'biological_process', 'GO:0007165', ('119', '136'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('36', '61'))	('channel activity', 'molecular_function', 'GO:0015267', ('5', '21'))	('programmed cell death', 'CPA', (63, 84))	('apoptosis signaling pathway', 'Pathway', (109, 136))	('programmed cell death', 'biological_process', 'GO:0012501', ('63', '84'))
46659	26147197	Different mutations in alpha subunit 1A lead to certain neuronal degradation diseases such as episodic ataxia type-2, familial hemiplegic migraine and spinocerebellar ataxia type-6.	('episodic ataxia type-2', 'Disease', (94, 116))	('neuronal degradation diseases', 'Disease', (56, 85))	('neuronal degradation diseases', 'Disease', 'MESH:D055959', (56, 85))	('lead to', 'Reg', (40, 47))	('spinocerebellar ataxia type-6', 'Disease', (151, 180))	('episodic ataxia', 'Phenotype', 'HP:0002131', (94, 109))	('ataxia', 'Phenotype', 'HP:0001251', (103, 109))	('degradation', 'biological_process', 'GO:0009056', ('65', '76'))	('migraine', 'Phenotype', 'HP:0002076', (138, 146))	('familial hemiplegic migraine', 'Disease', 'MESH:D020325', (118, 146))	('familial hemiplegic migraine', 'Disease', (118, 146))	('episodic ataxia type-2', 'Disease', 'MESH:C535506', (94, 116))	('spinocerebellar ataxia type-6', 'Disease', 'MESH:D020754', (151, 180))	('mutations', 'Var', (10, 19))	('ataxia', 'Phenotype', 'HP:0001251', (167, 173))
46703	26147197	The BMC Cancer database revealed CACNA1C expression in invasive lobular breast carcinoma/normal tissue with a 1.9-fold change (Table 2); thus, we speculated that patients with invasive lobular breast carcinoma with high expression of CACNA1C relative to normal tissue were at risk for metastasis to the gastrointestinal tract, peritoneum, retroperitoneum, and gynecological organs.	('gastrointestinal tract', 'Disease', (303, 325))	('metastasis', 'CPA', (285, 295))	('high expression', 'Var', (215, 230))	('patients', 'Species', '9606', (162, 170))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (55, 88))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (303, 325))	('CACNA1C', 'Gene', (234, 241))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (176, 209))	('breast carcinoma', 'Phenotype', 'HP:0003002', (72, 88))	('breast carcinoma', 'Phenotype', 'HP:0003002', (193, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('invasive lobular breast carcinoma', 'Disease', (55, 88))	('invasive lobular breast carcinoma', 'Disease', (176, 209))	('CACNA1C', 'Gene', '775', (33, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('CACNA1C', 'Gene', (33, 40))	('Cancer', 'Phenotype', 'HP:0002664', (8, 14))	('CACNA1C', 'Gene', '775', (234, 241))
46704	26147197	The TCGA and PNAS databases indicated that CACNA1D was significantly overexpressed relative to normal tissue in invasive lobular breast carcinoma with invasive ductal and lobular carcinoma (Table 2), which again implies that patients with high expression of CACNA1D were likely to develop those diseases.	('CACNA1D', 'Gene', (258, 265))	('lobular carcinoma', 'Disease', 'MESH:D018275', (171, 188))	('develop', 'PosReg', (281, 288))	('overexpressed', 'PosReg', (69, 82))	('lobular carcinoma', 'Disease', (171, 188))	('patients', 'Species', '9606', (225, 233))	('high expression', 'Var', (239, 254))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (171, 188))	('breast carcinoma', 'Phenotype', 'HP:0003002', (129, 145))	('invasive lobular breast carcinoma', 'Disease', 'MESH:D018275', (112, 145))	('CACNA1D', 'Gene', '776', (43, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('CACNA1D', 'Gene', (43, 50))	('CACNA1D', 'Gene', '776', (258, 265))	('invasive lobular breast carcinoma', 'Disease', (112, 145))
46708	26147197	The Nat Med database showed a 2.3-fold change in CACNA1I in invasive breast carcinoma stroma, again implying that patients with high CACNA1G expression would likely develop cancer.	('breast carcinoma', 'Phenotype', 'HP:0003002', (69, 85))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('Nat', 'Gene', '6046', (4, 7))	('develop', 'PosReg', (165, 172))	('CACNA1I', 'Gene', (49, 56))	('cancer', 'Disease', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('CACNA1I', 'Gene', '8911', (49, 56))	('Nat', 'Gene', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CACNA1G', 'Gene', (133, 140))	('CACNA1G', 'Gene', '8913', (133, 140))	('high', 'Var', (128, 132))	('invasive breast carcinoma stroma', 'Disease', (60, 92))	('patients', 'Species', '9606', (114, 122))	('invasive breast carcinoma stroma', 'Disease', 'MESH:D018270', (60, 92))	('change', 'Reg', (39, 45))
46730	26147197	A recent study indicated an association between oncogenic K-Ras IP3-dependent suppression and a calcium release mechanism that strongly suggests a role for IP3 in the function of ligand-gated calcium channels involved in colorectal cancer.	('ligand', 'molecular_function', 'GO:0005488', ('179', '185'))	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('calcium release mechanism', 'MPA', (96, 121))	('K-Ras', 'Gene', '3845', (58, 63))	('IP3', 'Chemical', 'MESH:D015544', (156, 159))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('oncogenic', 'Var', (48, 57))	('K-Ras', 'Gene', (58, 63))	('calcium', 'Chemical', 'MESH:D002118', (192, 199))	('calcium', 'Chemical', 'MESH:D002118', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('IP3', 'Chemical', 'MESH:D015544', (64, 67))	('suppression', 'NegReg', (78, 89))	('colorectal cancer', 'Disease', (221, 238))
46762	31508489	However, the only significant predictor of successful re-excision lumpectomy was node negative status (which the majority [76.1%] of these patients had).	('node negative status', 'Var', (81, 101))	('patients', 'Species', '9606', (139, 147))	('lumpectomy', 'Disease', (66, 76))
46795	26392358	In contrast to ductal tumors, most lobular tumors show loss of E-cadherin expression, which often results from inactivating gene mutation and subsequent loss of heterozygosity or promoter hypermethylation.	('inactivating gene mutation', 'Var', (111, 137))	('E-cadherin', 'Protein', (63, 73))	('expression', 'MPA', (74, 84))	('ductal tumors', 'Disease', 'MESH:D044584', (15, 28))	('loss', 'NegReg', (55, 59))	('lobular tumors', 'Disease', 'MESH:D018275', (35, 49))	('ductal tumors', 'Disease', (15, 28))	('loss', 'NegReg', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('lobular tumors', 'Disease', (35, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))	('promoter', 'MPA', (179, 187))
46797	26392358	Furthermore, pleomorphic ILC tumors have been reported to be significantly larger than classic ILC tumors, and pleomorphic ILC patients often present with lymph node involvement and a higher rate of metastatic disease compared to classical ILC.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('pleomorphic ILC tumors', 'Disease', 'MESH:C538229', (13, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('metastatic disease', 'CPA', (199, 217))	('patients', 'Species', '9606', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('pleomorphic ILC', 'Var', (111, 126))	('pleomorphic ILC tumors', 'Disease', (13, 35))	('lymph node involvement', 'CPA', (155, 177))	('tumors', 'Disease', (99, 105))
46798	26392358	Moreover, the overall survival and recurrence rates of pleomorphic ILC patients are worse compared to classic ILC patients, indicating that pleomorphic ILC is a more aggressive form of breast cancer than classic ILC.	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('patients', 'Species', '9606', (71, 79))	('breast cancer', 'Disease', (185, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('pleomorphic', 'Var', (140, 151))
46801	26392358	Cytosolic translocation of p120-catenin due to inactivation of E-cadherin is a hallmark of ILC, whereas classic and pleomorphic ILCs do not over-express the epidermal growth factor receptor (EGFR) gene.	('inactivation', 'Var', (47, 59))	('E-cadherin', 'Protein', (63, 73))	('epidermal growth factor receptor', 'Gene', (157, 189))	('EGFR', 'molecular_function', 'GO:0005006', ('191', '195'))	('Cytosolic translocation', 'MPA', (0, 23))	('p120-catenin', 'Gene', (27, 39))	('ILC', 'Disease', (91, 94))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('epidermal growth factor receptor', 'Gene', '1956', (157, 189))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('157', '180'))	('p120-catenin', 'Gene', '1500', (27, 39))	('cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))
46803	26392358	Moreover, although the somatic TP53 mutation frequency in pleomorphic ILC may be as high as 46 %, this is a rare event in classic ILC (approximately 6 %), suggesting a role for p53 loss in the etiology of pleomorphic ILC.	('pleomorphic ILC', 'Disease', (205, 220))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('pleomorphic ILC', 'Disease', (58, 73))	('loss', 'NegReg', (181, 185))	('mutation', 'Var', (36, 44))
46806	26392358	The origin of pleomorphic ILC tumors is still under debate and, since results from conditional mouse models have suggested that all lobular cancer types are evolutionary linked (reviewed in), It is currently unclear whether pleomorphic ILC is a dedifferentiated form of classic ILC or whether it evolves from ductal type tumors.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('pleomorphic ILC tumors', 'Disease', 'MESH:C538229', (14, 36))	('lobular cancer', 'Disease', 'MESH:D013274', (132, 146))	('pleomorphic', 'Var', (224, 235))	('mouse', 'Species', '10090', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('lobular cancer', 'Phenotype', 'HP:0030076', (132, 146))	('ductal type tumors', 'Disease', (309, 327))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lobular cancer', 'Disease', (132, 146))	('ductal type tumors', 'Disease', 'MESH:D044584', (309, 327))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('pleomorphic ILC tumors', 'Disease', (14, 36))
46811	26392358	Hence, methylation patterns may give insight in tumor progression and, thus, shed light on the precursor origin of pleomorphic ILC tumors.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (48, 53))	('pleomorphic ILC tumors', 'Disease', (115, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('methylation', 'Var', (7, 18))	('pleomorphic ILC tumors', 'Disease', 'MESH:C538229', (115, 137))	('tumor', 'Disease', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('insight', 'Reg', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
46829	26392358	The ME001-C2 MS-MLPA probe mix contains 26 probes, detecting the methylation status of promoter CpG sites of 24 established and putative tumor suppressor genes (Table 2) that are frequently silenced by hypermethylation in tumors, but not in blood-derived DNA of healthy individuals.	('hypermethylation', 'Var', (202, 218))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('tumor', 'Disease', (137, 142))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor suppressor', 'biological_process', 'GO:0051726', ('137', '153'))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('silenced', 'NegReg', (190, 198))	('ME001-C2 MS-MLPA', 'Disease', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('DNA', 'cellular_component', 'GO:0005574', ('255', '258'))	('tumors', 'Disease', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ME001-C2 MS-MLPA', 'Disease', 'OMIM:217000', (4, 20))
46836	26392358	In logistic regression analyses TP73 (p = 0.017) and RASSF1A (p = 0.005) showed a joint independent discriminative value for pleomorphic ILCs versus classic ILCs (area under the curve (AUC) 0.888, CI 0.764-1.000, p < 0.001), with a combined receiver operating characteristic (ROC) curve-based sensitivity and specificity of 81 and 100 %, respectively.	('TP73', 'Gene', '7161', (32, 36))	('TP73', 'Gene', (32, 36))	('pleomorphic', 'Var', (125, 136))
46837	26392358	After correction for multiple comparisons, we found that the methylation levels of both MLH1_y (p = 0.001) and BRCA1 (p = 0.002) were significantly lower in pleomorphic ILCs than in IDCs (Fig.	('methylation levels', 'MPA', (61, 79))	('MLH1', 'Gene', '4292', (88, 92))	('pleomorphic', 'Var', (157, 168))	('MLH1', 'Gene', (88, 92))	('BRCA1', 'Gene', '672', (111, 116))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('lower', 'NegReg', (148, 153))	('BRCA1', 'Gene', (111, 116))
46839	26392358	Logistic regression analysis showed that only BRCA1 methylation (p = 0.002) had an independent discriminative value for pleomorphic ILC versus IDC (area under the curve (AUC) 781, CI 0.623-0.939, p = 0.004), with a ROC curve-based sensitivity and specificity of 75 and 81 %, respectively.	('BRCA1', 'Gene', '672', (46, 51))	('pleomorphic ILC', 'Disease', (120, 135))	('BRCA1', 'Gene', (46, 51))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('methylation', 'Var', (52, 63))	('IDC', 'Disease', (143, 146))
46845	26392358	Interestingly, we found a significant association between the presence of MLH1_x (p = 0.013) and BRCA1 (p = 0.013) promoter methylation and a high MAI (>12), and between MLH1_x and BRCA1 promoter methylation (p = 0.004) (data not shown).	('BRCA1', 'Gene', '672', (181, 186))	('MLH1', 'Gene', '4292', (74, 78))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('MLH1', 'Gene', (74, 78))	('promoter methylation', 'MPA', (187, 207))	('BRCA1', 'Gene', (181, 186))	('BRCA1', 'Gene', '672', (97, 102))	('methylation', 'biological_process', 'GO:0032259', ('196', '207'))	('promoter', 'MPA', (115, 123))	('BRCA1', 'Gene', (97, 102))	('MLH1', 'Gene', '4292', (170, 174))	('MLH1', 'Gene', (170, 174))	('presence', 'Var', (62, 70))
46846	26392358	Previously, BRCA1 promoter methylation has been observed in 10-15 % of all sporadic breast cancer patients.	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('patients', 'Species', '9606', (98, 106))	('methylation', 'Var', (27, 38))	('BRCA1', 'Gene', '672', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))	('observed', 'Reg', (48, 56))	('BRCA1', 'Gene', (12, 17))
46847	26392358	Only 4-5 % of the lobular breast tumors carry a deleterious BRCA1 mutation, and none of the 11 previously analyzed ILC samples showed BRCA1 hypermethylation.	('BRCA1', 'Gene', (60, 65))	('lobular breast tumors', 'Disease', 'MESH:D018275', (18, 39))	('BRCA1', 'Gene', (134, 139))	('breast tumor', 'Phenotype', 'HP:0100013', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('lobular breast tumors', 'Disease', (18, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('mutation', 'Var', (66, 74))	('BRCA1', 'Gene', '672', (60, 65))	('BRCA1', 'Gene', '672', (134, 139))	('breast tumors', 'Phenotype', 'HP:0100013', (26, 39))
46854	26392358	Although TP73 promoter methylation has been correlated with a poor survival of breast cancer patients, this methylation also impairs binding of the transcriptional repressor ZEB1, which may result in an increase in TP73 expression.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('breast cancer', 'Disease', (79, 92))	('TP73', 'Gene', (215, 219))	('TP73', 'Gene', (9, 13))	('ZEB1', 'Gene', (174, 178))	('impairs', 'NegReg', (125, 132))	('patients', 'Species', '9606', (93, 101))	('methylation', 'Var', (108, 119))	('increase', 'PosReg', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('binding', 'molecular_function', 'GO:0005488', ('133', '140'))	('ZEB1', 'Gene', '6935', (174, 178))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('expression', 'MPA', (220, 230))	('TP73', 'Gene', '7161', (9, 13))	('TP73', 'Gene', '7161', (215, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('binding', 'Interaction', (133, 140))
46859	26392358	Also, hypermethylation of RASSF1A in pre-operative serum of breast cancer patients has been found to serve as an independent prognostic marker correlated with a poor overall survival.	('breast cancer', 'Disease', (60, 73))	('pre', 'molecular_function', 'GO:0003904', ('37', '40'))	('hypermethylation', 'Var', (6, 22))	('correlated with', 'Reg', (143, 158))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('RASSF1A', 'Gene', (26, 33))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
46860	26392358	Since RASSF1A hypermethylation is rarely observed in normal breast tissues, it is considered to be an early event in breast cancer development and, as such, it may serve as a promising breast cancer biomarker.	('hypermethylation', 'Var', (14, 30))	('RASSF1A', 'Gene', (6, 13))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('breast cancer', 'Disease', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
46866	26392358	These findings, combined with our data showing increased RASSF1A promoter methylation in pleomorphic ILC, renders RASSF1A into an interesting and functional biomarker for lobular breast cancer.	('promoter methylation', 'MPA', (65, 85))	('lobular breast cancer', 'Disease', (171, 192))	('RASSF1A', 'Var', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lobular breast cancer', 'Disease', 'MESH:D013274', (171, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('increased', 'PosReg', (47, 56))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (171, 192))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('RASSF1A', 'Gene', (57, 64))
46915	19267929	It was reported that one family member, ADAM23, is down-regulated by promoter hypermethylation.	('ADAM23', 'Gene', (40, 46))	('promoter hypermethylation', 'Var', (69, 94))	('down-regulated', 'NegReg', (51, 65))	('ADAM23', 'Gene', '8745', (40, 46))
46927	19267929	Methylation frequency in invasive lobular carcinoma (ILC) was 76.2% compared with 25.5% in invasive ductal carcinoma (IDC), and this difference was statistically significant (p = 0.0002).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('invasive lobular carcinoma', 'Disease', (25, 51))	('Methylation', 'Var', (0, 11))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (25, 51))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (34, 51))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (91, 116))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (100, 116))	('invasive ductal carcinoma', 'Disease', (91, 116))	('C', 'Chemical', 'MESH:D002244', (120, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
46928	19267929	ADAM33 gene silencing may be related to the discohesive histological appearance of ILCs.	('gene silencing', 'biological_process', 'GO:0016458', ('7', '21'))	('ADAM33', 'Gene', (0, 6))	('ADAM33', 'Gene', '80332', (0, 6))	('gene silencing', 'Var', (7, 21))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('ILCs', 'Disease', (83, 87))
46932	19267929	Several single-nucleotide polymorphisms have been associated with asthma and bronchial hyperresponsiveness.	('associated', 'Reg', (50, 60))	('asthma', 'Phenotype', 'HP:0002099', (66, 72))	('single-nucleotide polymorphisms', 'Var', (8, 39))	('asthma and bronchial hyperresponsiveness', 'Disease', 'MESH:D001249', (66, 106))
46940	19267929	It was recently reported that ADAM33 is silenced by methylation in airway epithelial cells.	('ADAM33', 'Gene', '80332', (30, 36))	('methylation', 'Var', (52, 63))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('ADAM33', 'Gene', (30, 36))
46941	19267929	Recently, aberrant epigenetic gene silencing in cancer has been reported by different groups.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('aberrant epigenetic gene silencing', 'Var', (10, 44))	('gene silencing', 'biological_process', 'GO:0016458', ('30', '44'))
46944	19267929	That study implicated promoter hypermethylation in transcriptional silencing in breast tumours at a more advanced stage.	('breast tumours', 'Disease', 'MESH:D001943', (80, 94))	('transcriptional', 'MPA', (51, 66))	('breast tumour', 'Phenotype', 'HP:0100013', (80, 93))	('promoter hypermethylation', 'Var', (22, 47))	('breast tumours', 'Disease', (80, 94))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))
46945	19267929	In breast cancer, a variety of critical genes have been shown to be silenced by methylation (e.g., BRCA1, 14-3-3, TIM3, ESR1, PGR and E-cadherin).	('PGR', 'Gene', '5241', (126, 129))	('14-3-3', 'Gene', (106, 112))	('BRCA1', 'Gene', (99, 104))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('silenced', 'NegReg', (68, 76))	('methylation', 'biological_process', 'GO:0032259', ('80', '91'))	('PGR', 'Gene', (126, 129))	('TIM3', 'Gene', (114, 118))	('ESR1', 'Gene', '2099', (120, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('TIM3', 'Gene', '84868', (114, 118))	('ESR1', 'Gene', (120, 124))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('breast cancer', 'Disease', (3, 16))	('E-cadherin', 'Gene', (134, 144))	('E-cadherin', 'Gene', '999', (134, 144))	('methylation', 'Var', (80, 91))
46957	19267929	Total RNA was kindly provided by Dr Michael O'Hare from the Ludwig Institute for Cancer Research (University College, England) from the following breast tumour cell lines: MDA-MB-134, MDA-MB-415, MDA-MB-175, MDA-MB436, MDA-MB-435, MDA-MB-468, MDA-MB456, BT-20, ZR-75-30, ZR-75-1, CAMA-1, GI101, 734B, CAL51, MCF7, SK-B-7; SK-BR-5, SK-BR-3, PMC42 and DU4475.	('MDA-MB-468', 'CellLine', 'CVCL:0419', (231, 241))	('SK-BR-5', 'CellLine', 'CVCL:5217', (322, 329))	('breast tumour', 'Disease', (146, 159))	('breast tumour', 'Phenotype', 'HP:0100013', (146, 159))	('SK', 'CellLine', 'CVCL:7020', (314, 316))	('SK', 'CellLine', 'CVCL:7020', (331, 333))	('MDA-MB-134', 'Var', (172, 182))	('SK', 'CellLine', 'CVCL:7020', (322, 324))	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('MDA-MB-415', 'CellLine', 'CVCL:0621', (184, 194))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('MDA-MB436', 'CellLine', 'CVCL:0623', (208, 217))	('C', 'Chemical', 'MESH:D002244', (342, 343))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('C', 'Chemical', 'MESH:D002244', (280, 281))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (219, 229))	('C', 'Chemical', 'MESH:D002244', (309, 310))	('MDA-MB-175', 'Var', (196, 206))	('Cancer', 'Disease', (81, 87))	('C', 'Chemical', 'MESH:D002244', (301, 302))	('MDA-MB-435', 'Var', (219, 229))	('MDA-MB456', 'CellLine', 'CVCL:0062', (243, 252))	('SK-BR-3', 'CellLine', 'CVCL:0033', (331, 338))	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('MCF7', 'CellLine', 'CVCL:0031', (308, 312))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('breast tumour', 'Disease', 'MESH:D001943', (146, 159))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (172, 182))	('MDA-MB-175', 'CellLine', 'CVCL:1400', (196, 206))
46970	19267929	Hybridisations were carried out as previously described using ADAM33 or GAPDH cDNA probes fragments corresponding to nucleotides 2191-2515 and 486-778, respectively.	('486-778', 'Var', (143, 150))	('nucleotides 2191-2515', 'Var', (117, 138))	('GAPDH', 'Gene', '2597', (72, 77))	('ADAM33', 'Gene', '80332', (62, 68))	('GAPDH', 'Gene', (72, 77))	('ADAM33', 'Gene', (62, 68))
47012	19267929	Sodium bisulphite sequencing was carried out on a region containing 77 CpG dinucleotides (-472 to +389), 71 of which were located within one of the CpG islands (-421 to +324) of the TSS (Figure 2A).	('Sodium bisulphite', 'Chemical', '-', (0, 17))	('-421', 'Var', (161, 165))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('-472 to +389', 'Var', (90, 102))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (71, 88))
47015	19267929	All cell lines that exhibited hypermethylation showed down-regulation of ADAM33 expression (Figure 1A).	('ADAM33', 'Gene', (73, 79))	('down-regulation', 'NegReg', (54, 69))	('regulation', 'biological_process', 'GO:0065007', ('59', '69'))	('ADAM33', 'Gene', '80332', (73, 79))	('expression', 'MPA', (80, 90))	('hypermethylation', 'Var', (30, 46))
47017	19267929	Comparing Figure 1A with Figure 3, it is clear that ADAM33 transcripts from cell lines with a lower methylation density were expressed at higher levels than in cells with a higher methylation density.	('ADAM33', 'Gene', (52, 58))	('methylation density', 'Var', (100, 119))	('methylation', 'biological_process', 'GO:0032259', ('180', '191'))	('ADAM33', 'Gene', '80332', (52, 58))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))
47022	19267929	Moreover, methyl-binding proteins physically associate with methylated CpG and attract repressive complexes such as histone deacetylases (HDAC).	('histone', 'MPA', (116, 123))	('methylated', 'Var', (60, 70))	('CpG', 'Protein', (71, 74))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('binding', 'molecular_function', 'GO:0005488', ('17', '24'))	('attract', 'PosReg', (79, 86))	('associate', 'Interaction', (45, 54))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('methyl-binding proteins', 'Protein', (10, 33))
47024	19267929	Another possibility is that the biallelic inactivation of tumour suppressor genes involves DNA methylation, deletion or point mutation.	('DNA methylation', 'biological_process', 'GO:0006306', ('91', '106'))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('DNA methylation', 'Var', (91, 106))	('tumour', 'Disease', (58, 64))	('biallelic inactivation', 'Var', (32, 54))	('point mutation', 'Var', (120, 134))	('deletion', 'Var', (108, 116))
47031	19267929	Methylation was frequently observed in ILC (Figure 2D).	('C', 'Chemical', 'MESH:D002244', (41, 42))	('Methylation', 'Var', (0, 11))	('ILC', 'Disease', (39, 42))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('observed', 'Reg', (27, 35))
47032	19267929	The presence of contaminating normal tissue or infiltrating lymphocytes explains the unmethylated DNA in all tumour samples.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Disease', (109, 115))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('unmethylated', 'Var', (85, 97))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
47036	19267929	Abnormal methylation of the ADAM33 promoter region in breast carcinomas was not associated with any significant difference in tumour stage (p = 0.641), histological differentiation grade (SBR; p = 0.799), lymph node status (p = 0.965), hormone receptor status (ER, p = 0.751; PR, p = 0.678), ERBB2 status (p = 0.378) or metastasis status (p = 0.548).	('methylation', 'Var', (9, 20))	('Abnormal methylation', 'Var', (0, 20))	('hormone receptor', 'Gene', '3164', (236, 252))	('ADAM33', 'Gene', (28, 34))	('ER', 'Gene', '2099', (261, 263))	('ER', 'Gene', '2099', (292, 294))	('ADAM33', 'Gene', '80332', (28, 34))	('PR', 'Gene', '5241', (276, 278))	('ERBB2', 'Gene', (292, 297))	('breast carcinomas', 'Disease', 'MESH:D001943', (54, 71))	('breast carcinomas', 'Disease', (54, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('ERBB2', 'Gene', '2064', (292, 297))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('hormone receptor', 'Gene', (236, 252))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('breast carcinomas', 'Phenotype', 'HP:0003002', (54, 71))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))
47038	19267929	The methylation frequencies were similar for tumours of size T1 (30.0%) and T2 (36.8%), whereas frequencies of up to 60% were observed in tumours of size T3 and T4.	('tumours', 'Disease', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('methylation', 'Var', (4, 15))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumours', 'Disease', (138, 145))
47039	19267929	Another potentially important observation is that in samples showing local tumour recurrence, the ADAM33 promoter methylation frequency was 66.7%, compared to 36.5% for non-recurrent samples (p = 0.201).	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('ADAM33', 'Gene', '80332', (98, 104))	('tumour', 'Disease', (75, 81))	('promoter', 'MPA', (105, 113))	('methylation', 'Var', (114, 125))	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('ADAM33', 'Gene', (98, 104))
47043	19267929	This probably occurs by selective DNA hypermethylation in many breast carcinomas, especially those of the invasive lobular histological type (ILC).	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('breast carcinomas', 'Disease', 'MESH:D001943', (63, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('breast carcinomas', 'Disease', (63, 80))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('34', '54'))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('breast carcinomas', 'Phenotype', 'HP:0003002', (63, 80))	('C', 'Chemical', 'MESH:D002244', (144, 145))	('selective', 'Var', (24, 33))	('invasive lobular histological type', 'Disease', (106, 140))
47067	19267929	Further studies are also needed to determine the prognostic and predictive significance of ADAM33 methylation and silencing in invasive lobular carcinoma.	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (127, 153))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('methylation', 'Var', (98, 109))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (136, 153))	('ADAM33', 'Gene', (91, 97))	('silencing', 'MPA', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('invasive lobular carcinoma', 'Disease', (127, 153))	('ADAM33', 'Gene', '80332', (91, 97))
47079	32661241	Further transcriptional profiling uncovered unique upregulation of the inhibitors of differentiation family transcription factors ID1 and ID3 in ILC ULA culture, the knockdown of which diminished the anchorage-independent growth of ILC cell lines through cell cycle arrest.	('upregulation', 'PosReg', (51, 63))	('knockdown', 'Var', (166, 175))	('ID3', 'Gene', (138, 141))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (255, 272))	('diminished', 'NegReg', (185, 195))	('ULA', 'Chemical', '-', (149, 152))	('arrest', 'Disease', 'MESH:D006323', (266, 272))	('arrest', 'Disease', (266, 272))	('anchorage-independent growth', 'CPA', (200, 228))	('transcription', 'biological_process', 'GO:0006351', ('108', '121'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('255', '272'))	('ID1', 'Gene', (130, 133))
47092	32661241	Anchorage-independence has previously been described in mouse models of lobular cancer, where combined somatic inactivation of p53 and E-cadherin induces ER-negative metastatic ILC through induction of anoikis resistance.	('cancer', 'Disease', (80, 86))	('p53', 'Gene', '22060', (127, 130))	('E-cadherin', 'Protein', (135, 145))	('induction', 'Reg', (189, 198))	('lobular cancer', 'Phenotype', 'HP:0030076', (72, 86))	('ER-negative metastatic ILC', 'CPA', (154, 180))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mouse', 'Species', '10090', (56, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('137', '145'))	('anoikis', 'biological_process', 'GO:0043276', ('202', '209'))	('induces', 'PosReg', (146, 153))	('anoikis resistance', 'CPA', (202, 220))	('inactivation', 'Var', (111, 123))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('p53', 'Gene', (127, 130))
47094	32661241	Furthermore, loss of other adherens junction proteins such as p120-catenin (p120) similarly drive the survival of mouse ILC cell lines and primary metastatic human ILC cells through ROCK1-mediated anoikis resistance.	('p120', 'Var', (76, 80))	('adherens junction', 'cellular_component', 'GO:0005912', ('27', '44'))	('drive', 'PosReg', (92, 97))	('human', 'Species', '9606', (158, 163))	('survival', 'CPA', (102, 110))	('p120-catenin', 'Gene', '12388', (62, 74))	('anoikis', 'biological_process', 'GO:0043276', ('197', '204'))	('mouse', 'Species', '10090', (114, 119))	('ROCK1', 'Gene', '6093', (182, 187))	('p120-catenin', 'Gene', (62, 74))	('ROCK1', 'Gene', (182, 187))	('loss', 'NegReg', (13, 17))
47103	32661241	We have previously shown that the ER-positive human ILC cell lines MDA-MB-134 (MM134), SUM44PE (SUM44), MDA-MB-330 (MM330) and BCK4 can grow efficiently in ULA suspension culture, as compared to the limited growth of the ER-positive human IDC cell lines MCF7 and T47D, and the ER-negative human IDC cell line MDA-MB-231 (MM231) under the same conditions relative to their 2D growth.	('IDC', 'Gene', '4000', (239, 242))	('IDC', 'Gene', '4000', (295, 298))	('human', 'Species', '9606', (233, 238))	('IDC', 'Gene', (239, 242))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (67, 77))	('IDC', 'Gene', (295, 298))	('BCK', 'molecular_function', 'GO:0047323', ('127', '130'))	('human', 'Species', '9606', (289, 294))	('MM330', 'Var', (116, 121))	('human', 'Species', '9606', (46, 51))	('SUM44PE', 'Var', (87, 94))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (309, 319))	('MDA-MB-330', 'Var', (104, 114))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (104, 114))	('MM231', 'CellLine', 'CVCL:H241', (321, 326))	('MCF7', 'CellLine', 'CVCL:0031', (254, 258))	('limited growth', 'Phenotype', 'HP:0001510', (199, 213))	('ULA', 'Chemical', '-', (156, 159))	('T47D', 'CellLine', 'CVCL:0553', (263, 267))
47114	32661241	FACS-based Hoechst staining revealed similar cell cycle profiles for MM134 and SUM44 in 2D and ULA, whereas MCF7 and T47D exhibited more cells arrested in G0/G1, concomitant with a decrease in the percentage of cells in the S and G2/M phases in ULA compared to 2D conditions (Fig.	('MM134', 'Var', (69, 74))	('MCF7', 'CellLine', 'CVCL:0031', (108, 112))	('arrest', 'Disease', (143, 149))	('T47D', 'CellLine', 'CVCL:0553', (117, 121))	('decrease', 'NegReg', (181, 189))	('MCF7', 'Var', (108, 112))	('T47D', 'Var', (117, 121))	('Hoechst', 'Chemical', '-', (11, 18))	('cell cycle', 'biological_process', 'GO:0007049', ('45', '55'))	('G0/G1', 'CPA', (155, 160))	('arrest', 'Disease', 'MESH:D006323', (143, 149))	('ULA', 'Chemical', '-', (245, 248))	('ULA', 'Chemical', '-', (95, 98))
47120	32661241	As a complementary approach, we also stably knocked out E-cadherin in MCF7 and T47D cells using CRISPR-mediated genome editing, which led to a rounded cell morphology and partially rescued the growth in ULA culture, but not fully to the levels of growth in 2D culture (Fig.	('growth', 'MPA', (193, 199))	('cadherin', 'molecular_function', 'GO:0008014', ('58', '66'))	('E-cadherin', 'Protein', (56, 66))	('T47D', 'CellLine', 'CVCL:0553', (79, 83))	('MCF7', 'CellLine', 'CVCL:0031', (70, 74))	('ULA', 'Chemical', '-', (203, 206))	('knocked out', 'Var', (44, 55))	('rescued', 'PosReg', (181, 188))	('led to', 'Reg', (134, 140))
47122	32661241	Besides E-cadherin, we assessed the effects of a number of other pathways additionally implicated in anchorage-independence such as YAP/Hippo, p120 and Rho/ROCK.	('ROCK', 'Gene', '6093', (156, 160))	('YAP', 'Gene', '10413', (132, 135))	('YAP', 'Gene', (132, 135))	('p120', 'Var', (143, 147))	('ROCK', 'Gene', (156, 160))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))
47126	32661241	In addition, we also used siRNAs to transiently knockdown ROCK1, p120 and YAP in MM134 and SUM44 cells, where we observed cell line-dependent effects: We failed to observe effects in SUM44 cells, but did note effects of loss of YAP1 and p120 on growth of MM134 cells (Supplementary Fig.	('p120', 'Var', (237, 241))	('loss', 'Var', (220, 224))	('YAP', 'Gene', '10413', (228, 231))	('YAP', 'Gene', '10413', (74, 77))	('YAP', 'Gene', (228, 231))	('ROCK1', 'Gene', '6093', (58, 63))	('ROCK1', 'Gene', (58, 63))	('YAP1', 'Gene', (228, 232))	('YAP', 'Gene', (74, 77))	('YAP1', 'Gene', '10413', (228, 232))
47134	32661241	Interestingly, while the PDK1-induced phosphorylation of Akt (T308) and the Akt target PRAS40 (T246) were sustained in ULA culture in MM134 cells, the mTOR-induced phosphorylation of Akt (S473) and downstream PI3K/Akt targets were paradoxically downregulated.	('ULA', 'Chemical', '-', (119, 122))	('T246', 'Var', (95, 99))	('PDK1', 'molecular_function', 'GO:0004740', ('25', '29'))	('phosphorylation', 'MPA', (38, 53))	('Akt', 'Pathway', (183, 186))	('PDK1', 'Gene', '5163', (25, 29))	('PDK1', 'Gene', (25, 29))	('S473', 'Var', (188, 192))	('Akt', 'Protein', (57, 60))	('PI3K', 'molecular_function', 'GO:0016303', ('209', '213'))	('phosphorylation', 'biological_process', 'GO:0016310', ('164', '179'))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('downregulated', 'NegReg', (245, 258))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('PRAS40', 'Gene', '84335', (87, 93))	('PRAS40', 'Gene', (87, 93))	('T308', 'Var', (62, 66))
47141	32661241	Interestingly, LY-294002, which only targets PI3K, had the strongest efficacy in the IDC cell lines in both conditions (Fig.	('IDC', 'Gene', '4000', (85, 88))	('LY-294002', 'Var', (15, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('IDC', 'Gene', (85, 88))	('LY-294002', 'Chemical', 'MESH:C085911', (15, 24))
47143	32661241	4e), consistent with the inactivating MAP2K4 mutation in this cell line.	('MAP2K4', 'Gene', '6416', (38, 44))	('mutation', 'Var', (45, 53))	('MAP2K4', 'Gene', (38, 44))	('MAP2K', 'molecular_function', 'GO:0004708', ('38', '43'))
47151	32661241	Transient inhibition of ID1 or ID3 resulted in reduced cell growth in both cell lines, generally with stronger effects for ID1 than ID3 and in ULA versus 2D culture (Fig.	('ID3', 'Gene', (31, 34))	('inhibition', 'NegReg', (10, 20))	('ULA', 'Chemical', '-', (143, 146))	('ID1', 'Gene', (24, 27))	('ID1', 'Var', (123, 126))	('cell growth', 'biological_process', 'GO:0016049', ('55', '66'))	('reduced', 'NegReg', (47, 54))	('cell growth', 'CPA', (55, 66))
47155	32661241	Finally, we found that high combined ID1 and ID3 expression is correlated with significantly lower disease-specific survival in the LumA ILC but not LumA IDC patients in the METABRIC cohort (Fig.	('ID3', 'Gene', (45, 48))	('IDC', 'Gene', '4000', (154, 157))	('disease-specific survival', 'CPA', (99, 124))	('high', 'Var', (23, 27))	('IDC', 'Gene', (154, 157))	('LumA', 'Gene', (132, 136))	('expression', 'MPA', (49, 59))	('LumA', 'Gene', '79188', (132, 136))	('lower', 'NegReg', (93, 98))	('LumA', 'Gene', (149, 153))	('LumA', 'Gene', '79188', (149, 153))	('ID1', 'Gene', (37, 40))	('patients', 'Species', '9606', (158, 166))
47173	32661241	These data are in agreement with a recent study showing similar dose responses in adherent and suspension culture to Akt inhibitors in ER-negative mouse and human ILC cell lines, as well as reporting PI3K/Akt activation in the ER-positive IDC cell line MCF7 following knockout of E-cadherin.	('mouse', 'Species', '10090', (147, 152))	('IDC', 'Gene', '4000', (239, 242))	('PI3K/Akt', 'Pathway', (200, 208))	('IDC', 'Gene', (239, 242))	('human', 'Species', '9606', (157, 162))	('PI3K', 'molecular_function', 'GO:0016303', ('200', '204'))	('MCF7', 'CellLine', 'CVCL:0031', (253, 257))	('activation', 'PosReg', (209, 219))	('cadherin', 'molecular_function', 'GO:0008014', ('282', '290'))	('knockout', 'Var', (268, 276))
47174	32661241	While we noted stronger effects of the PI3K/mTOR dual inhibitor in ILC versus IDC cells in ULA only at the highest doses, a single PI3K inhibitor was conversely more effective in IDC versus ILC cell lines in both culture conditions despite decreased PI3K/Akt signaling in ULA, likely due to the PI3K mutations in MCF7 and T47D.	('PI3K', 'molecular_function', 'GO:0016303', ('39', '43'))	('decreased', 'NegReg', (240, 249))	('Akt signaling', 'biological_process', 'GO:0043491', ('255', '268'))	('mTOR', 'Gene', '2475', (44, 48))	('PI3K', 'molecular_function', 'GO:0016303', ('250', '254'))	('MCF7', 'CellLine', 'CVCL:0031', (313, 317))	('IDC', 'Gene', '4000', (78, 81))	('IDC', 'Gene', (78, 81))	('ULA', 'Chemical', '-', (272, 275))	('PI3K', 'molecular_function', 'GO:0016303', ('295', '299'))	('T47D', 'CellLine', 'CVCL:0553', (322, 326))	('T47D', 'Var', (322, 326))	('PI3K/Akt signaling', 'Pathway', (250, 268))	('mutations', 'Var', (300, 309))	('IDC', 'Gene', '4000', (179, 182))	('MCF7', 'Gene', (313, 317))	('IDC', 'Gene', (179, 182))	('PI3K', 'molecular_function', 'GO:0016303', ('131', '135'))	('mTOR', 'Gene', (44, 48))	('ULA', 'Chemical', '-', (91, 94))
47176	32661241	Interestingly, p90RSK has previously been implicated in soft agar and Matrigel growth of MM134 and mouse ILC cell lines downstream of FGFR1 and MEK/MAPK.	('mouse', 'Species', '10090', (99, 104))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('FGFR1', 'Gene', (134, 139))	('FGFR1', 'Gene', '14182', (134, 139))	('p90RSK', 'Var', (15, 21))	('implicated', 'Reg', (42, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('134', '138'))
47177	32661241	Here we report that ULA culture induces ILC-unique p90RSK phosphorylation, which is uncoupled from upstream MEK/MAPK signaling in the MAP2K4 and K-RAS mutant MM134 cells.	('mutant', 'Var', (151, 157))	('ULA', 'Chemical', '-', (20, 23))	('K-RAS', 'Gene', '3845', (145, 150))	('p90RSK phosphorylation', 'MPA', (51, 73))	('MAP2K4', 'Gene', '6416', (134, 140))	('MAP2K', 'molecular_function', 'GO:0004708', ('134', '139'))	('K-RAS', 'Gene', (145, 150))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('112', '126'))	('MAP2K4', 'Gene', (134, 140))	('induces', 'Reg', (32, 39))	('MAPK', 'molecular_function', 'GO:0004707', ('112', '116'))
47179	32661241	In our functional studies, transient siRNA-mediated knockdown of ID1 or ID3 in ILC cells resulted in reduced viability and impacted the cell cycle but not apoptosis, effects that were generally stronger for ID1 than for ID3 and in ULA versus 2D.	('ID1', 'Gene', (65, 68))	('ID3', 'Gene', (72, 75))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('reduced', 'NegReg', (101, 108))	('cell cycle', 'CPA', (136, 146))	('ULA', 'Chemical', '-', (231, 234))	('cell cycle', 'biological_process', 'GO:0007049', ('136', '146'))	('knockdown', 'Var', (52, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('impacted', 'Reg', (123, 131))
47184	32661241	Furthermore, combined high expression of ID1 and ID3 was correlated with significantly worse disease-specific survival in the ILC but not IDC LumA METABRIC cohorts.	('ID3', 'Gene', (49, 52))	('high', 'Var', (22, 26))	('worse', 'NegReg', (87, 92))	('LumA', 'Gene', (142, 146))	('expression', 'MPA', (27, 37))	('LumA', 'Gene', '79188', (142, 146))	('IDC', 'Gene', '4000', (138, 141))	('disease-specific survival', 'CPA', (93, 118))	('ILC', 'Disease', (126, 129))	('IDC', 'Gene', (138, 141))	('ID1', 'Gene', (41, 44))
47187	32661241	While peptide-conjugated antisense oligonucleotides have allowed more precise targeting, they have not been very amenable to clinical translation.	('translation', 'biological_process', 'GO:0006412', ('134', '145'))	('targeting', 'MPA', (78, 87))	('antisense', 'Var', (25, 34))	('oligonucleotides', 'Chemical', 'MESH:D009841', (35, 51))
47190	32661241	MDA-MB-134-VI (MM134), MDA-MB-330 (MM330), MCF7, T47D, MDA-MB-231 (MM231) and SKBR3 cells were obtained from the American Type Culture Collection.	('MM231', 'Var', (67, 72))	('T47D', 'CellLine', 'CVCL:0553', (49, 53))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (55, 65))	('MM330', 'Var', (35, 40))	('MM134', 'Var', (15, 20))	('SKBR3', 'CellLine', 'CVCL:0033', (78, 83))	('MCF7', 'CellLine', 'CVCL:0031', (43, 47))	('MM231', 'CellLine', 'CVCL:H241', (67, 72))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (0, 10))	('MDA-MB-330', 'CellLine', 'CVCL:0619', (23, 33))
47191	32661241	Cell lines were maintained as previously described in the following media (Life Technologies) with 10% FBS: MM134 and MM330 in 1:1 DMEM:L-15, MCF7 and MM231 in DMEM, T47D in RPMI, SKBR3 in McCoy's 5A, BCK4 in MEM with non-essential amino acids (Life Technologies) and insulin (Sigma-Aldrich).	('insulin', 'Gene', '3630', (268, 275))	('MCF7', 'CellLine', 'CVCL:0031', (142, 146))	('MM134', 'Var', (108, 113))	('FBS', 'Disease', (103, 106))	('MM231', 'CellLine', 'CVCL:H241', (151, 156))	('MCF7', 'Var', (142, 146))	('T47D', 'CellLine', 'CVCL:0553', (166, 170))	('BCK', 'molecular_function', 'GO:0047323', ('201', '204'))	('FBS', 'Disease', 'MESH:D005198', (103, 106))	('T47D', 'Var', (166, 170))	('MM231', 'Var', (151, 156))	('MM330', 'Var', (118, 123))	('insulin', 'molecular_function', 'GO:0016088', ('268', '275'))	('insulin', 'Gene', (268, 275))	('SKBR3', 'CellLine', 'CVCL:0033', (180, 185))
47193	32661241	ON-TARGETplus SMARTpool small interfering RNAs (siRNAs) were purchased from Dharmacon: ID1 (#L-005051-00-0005), ID3 (#L-009905-00-0005), ROCK1 (#L-003536-00-0005), p120 (#L-012572-00-0005), YAP (#L-012200-00-0005), non-targeting control (#D-001810-10-50).	('#L-012572-00-0005', 'Var', (170, 187))	('#L-003536-00-0005', 'Var', (144, 161))	('YAP', 'Gene', '10413', (190, 193))	('ROCK1', 'Gene', '6093', (137, 142))	('ROCK1', 'Gene', (137, 142))	('YAP', 'Gene', (190, 193))	('#L-005051-00-0005', 'Var', (92, 109))	('#L-009905-00-0005', 'Var', (117, 134))	('#L-012200-00-0005', 'Var', (195, 212))
47545	29587177	Advances in functional genetic screening with transposons and CRISPR/Cas9 to illuminate cancer biology Large-scale genome sequencing studies have identified a wealth of mutations in human tumors and have dramatically advanced the field of cancer genetics.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Disease', (188, 194))	('mutations', 'Var', (169, 178))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('advanced', 'PosReg', (217, 225))	('human', 'Species', '9606', (182, 187))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Cas', 'cellular_component', 'GO:0005650', ('69', '72'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
47546	29587177	However, the functional consequences of an altered gene in tumor progression cannot always be inferred from mutation status alone.	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('altered', 'Var', (43, 50))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))
47558	29587177	Insertion of the transposon harboring the gene trap into a new genomic location disrupts gene function by introducing gain-of-function or loss-of-function mutations depending on the orientation and location of the element (Figure 1).	('gene function', 'MPA', (89, 102))	('mutations', 'Var', (155, 164))	('trap', 'Gene', '11433', (47, 51))	('loss-of-function', 'NegReg', (138, 154))	('trap', 'Gene', (47, 51))	('disrupts', 'NegReg', (80, 88))	('gain-of-function', 'PosReg', (118, 134))
47560	29587177	Remarkably, tumors that arise from transposon mutagenesis in mice accurately model the anatomical and histological features of human cancers.	('mice', 'Species', '10090', (61, 65))	('human', 'Species', '9606', (127, 132))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('mutagenesis', 'Var', (46, 57))	('cancers', 'Disease', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('mutagenesis', 'biological_process', 'GO:0006280', ('46', '57'))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
47564	29587177	Transposon mobilization has been shown to promote tumorigenesis alone or in cooperation with sensitized genetic backgrounds.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Transposon mobilization', 'Var', (0, 23))	('promote', 'PosReg', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
47565	29587177	Several important factors must be considered for any transposon screen, including the choice of the transposon gene trap and transposase, the selection of the Cre driver line used to induce tissue-specific expression of the transposase, the scale and duration of the genetic screen, and the specific methods used for the identification and analysis of transposon insertions (Figure 2).	('insertions', 'Var', (363, 373))	('transposon', 'Gene', (352, 362))	('trap', 'Gene', '11433', (116, 120))	('trap', 'Gene', (116, 120))
47569	29587177	One SB screen performed in mammary-specific Cdh1 deficient mice uncovered recurrent and mutually exclusive insertions in genes implicated in actin cytoskeleton regulation in ILC.	('mice', 'Species', '10090', (59, 63))	('regulation', 'biological_process', 'GO:0065007', ('160', '170'))	('insertions', 'Var', (107, 117))	('ILC', 'Disease', (174, 177))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('141', '159'))	('Cdh1', 'Gene', (44, 48))	('Cdh1', 'Gene', '12550', (44, 48))	('SB', 'Chemical', '-', (4, 6))
47573	29587177	Analysis of human ILCs revealed that MYH9 was commonly altered by heterozygous copy number loss, which correlated with reduced expression of MYH9 mRNA.	('copy number loss', 'Var', (79, 95))	('MYH9', 'Gene', (141, 145))	('expression', 'MPA', (127, 137))	('MYH9', 'Gene', (37, 41))	('altered', 'Reg', (55, 62))	('human', 'Species', '9606', (12, 17))	('reduced', 'NegReg', (119, 126))
47578	29587177	Subsequent validation studies showed that SB insertions in these two genes caused truncation of the PP1-targeting subunits, and that expression of the truncated subunits induced tumor formation in genetically engineered mice.	('induced', 'Reg', (170, 177))	('tumor', 'Disease', (178, 183))	('truncation', 'MPA', (82, 92))	('mice', 'Species', '10090', (220, 224))	('insertions', 'Var', (45, 55))	('PP1-targeting', 'Protein', (100, 113))	('caused', 'Reg', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('formation', 'biological_process', 'GO:0009058', ('184', '193'))	('SB', 'Chemical', '-', (42, 44))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
47579	29587177	This demonstrates the power of integrating CIS gene lists with available copy number data to prioritize driver genes that are present in large windows of amplifications or deletions in human cancer.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('human', 'Species', '9606', (185, 190))	('deletions', 'Var', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
47581	29587177	Classification of SB-induced tumors in Pten mutant mice identified a collection of different breast cancer subtypes, including basal-like (triple negative), luminal A, and HER2 positive tumors.	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('HER2', 'Gene', (172, 176))	('luminal A', 'Disease', (157, 166))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('tumors', 'Disease', (29, 35))	('SB', 'Chemical', '-', (18, 20))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('HER2', 'Gene', '13866', (172, 176))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('basal-like', 'Disease', (127, 137))	('Pten', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Pten', 'Gene', '19211', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('mutant', 'Var', (44, 50))
47585	29587177	Chen and colleagues performed SB mutagenesis in breast epithelial cells alone or in combination with stabilized N-terminally truncated beta-catenin.	('beta-catenin', 'Gene', (135, 147))	('mutagenesis', 'biological_process', 'GO:0006280', ('33', '44'))	('SB', 'Chemical', '-', (30, 32))	('mutagenesis', 'Var', (33, 44))	('beta-catenin', 'Gene', '12387', (135, 147))
47589	29587177	The first liver-specific screen for HCC, performed on a mutant Tp53 background, identified known driver genes (Epidermal growth factor receptor, Egfr, and Tyrosine-protein kinase Met) and new potential therapeutic targets including Ubiquitin conjugating enzyme E2H (Ube2h).	('Ubiquitin conjugating enzyme E2H', 'Gene', '22214', (232, 264))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('111', '134'))	('Ube2h', 'Gene', '22214', (266, 271))	('Egfr', 'Gene', (145, 149))	('Tp53', 'Gene', (63, 67))	('mutant', 'Var', (56, 62))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('Ubiquitin conjugating enzyme E2H', 'Gene', (232, 264))	('Egfr', 'Gene', '13649', (145, 149))	('Egfr', 'molecular_function', 'GO:0005006', ('145', '149'))	('Tp53', 'Gene', '22059', (63, 67))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('Ube2h', 'Gene', (266, 271))	('Epidermal growth factor receptor', 'Gene', '13649', (111, 143))	('Epidermal growth factor receptor', 'Gene', (111, 143))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('232', '241'))
47605	29587177	While this may cause less genomic damage during mutagenesis, it may also preclude the identification of some PB insertions.	('insertions', 'Var', (112, 122))	('mutagenesis', 'biological_process', 'GO:0006280', ('48', '59'))	('preclude', 'NegReg', (73, 81))	('PB', 'Chemical', '-', (109, 111))
47606	29587177	Finally, SB exhibits more local hopping, whereby the transposon favors mobilization to sites in proximity to the donor concatemer in transgenic mice.	('transposon', 'Var', (53, 63))	('favors', 'PosReg', (64, 70))	('SB', 'Chemical', '-', (9, 11))	('mobilization', 'MPA', (71, 83))	('transgenic mice', 'Species', '10090', (133, 148))	('donor', 'Species', '9606', (113, 118))
47613	29587177	Early SB screens using the T2/Onc or T2/Onc2 mouse strains, which utilized the MSCV promoter, exhibited a tendency to develop hematopoietic tumors.	('SB', 'Chemical', '-', (6, 8))	('T2/Onc2', 'Var', (37, 44))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (126, 146))	('MSCV', 'Species', '258023', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('mouse', 'Species', '10090', (45, 50))	('hematopoietic tumors', 'Disease', (126, 146))	('develop', 'PosReg', (118, 125))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
47618	29587177	Insertions in Fidgetin (Fign), which encodes a member of the AAA-ATPase superfamily, were significantly enriched in hepatoid tumors, a rare pancreatic cancer subtype.	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('hepatoid tumors', 'Disease', (116, 131))	('Fidgetin', 'Gene', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Insertions', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('Fidgetin', 'Gene', '60344', (14, 22))	('hepatoid tumors', 'Disease', 'MESH:D009369', (116, 131))	('pancreatic cancer', 'Disease', (140, 157))
47625	29587177	Further refinement of sequencing methods has uncovered transposon insertions in single tumor cells (SBCapSeq).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('insertions', 'Var', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('transposon insertions', 'Var', (55, 76))	('BC', 'Phenotype', 'HP:0003002', (101, 103))	('SB', 'Chemical', '-', (100, 102))
47627	29587177	RNA sequencing of SB-induced tumors has been particularly useful for identifying fusion transcripts between the transposon elements and endogenous transcripts in order to determine whether a specific SB insertion generates a gain-of-function or loss-of-function mutation.	('SB', 'Chemical', '-', (18, 20))	('SB', 'Chemical', '-', (200, 202))	('loss-of-function', 'NegReg', (245, 261))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('insertion', 'Var', (203, 212))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('gain-of-function', 'PosReg', (225, 241))
47630	29587177	Second, transposition occurred simultaneously in the same cells that underwent Pten inactivation, potentially enhancing the sensitivity of the screen.	('Pten', 'Gene', '19211', (79, 83))	('sensitivity', 'MPA', (124, 135))	('transposition', 'biological_process', 'GO:0032196', ('8', '21'))	('enhancing', 'PosReg', (110, 119))	('Pten', 'Gene', (79, 83))	('inactivation', 'Var', (84, 96))
47631	29587177	Finally, unlike most other SB screens, the gene trap promoted only inactivating mutations but not activating mutations.	('inactivating mutations', 'Var', (67, 89))	('SB', 'Chemical', '-', (27, 29))	('trap', 'Gene', '11433', (48, 52))	('trap', 'Gene', (48, 52))
47637	29587177	Sequencing of SB-induced tumors revealed a poor degree of overlap between the SB insertions in primary mouse tumors and the insertions in tumors that recurred after treatment.	('SB', 'Chemical', '-', (14, 16))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mouse', 'Species', '10090', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('SB', 'Chemical', '-', (78, 80))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('insertions', 'Var', (81, 91))
47640	29587177	The authors proposed that therapeutic strategies targeting truncal mutations in the primary tumor are destined to fail if the mutation is lacking after recurrence.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('truncal mutations', 'Var', (59, 76))	('tumor', 'Disease', (92, 97))
47646	29587177	Mutagenesis of human bone explant mesenchymal cells utilizing a hybrid lentiviral and SB mutagenesis system generated myxofibrosarcomas when transplanted into mice.	('Mutagenesis', 'biological_process', 'GO:0006280', ('0', '11'))	('Mutagenesis', 'Var', (0, 11))	('myxofibrosarcomas', 'Disease', 'None', (118, 135))	('mice', 'Species', '10090', (159, 163))	('myxofibrosarcomas', 'Disease', (118, 135))	('mutagenesis', 'biological_process', 'GO:0006280', ('89', '100'))	('human', 'Species', '9606', (15, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (127, 135))	('SB', 'Chemical', '-', (86, 88))
47648	29587177	One of the largest ex vivo SB screens performed to date identified genes that promote growth factor independence and transformation of Ba/F3 cells, an IL-3-dependent murine pro-B cell line.	('IL-3', 'molecular_function', 'GO:0005135', ('151', '155'))	('transformation', 'CPA', (117, 131))	('murine', 'Species', '10090', (166, 172))	('promote', 'PosReg', (78, 85))	('growth factor independence', 'CPA', (86, 112))	('genes', 'Var', (67, 72))	('IL-3', 'Gene', '16187', (151, 155))	('IL-3', 'Gene', (151, 155))	('SB', 'Chemical', '-', (27, 29))	('Ba/F3', 'CellLine', 'CVCL:0161', (135, 140))
47649	29587177	Recurrent insertions were identified in JAK/STAT and MAPK pathway genes in addition to a large number of genes that are mutated or associate with survival of leukemia patients but had not previously been linked to these pathways.	('JAK/STAT', 'Gene', (40, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('leukemia', 'Disease', (158, 166))	('patients', 'Species', '9606', (167, 175))	('associate with', 'Reg', (131, 145))	('leukemia', 'Disease', 'MESH:D007938', (158, 166))	('insertions', 'Var', (10, 20))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('MAPK pathway genes', 'Gene', (53, 71))	('JAK', 'molecular_function', 'GO:0004713', ('40', '43'))
47651	29587177	Finally, an ex vivo recellularized human colon model identified genes that drive colorectal cancer progression.	('drive', 'Reg', (75, 80))	('colorectal cancer', 'Disease', (81, 98))	('human', 'Species', '9606', (35, 40))	('genes', 'Var', (64, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))
47657	29587177	In contrast, transposon screening allows for simultaneous identification of GOF and LOF mutations in the same mutagenized tumor or clone, which may more accurately reflect the complexity of human tumors.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (196, 201))	('tumors', 'Disease', (196, 202))	('mutations', 'Var', (88, 97))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('LOF', 'NegReg', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('human', 'Species', '9606', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
47662	29587177	In summary, transposon mutagenesis studies have provided important insights into the functional consequences of mutated genes in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('mutagenesis', 'biological_process', 'GO:0006280', ('23', '34'))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('human', 'Species', '9606', (129, 134))	('mutated', 'Var', (112, 119))
47665	29587177	One current limitation of transposon mutagenesis is that it does not faithfully reproduce the full spectrum of mutations seen in human cancer, namely point mutations and reciprocal translocations.	('point mutations', 'Var', (150, 165))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutagenesis', 'biological_process', 'GO:0006280', ('37', '48'))	('mutagenesis', 'Var', (37, 48))	('human', 'Species', '9606', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
47694	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))
47721	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))
47780	25893416	In multivariate analysis, pathologic tumor size (OR, 2.7; 95%CI, 1.8-3.9; p<0.0001), multifocality (OR, 3.5; 95%CI, 2.4-5.0; p<0.001), histological subtype (OR, 1.5; 95%CI, 1.02-2.1; p=0.04) and HER2 positivity (OR, 2.4; 95%CI, 1.1-5.0; p=0.02) were found to be significant factors associated with the decision to perform a mastectomy.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('associated', 'Reg', (282, 292))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('HER2', 'Gene', (195, 199))	('positivity', 'Var', (200, 210))	('HER2', 'Gene', '2064', (195, 199))
47808	26451490	Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3 and FOXA1 as ILC enriched features.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('PTEN', 'Gene', '5728', (96, 100))	('mutations', 'Var', (76, 85))	('ILC ', 'Gene', (120, 124))	('TBX3', 'Gene', '6926', (102, 106))	('FOXA1', 'Gene', (111, 116))	('TBX3', 'Gene', (102, 106))	('cadherin', 'molecular_function', 'GO:0008014', ('10', '18'))	('ILC ', 'Gene', '10850', (40, 44))	('ILC ', 'Gene', '10850', (120, 124))	('FOXA1', 'Gene', '3169', (111, 116))	('PTEN', 'Gene', (96, 100))	('ILC ', 'Gene', (40, 44))
47810	26451490	Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity.	('FOXA1', 'Gene', (20, 25))	('activity', 'MPA', (83, 91))	('increased', 'PosReg', (52, 61))	('expression', 'MPA', (68, 78))	('FOXA1', 'Gene', (62, 67))	('FOXA1', 'Gene', '3169', (20, 25))	('mutations', 'Var', (26, 35))	('FOXA1', 'Gene', '3169', (62, 67))
47811	26451490	Conversely, GATA3 mutations and high expression characterized Luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC.	('ILC ', 'Gene', (130, 134))	('GATA3', 'Gene', (12, 17))	('Luminal A', 'Gene', (62, 71))	('Luminal A', 'Gene', '79188', (62, 71))	('GATA3', 'Gene', '2625', (12, 17))	('ILC ', 'Gene', '10850', (130, 134))	('mutations', 'Var', (18, 27))
47824	26451490	ILC was represented by only 36 samples and, no lobular-specific features were noted besides mutations and decreased mRNA and protein expression of CDH1.	('decreased', 'NegReg', (106, 115))	('CDH1', 'Gene', '999', (147, 151))	('ILC ', 'Gene', (0, 4))	('mutations', 'Var', (92, 101))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('ILC ', 'Gene', '10850', (0, 4))	('CDH1', 'Gene', (147, 151))
47831	26451490	Recurrently mutated genes in ILC were identified by MutSigCV2 and included many genes previously implicated in breast cancer (Figure 1B, Table 1).	('mutated', 'Var', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ILC ', 'Gene', '10850', (29, 33))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('ILC ', 'Gene', (29, 33))
47832	26451490	Similarly, recurrent copy number alterations in ILC estimated by GISTIC recapitulated known breast cancer gains and losses, in particular those observed in ER+/Luminal tumors (Figure S1A).	('breast cancer gains', 'Disease', 'MESH:D001943', (92, 111))	('ILC ', 'Gene', '10850', (48, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('copy number alterations', 'Var', (21, 44))	('losses', 'NegReg', (116, 122))	('ILC ', 'Gene', (48, 52))	('Luminal tumors', 'Disease', 'MESH:D009369', (160, 174))	('breast cancer gains', 'Disease', (92, 111))	('Luminal tumors', 'Disease', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
47835	26451490	ILC cases were significantly enriched for CDH1 mutations, (63% in ILC vs. 2% in IDC, q=3.94E-53), most of them truncating, and mutations affecting TBX3 (9% vs. 2%, q=0.003), RUNX1 (10% vs. 3%, q=0.008), PIK3CA (48% vs. 33%, q=0.02) and FOXA1 (7% vs. 2%, q=0.08).	('RUNX1', 'Gene', '861', (174, 179))	('CDH1', 'Gene', (42, 46))	('ILC ', 'Gene', '10850', (66, 70))	('PIK3CA', 'Gene', (203, 209))	('CDH1', 'Gene', '999', (42, 46))	('TBX3', 'Gene', '6926', (147, 151))	('FOXA1', 'Gene', '3169', (236, 241))	('ILC ', 'Gene', (0, 4))	('mutations', 'Var', (47, 56))	('ILC ', 'Gene', (66, 70))	('PIK3CA', 'Gene', '5290', (203, 209))	('TBX3', 'Gene', (147, 151))	('FOXA1', 'Gene', (236, 241))	('RUNX1', 'Gene', (174, 179))	('truncating', 'Var', (111, 121))	('ILC ', 'Gene', '10850', (0, 4))	('mutations', 'Var', (127, 136))
47836	26451490	By contrast, alterations typically observed in ER-/Basal-like tumors were less frequent in ILC including TP53 mutations (8% in ILC vs. 44% in IDC, q=1.9E-14) and focal amplification of MYC (6% vs. 27%, q=7.42E-7) and CCNE1 (0% vs. 7%, q=0.01).	('Basal-like tumors', 'Phenotype', 'HP:0002671', (51, 68))	('MYC', 'Gene', (185, 188))	('mutations', 'Var', (110, 119))	('ILC ', 'Gene', (127, 131))	('ILC ', 'Gene', (91, 95))	('ILC ', 'Gene', '10850', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('CCNE1', 'Gene', '898', (217, 222))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('MYC', 'Gene', '4609', (185, 188))	('CCNE1', 'Gene', (217, 222))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('ILC ', 'Gene', '10850', (127, 131))	('focal amplification', 'Var', (162, 181))
47838	26451490	Nonetheless, unexpected differences did emerge including a lower incidence of GATA3 mutations in ILC compared to IDC (5% in ILC vs. 13% in IDC, q=0.03) (Figure 1C).	('ILC ', 'Gene', '10850', (124, 128))	('ILC ', 'Gene', '10850', (97, 101))	('lower', 'NegReg', (59, 64))	('mutations', 'Var', (84, 93))	('ILC ', 'Gene', (124, 128))	('GATA3', 'Gene', (78, 83))	('ILC ', 'Gene', (97, 101))	('GATA3', 'Gene', '2625', (78, 83))
47840	26451490	This analysis confirmed a high incidence of CDH1 (q=1.4E-30), TBX3 (q=0.05) and FOXA1 (q=0.065) mutations in ILC, while the frequency of RUNX1 and PIK3CA mutations was no longer significantly different.	('PIK3CA', 'Gene', (147, 153))	('PIK3CA', 'Gene', '5290', (147, 153))	('FOXA1', 'Gene', (80, 85))	('TBX3', 'Gene', '6926', (62, 66))	('RUNX1', 'Gene', (137, 142))	('CDH1', 'Gene', (44, 48))	('TBX3', 'Gene', (62, 66))	('RUNX1', 'Gene', '861', (137, 142))	('CDH1', 'Gene', '999', (44, 48))	('mutations', 'Var', (96, 105))	('FOXA1', 'Gene', '3169', (80, 85))
47841	26451490	GATA3 mutations (5% ILC vs. 20% IDC, q=0.003) were the second most discriminant event after CDH1 mutations, mostly affecting IDC tumors.	('GATA3', 'Gene', '2625', (0, 5))	('mutations', 'Var', (97, 106))	('IDC tumors', 'Disease', 'MESH:D009369', (125, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('IDC tumors', 'Disease', (125, 135))	('ILC ', 'Gene', (20, 24))	('CDH1', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('GATA3', 'Gene', (0, 5))	('affecting', 'Reg', (115, 124))	('ILC ', 'Gene', '10850', (20, 24))	('CDH1', 'Gene', '999', (92, 96))	('mutations', 'Var', (6, 15))
47843	26451490	Finally, homozygous losses of the PTEN locus (10q23) were more frequent in ILC (q=0.035) as were PTEN mutations (8% vs. 3%).	('PTEN', 'Gene', (97, 101))	('ILC ', 'Gene', (75, 79))	('PTEN', 'Gene', '5728', (97, 101))	('mutations', 'Var', (102, 111))	('ILC ', 'Gene', '10850', (75, 79))	('10q23', 'Var', (46, 51))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
47847	26451490	Loss-of-function mutations targeting CDH1 are present in 50-60% of ILC and are believed to be an early event often observed in matching lobular carcinoma in situ (LCIS).	('lobular carcinoma', 'Disease', 'MESH:D018275', (136, 153))	('Loss-of-function', 'NegReg', (0, 16))	('ILC ', 'Gene', (67, 71))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (144, 161))	('lobular carcinoma', 'Disease', (136, 153))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (136, 153))	('lobular carcinoma in situ', 'Phenotype', 'HP:0030076', (136, 161))	('CDH1', 'Gene', (37, 41))	('ILC ', 'Gene', '10850', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('LCIS', 'Phenotype', 'HP:0030076', (163, 167))	('mutations', 'Var', (17, 26))	('CDH1', 'Gene', '999', (37, 41))
47848	26451490	CDH1 mutations typically occur in combination with chromosome 16q loss, where CDH1 is located, thus inducing complete loss of the protein.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('CDH1', 'Gene', '999', (0, 4))	('mutations', 'Var', (5, 14))	('loss', 'NegReg', (118, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('CDH1', 'Gene', (78, 82))	('protein', 'Protein', (130, 137))	('CDH1', 'Gene', '999', (78, 82))	('CDH1', 'Gene', (0, 4))
47849	26451490	We identified 108 mutations in the coding sequence of CDH1 in 107/817 patients (63%); 80 of these occurred in ILC cases.	('patients', 'Species', '9606', (70, 78))	('ILC ', 'Gene', '10850', (110, 114))	('ILC ', 'Gene', (110, 114))	('CDH1', 'Gene', (54, 58))	('occurred', 'Reg', (98, 106))	('CDH1', 'Gene', '999', (54, 58))	('mutations', 'Var', (18, 27))
47850	26451490	CDH1 mutations almost invariably co-occurred with heterozygous loss of 16q (affecting 89% of ILC cases), and were associated with down-regulation of both CDH1 transcript and protein levels (Figures 2B and S2A).	('CDH1', 'Gene', (154, 158))	('ILC ', 'Gene', '10850', (93, 97))	('CDH1', 'Gene', '999', (154, 158))	('regulation', 'biological_process', 'GO:0065007', ('135', '145'))	('CDH1', 'Gene', '999', (0, 4))	('16q', 'Protein', (71, 74))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('mutations', 'Var', (5, 14))	('down-regulation', 'NegReg', (130, 145))	('protein levels', 'MPA', (174, 188))	('ILC ', 'Gene', (93, 97))	('loss', 'NegReg', (63, 67))	('CDH1', 'Gene', (0, 4))
47851	26451490	By combining somatic mutations, copy number losses, and mRNA and low protein expression (the latter when available), we identified E-cadherin alterations in 120/127 (95%) cases with DNA and RNA data, and in all 79 cases with DNA, RNA, and protein data (Figure S2A-C).	('E-cadherin', 'Gene', '999', (131, 141))	('alterations', 'Var', (142, 153))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))	('copy number losses', 'Var', (32, 50))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('RNA', 'cellular_component', 'GO:0005562', ('230', '233'))	('cadherin', 'molecular_function', 'GO:0008014', ('133', '141'))	('low', 'NegReg', (65, 68))	('DNA', 'cellular_component', 'GO:0005574', ('225', '228'))	('mRNA and', 'MPA', (56, 64))	('RNA', 'cellular_component', 'GO:0005562', ('190', '193'))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))	('E-cadherin', 'Gene', (131, 141))	('mutations', 'Var', (21, 30))
47852	26451490	Previous studies reported sporadic cases of multiple cancer types with high DNA methylation levels at the CDH1 promoter, suggesting epigenetic silencing as an alternative mechanism for down-regulation of CDH1.	('DNA methylation', 'biological_process', 'GO:0006306', ('76', '91'))	('CDH1', 'Gene', '999', (106, 110))	('multiple cancer', 'Disease', (44, 59))	('regulation', 'biological_process', 'GO:0065007', ('190', '200'))	('multiple cancer', 'Disease', 'MESH:D009369', (44, 59))	('epigenetic silencing', 'Var', (132, 152))	('CDH1', 'Gene', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('CDH1', 'Gene', '999', (204, 208))	('CDH1', 'Gene', (106, 110))	('down-regulation', 'NegReg', (185, 200))
47855	26451490	Moderately increased methylation was observed in a few cases near exon 2, however DNA methylation at this site correlated with lower tumor purity and increased leukocyte infiltration, and indeed it mimicked methylation levels at this CpG site in normal leukocytes (Figure S2F-G).	('methylation', 'biological_process', 'GO:0032259', ('207', '218'))	('leukocyte infiltration', 'CPA', (160, 182))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('methylation', 'MPA', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('DNA methylation', 'biological_process', 'GO:0006306', ('82', '97'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('lower', 'NegReg', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('methylation', 'Var', (86, 97))	('tumor', 'Disease', (133, 138))	('increased', 'PosReg', (150, 159))	('increased leukocyte', 'Phenotype', 'HP:0001974', (150, 169))
47858	26451490	Our results on 817 invasive breast tumors thus confirmed Ecadherin loss as ILC defining molecular feature, but do not support the reported occurrence of CDH1 epigenetic silencing in invasive breast cancer.	('invasive breast cancer', 'Disease', (182, 204))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ILC ', 'Gene', (75, 79))	('invasive breast tumors', 'Disease', 'MESH:D001943', (19, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('CDH1', 'Gene', (153, 157))	('loss', 'NegReg', (67, 71))	('Ecadherin', 'Gene', (57, 66))	('ILC ', 'Gene', '10850', (75, 79))	('CDH1', 'Gene', '999', (153, 157))	('epigenetic', 'Var', (158, 168))	('invasive breast cancer', 'Disease', 'MESH:D001943', (182, 204))	('breast tumors', 'Phenotype', 'HP:0100013', (28, 41))	('Ecadherin', 'Gene', '999', (57, 66))	('invasive breast tumors', 'Disease', (19, 41))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('breast tumor', 'Phenotype', 'HP:0100013', (28, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
47860	26451490	High FOXA1 expression has been previously reported in breast and prostate cancer and somatic mutations in the FOXA1 gene have been reported in these tumor types in about 3-4% of the cases.	('breast and prostate cancer', 'Disease', 'MESH:D011471', (54, 80))	('mutations', 'Var', (93, 102))	('FOXA1', 'Gene', '3169', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('expression', 'MPA', (11, 21))	('High', 'PosReg', (0, 4))	('reported', 'Reg', (42, 50))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('reported', 'Reg', (131, 139))	('FOXA1', 'Gene', (110, 115))	('FOXA1', 'Gene', (5, 10))	('tumor', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('FOXA1', 'Gene', '3169', (110, 115))
47861	26451490	Here, we observed a total of 33 FOXA1 mutations in 30/817 (3.7%) tumors (Figure 3A) and the large sample set allowed us to identify regional hotspots in the FOXA1 mutation distribution.	('FOXA1', 'Gene', '3169', (32, 37))	('FOXA1', 'Gene', '3169', (157, 162))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('FOXA1', 'Gene', (32, 37))	('mutations', 'Var', (38, 47))	('FOXA1', 'Gene', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
47864	26451490	Eleven FOXA1 mutations were observed in 9/127 (7%) ILC cases.	('FOXA1', 'Gene', (7, 12))	('ILC ', 'Gene', (51, 55))	('FOXA1', 'Gene', '3169', (7, 12))	('mutations', 'Var', (13, 22))	('ILC ', 'Gene', '10850', (51, 55))	('observed', 'Reg', (28, 36))
47865	26451490	All FOXA1 mutations in ILC were in the FK domain, whereas mutations in IDC (n=11) were observed both in FK (n=6) and other structural elements (n=5), without a specific preference.	('ILC ', 'Gene', (23, 27))	('FOXA1', 'Gene', (4, 9))	('ILC ', 'Gene', '10850', (23, 27))	('FOXA1', 'Gene', '3169', (4, 9))	('mutations', 'Var', (10, 19))
47866	26451490	FOXA1 mutations in FK clustered prevalently in the W2 loop.	('FOXA1', 'Gene', (0, 5))	('FOXA1', 'Gene', '3169', (0, 5))	('mutations', 'Var', (6, 15))
47867	26451490	Notably, 8/127 ILC cases have FOXA1 mutations within this MSH compared to 4/490 IDC cases (p=6E-4), further supporting FOXA1 selected mutations as an ILC feature.	('FOXA1', 'Gene', (30, 35))	('ILC ', 'Gene', (150, 154))	('FOXA1', 'Gene', '3169', (119, 124))	('FOXA1', 'Gene', '3169', (30, 35))	('mutations', 'Var', (36, 45))	('ILC ', 'Gene', '10850', (15, 19))	('ILC ', 'Gene', '10850', (150, 154))	('ILC ', 'Gene', (15, 19))	('FOXA1', 'Gene', (119, 124))
47869	26451490	Only a few residues predicted or experimentally shown to interact with the DNA were mutated (Figure 3B-E) suggesting that these events are unlikely to affect FOXA1 DNA binding.	('FOXA1', 'Gene', (158, 163))	('binding', 'Interaction', (168, 175))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('mutated', 'Var', (84, 91))	('FOXA1', 'Gene', '3169', (158, 163))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('DNA binding', 'molecular_function', 'GO:0003677', ('164', '175'))
47873	26451490	DNA methylation of these sites was substantially lower when FOXA1 and ESR1 were highly expressed, while it remained high in FOXA1-negative cases and adjacent normal tissue (Figure 3F).	('ESR1', 'Gene', '2099', (70, 74))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('expressed', 'Var', (87, 96))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('FOXA1', 'Gene', '3169', (60, 65))	('FOXA1', 'Gene', (124, 129))	('ESR1', 'Gene', (70, 74))	('lower', 'NegReg', (49, 54))	('FOXA1', 'Gene', '3169', (124, 129))	('FOXA1', 'Gene', (60, 65))
47877	26451490	FOXA1 mutations were positively associated with its mRNA expression (p=0.002) and maintained a similar anti-correlation with DNA methylation at FOXA1 binding sites (Figure 3F).	('FOXA1', 'Gene', (0, 5))	('associated', 'Interaction', (32, 42))	('FOXA1', 'Gene', (144, 149))	('DNA methylation', 'biological_process', 'GO:0006306', ('125', '140'))	('FOXA1', 'Gene', '3169', (0, 5))	('FOXA1', 'Gene', '3169', (144, 149))	('DNA methylation', 'MPA', (125, 140))	('mRNA expression', 'MPA', (52, 67))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('mutations', 'Var', (6, 15))	('binding', 'molecular_function', 'GO:0005488', ('150', '157'))
47879	26451490	These data collectively indicate that FOXA1 mutations do not abolish protein function and, in fact, they may activate alternative mechanisms to affect ER transcriptional programs.	('FOXA1', 'Gene', (38, 43))	('activate', 'Reg', (109, 117))	('FOXA1', 'Gene', '3169', (38, 43))	('mutations', 'Var', (44, 53))	('affect', 'Reg', (144, 150))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('ER transcriptional', 'MPA', (151, 169))
47880	26451490	Differential expression analyses between FOXA1 mutant and wild type cases within distinct subsets of samples found consistent up-regulation of neuroendocrine secretory proteins SCG1 (CHGB) and SCG2, chemokine-like factor CMTM8, neuroendocrine tumor associated transcription factor NKX2-2 and Kallikrein serine proteases KLK12, KLK13, and KLK14 (Figure S3D and Table S5).	('Kallikrein', 'molecular_function', 'GO:0003807', ('292', '302'))	('neuroendocrine tumor', 'Disease', (228, 248))	('FOXA1', 'Gene', (41, 46))	('SCG2', 'Gene', '7857', (193, 197))	('Kallikrein', 'molecular_function', 'GO:0004293', ('292', '302'))	('CMTM8', 'Gene', '152189', (221, 226))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (228, 248))	('NKX2-2', 'Gene', (281, 287))	('CMTM8', 'Gene', (221, 226))	('KLK12', 'Gene', '43849', (320, 325))	('CHGB', 'Gene', '1114', (183, 187))	('KLK14', 'Gene', '43847', (338, 343))	('SCG1', 'Gene', '1114', (177, 181))	('KLK13', 'Gene', '26085', (327, 332))	('transcription', 'biological_process', 'GO:0006351', ('260', '273'))	('transcription factor', 'molecular_function', 'GO:0000981', ('260', '280'))	('up-regulation', 'PosReg', (126, 139))	('CHGB', 'Gene', (183, 187))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (228, 248))	('mutant', 'Var', (47, 53))	('SCG1', 'Gene', (177, 181))	('SCG2', 'Gene', (193, 197))	('KLK14', 'Gene', (338, 343))	('Kallikrein', 'Gene', (292, 302))	('regulation', 'biological_process', 'GO:0065007', ('129', '139'))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('Kallikrein', 'Gene', '9622', (292, 302))	('KLK12', 'Gene', (320, 325))	('KLK13', 'Gene', (327, 332))	('FOXA1', 'Gene', '3169', (41, 46))	('NKX2-2', 'Gene', '4821', (281, 287))
47881	26451490	While the relatively low number of FOXA1 mutations and breast cancer heterogeneity prevented the identification of strong transcriptional signals associated with FOXA1 mutations, several upregulated targets in FOXA1 mutant cases with part of them consistently found as significant suggests these lesions might drive novel binding events.	('mutant', 'Var', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('FOXA1', 'Gene', '3169', (35, 40))	('FOXA1', 'Gene', (210, 215))	('FOXA1', 'Gene', (35, 40))	('FOXA1', 'Gene', '3169', (210, 215))	('binding', 'molecular_function', 'GO:0005488', ('322', '329'))	('upregulated', 'PosReg', (187, 198))	('FOXA1', 'Gene', (162, 167))	('transcriptional signals', 'MPA', (122, 145))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('FOXA1', 'Gene', '3169', (162, 167))	('binding', 'Interaction', (322, 329))	('mutations', 'Var', (168, 177))
47882	26451490	Interestingly, while ILC cases were enriched for FOXA1 mutations and in particular for those targeting the FK domain, ILC showed significantly fewer GATA3 mutations, another key ER modulator.	('GATA3', 'Gene', (149, 154))	('mutations', 'Var', (55, 64))	('FOXA1', 'Gene', (49, 54))	('ILC ', 'Gene', (21, 25))	('GATA3', 'Gene', '2625', (149, 154))	('ILC ', 'Gene', '10850', (118, 122))	('FOXA1', 'Gene', '3169', (49, 54))	('fewer', 'NegReg', (143, 148))	('ILC ', 'Gene', (118, 122))	('ILC ', 'Gene', '10850', (21, 25))
47883	26451490	Mutations in GATA3 were more frequent in LumA IDC (Figure 1D) and mutually exclusive with FOXA1 events.	('LumA', 'Gene', (41, 45))	('LumA', 'Gene', '79188', (41, 45))	('frequent', 'Reg', (29, 37))	('FOXA1', 'Gene', (90, 95))	('Mutations', 'Var', (0, 9))	('GATA3', 'Gene', (13, 18))	('FOXA1', 'Gene', '3169', (90, 95))	('GATA3', 'Gene', '2625', (13, 18))
47885	26451490	Taken together, the differential expression patterns and enrichment for hotspot mutations of GATA3 in IDC and of FOXA1 in ILC, suggest a preferential requirement for distinct ER modulators in ILC and IDC.	('ILC ', 'Gene', (192, 196))	('mutations', 'Var', (80, 89))	('GATA3', 'Gene', '2625', (93, 98))	('FOXA1', 'Gene', '3169', (113, 118))	('IDC', 'Disease', (200, 203))	('IDC', 'Disease', (102, 105))	('ILC ', 'Gene', '10850', (192, 196))	('FOXA1', 'Gene', (113, 118))	('GATA3', 'Gene', (93, 98))
47887	26451490	PTEN genetic alterations across all ILC cases included homozygous deletions (6%) and somatic mutations (7%), and were largely mutually exclusive with PIK3CA mutations (48%) (Figure S4A).	('PIK3CA', 'Gene', (150, 156))	('PIK3CA', 'Gene', '5290', (150, 156))	('ILC ', 'Gene', '10850', (36, 40))	('ILC ', 'Gene', (36, 40))	('homozygous deletions', 'Var', (55, 75))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
47889	26451490	Consistent with PTEN function as a negative regulator of Akt activity, ILC tumors also showed significantly increased Akt phosphorylation at both S473 (p=0.004) and T308 (p=7E-5) (Figure 4A).	('ILC tumors', 'Disease', (71, 81))	('S473', 'Var', (146, 150))	('Akt', 'Gene', '207', (57, 60))	('Akt', 'Gene', (118, 121))	('increased', 'PosReg', (108, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('122', '137'))	('PTEN', 'Gene', (16, 20))	('PTEN', 'Gene', '5728', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Akt', 'Gene', (57, 60))	('T308', 'Var', (165, 169))	('Akt', 'Gene', '207', (118, 121))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
47890	26451490	Upstream of the Akt pathway, we found significant up-regulation of total EGFR (p=1E-4) and phospho-EGFR at Y1068 (p=0.005) and Y1173 (p=0.007), as well as phospho-STAT3 at Y705 (p=7E-4), supporting up-regulation of signaling axes converging on Akt activation.	('STAT3', 'Gene', '6774', (163, 168))	('EGFR', 'Gene', (99, 103))	('Y1173', 'Var', (127, 132))	('EGFR', 'Gene', '1956', (73, 77))	('regulation of signaling', 'biological_process', 'GO:0023051', ('201', '224'))	('up-regulation', 'PosReg', (50, 63))	('STAT3', 'Gene', (163, 168))	('EGFR', 'Gene', (73, 77))	('Akt', 'Gene', (16, 19))	('regulation', 'biological_process', 'GO:0065007', ('53', '63'))	('Akt', 'Gene', '207', (244, 247))	('Y1068', 'Var', (107, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('99', '103'))	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('Akt', 'Gene', '207', (16, 19))	('Akt', 'Gene', (244, 247))
47891	26451490	We also identified increased phospho-p27 at T157 (p=0.002), an Akt substrate, and phospho-p70S6 kinase at T389 (p=1E-4), a direct mTOR target.	('phospho-p70S6', 'Var', (82, 95))	('phospho-p27 at T157', 'Var', (29, 48))	('increased', 'PosReg', (19, 28))	('mTOR', 'Gene', (130, 134))	('Akt', 'Gene', '207', (63, 66))	('mTOR', 'Gene', '2475', (130, 134))	('Akt', 'Gene', (63, 66))
47896	26451490	PTEN protein loss and increased Akt phosphorylation were observed in association with PTEN genetic alterations, as well as in multiple ILC PTEN wild-type cases indicating that additional mechanisms contribute to the activation of the pathway.	('Akt', 'Gene', '207', (32, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('PTEN', 'Gene', (86, 90))	('PTEN', 'Gene', '5728', (86, 90))	('Akt', 'Gene', (32, 35))	('PTEN', 'Gene', (139, 143))	('genetic alterations', 'Var', (91, 110))	('PTEN', 'Gene', '5728', (139, 143))	('PTEN', 'Gene', (0, 4))	('increased', 'PosReg', (22, 31))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('loss', 'NegReg', (13, 17))	('protein', 'Protein', (5, 12))	('phosphorylation', 'MPA', (36, 51))	('PTEN', 'Gene', '5728', (0, 4))
47897	26451490	While PIK3CA mutations were frequent in LumA ILC tumors, these mutations were not associated with increased levels of phospho-Akt or pathway activity in our dataset.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Akt', 'Gene', '207', (126, 129))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('PIK3CA', 'Gene', (6, 12))	('LumA', 'Gene', (40, 44))	('LumA', 'Gene', '79188', (40, 44))	('PIK3CA', 'Gene', '5290', (6, 12))	('frequent', 'Reg', (28, 36))	('mutations', 'Var', (13, 22))	('Akt', 'Gene', (126, 129))
47898	26451490	Using MEMo, we highlighted multiple genetic alterations converging on Akt/mTOR signaling in 45% of the samples (Figure S4D, Table S7).	('Akt', 'Gene', (70, 73))	('mTOR', 'Gene', (74, 78))	('genetic alterations', 'Var', (36, 55))	('mTOR', 'Gene', '2475', (74, 78))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('Akt', 'Gene', '207', (70, 73))
47899	26451490	Among these, alterations acting upstream of Akt were identified in 40% of ILC cases and were associated with increased Akt phosphorylation and PI3K/Akt score (Figure 4E) providing an apparent molecular explanation for Akt activation in these samples.	('Akt', 'Gene', '207', (44, 47))	('Akt', 'Gene', '207', (218, 221))	('Akt', 'Gene', (148, 151))	('Akt', 'Gene', '207', (119, 122))	('alterations', 'Var', (13, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('143', '147'))	('ILC ', 'Gene', '10850', (74, 78))	('Akt', 'Gene', (119, 122))	('Akt', 'Gene', (44, 47))	('Akt', 'Gene', (218, 221))	('increased', 'PosReg', (109, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))	('ILC ', 'Gene', (74, 78))	('Akt', 'Gene', '207', (148, 151))
47900	26451490	Interestingly, these events included ERBB2 amplification and mutations (Figure 4E), both of which have been identified in relapsed ILC.	('ERBB2', 'Gene', (37, 42))	('ERBB2', 'Gene', '2064', (37, 42))	('mutations', 'Var', (61, 70))
47905	26451490	Of these, 1005 were highly expressed in reactive-like tumors, which had lower tumor purity as determined by ABSOLUTE (Figures 5A and S5P), and included genes consistent with epithelial and stromal-associated signaling including keratin, kallikrein, and claudin genes as well as the oncogenes EGFR, MET, PDGFRA and KIT (Table S14 to Table S8).	('kallikrein', 'molecular_function', 'GO:0004293', ('237', '247'))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('kallikrein', 'Gene', (237, 247))	('kallikrein', 'Gene', '9622', (237, 247))	('KIT', 'molecular_function', 'GO:0005020', ('314', '317'))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('EGFR', 'Gene', '1956', (292, 296))	('S14', 'Gene', '6208', (325, 328))	('KIT', 'Gene', (314, 317))	('1005', 'Var', (10, 14))	('included', 'Reg', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('292', '296'))	('S14', 'Gene', (325, 328))	('lower', 'NegReg', (72, 77))	('tumor', 'Disease', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('kallikrein', 'molecular_function', 'GO:0003807', ('237', '247'))	('MET', 'Gene', (298, 301))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('EGFR', 'Gene', (292, 296))	('PDGFRA', 'Gene', '5156', (303, 309))	('PDGFRA', 'Gene', (303, 309))	('tumor', 'Disease', (54, 59))
47914	26451490	Decreased levels were observed instead for p70S6 kinase (p=0.017), Raptor (p=0.027) and eIF4G (p=0.024).	('Raptor', 'Gene', '57521', (67, 73))	('p70S6', 'Var', (43, 48))	('eIF4G', 'Gene', '1981', (88, 93))	('eIF4', 'cellular_component', 'GO:0008304', ('88', '92'))	('eIF4G', 'Gene', (88, 93))	('Raptor', 'Gene', (67, 73))
47915	26451490	Immune-related tumors had higher levels of immune modulator STAT5 alpha (p=0.019), PI3K/Akt targets phospho-PRAS40 (T246, p=0.016) and mTOR (S2448, p=0.019), and total (p=0.004) and phospho-MEK1 (S217-S221, p=0.022).	('Akt', 'Gene', '207', (88, 91))	('MEK1', 'molecular_function', 'GO:0004708', ('190', '194'))	('STAT5 alpha', 'Gene', '6776', (60, 71))	('MEK1', 'Gene', (190, 194))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('higher', 'PosReg', (26, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('mTOR', 'Gene', '2475', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('mTOR', 'Gene', (135, 139))	('S2448', 'Var', (141, 146))	('STAT5 alpha', 'Gene', (60, 71))	('Akt', 'Gene', (88, 91))	('MEK1', 'Gene', '5604', (190, 194))	('PRAS40', 'Gene', (108, 114))	('PRAS40', 'Gene', '84335', (108, 114))	('tumors', 'Disease', (15, 21))
47917	26451490	Decreased expression was observed for total (p=0.014) and phospho-MAPK (T202-Y204, p=0.038), and phosphorylated MEK1 (S217-S221, p=0.019), PKC alpha (S657, p=0.006), PKC beta (S660, p=0.037), and Src (Y527, p=0.026).	('PKC beta', 'Gene', (166, 174))	('S660', 'Var', (176, 180))	('PKC alpha', 'Gene', (139, 148))	('MEK1', 'Gene', '5604', (112, 116))	('S657', 'Var', (150, 154))	('S217-S221', 'Var', (118, 127))	('Src', 'Gene', (196, 199))	('Decreased', 'NegReg', (0, 9))	('Src', 'Gene', '6714', (196, 199))	('PKC', 'molecular_function', 'GO:0004697', ('139', '142'))	('expression', 'MPA', (10, 20))	('MEK1', 'Gene', (112, 116))	('PKC alpha', 'Gene', '5578', (139, 148))	('PKC', 'molecular_function', 'GO:0004697', ('166', '169'))	('PKC beta', 'Gene', '5579', (166, 174))	('MEK1', 'molecular_function', 'GO:0004708', ('112', '116'))	('T202-Y204', 'Var', (72, 81))	('MAPK', 'molecular_function', 'GO:0004707', ('66', '70'))
47922	26451490	greater than the median PAM50 proliferation signature score) had worse DSS (p=0.025, HR: 2.0) and a tendency towards worse OS (p=0.058, HR: 0.63) compared to patients with a lower proliferation score (Figure S5N-O).	('DSS', 'Chemical', '-', (71, 74))	('PAM50', 'Var', (24, 29))	('patients', 'Species', '9606', (158, 166))	('DSS', 'MPA', (71, 74))	('OS', 'Chemical', '-', (123, 125))
47933	26451490	We next evaluated the resemblance of mixed tumors to IDC and ILC based on the previously determined selected set of copy number alterations (CNAs) and mutations (Table S2).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('ILC ', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('IDC', 'Disease', (53, 56))	('tumors', 'Disease', (43, 49))	('ILC ', 'Gene', '10850', (61, 65))	('copy number alterations', 'Var', (116, 139))	('mutations', 'Var', (151, 160))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
47934	26451490	Mixed tumors were enriched for IDC recurrent CNAs and mutations when compared to ILC, and vice versa (Figure S6B), indicating ILC and IDC genetic alterations were both present in these tumors, either simultaneously or in separate IDC-like and ILC-like subgroups.	('IDC-like', 'Disease', (230, 238))	('ILC ', 'Gene', (126, 130))	('tumors', 'Disease', (185, 191))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('IDC', 'Gene', (134, 137))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('ILC ', 'Gene', '10850', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
47938	26451490	A few CDH1 wild-type mixed cases were also classified as ILC-like and characterized by ILC-enriched events such as mutations in RUNX1 (3/4 mutated cases), TBX3 (2/4) and FOXA1 (2/6).	('TBX3', 'Gene', (155, 159))	('ILC-like', 'Disease', (57, 65))	('FOXA1', 'Gene', '3169', (170, 175))	('mutations', 'Var', (115, 124))	('RUNX1', 'Gene', (128, 133))	('CDH1', 'Gene', '999', (6, 10))	('FOXA1', 'Gene', (170, 175))	('RUNX1', 'Gene', '861', (128, 133))	('TBX3', 'Gene', '6926', (155, 159))	('CDH1', 'Gene', (6, 10))
47941	26451490	These were enriched for the LumA subtype, CDH1 mutations and loss of E-cadherin mRNA expression (Figures 6B and S6E).	('E-cadherin', 'Gene', '999', (69, 79))	('CDH1', 'Gene', (42, 46))	('CDH1', 'Gene', '999', (42, 46))	('LumA', 'Gene', (28, 32))	('LumA', 'Gene', '79188', (28, 32))	('mutations', 'Var', (47, 56))	('cadherin', 'molecular_function', 'GO:0008014', ('71', '79'))	('loss', 'NegReg', (61, 65))	('E-cadherin', 'Gene', (69, 79))
47947	26451490	Moreover, 12/27 CDH1 mutations in non-ILC cases occurred in mixed tumors strongly resembling ILC at the molecular level.	('occurred in', 'Reg', (48, 59))	('CDH1', 'Gene', '999', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('ILC ', 'Gene', '10850', (93, 97))	('ILC ', 'Gene', (38, 42))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('CDH1', 'Gene', (16, 20))	('ILC ', 'Gene', (93, 97))	('ILC ', 'Gene', '10850', (38, 42))	('mutations', 'Var', (21, 30))
47950	26451490	The lower incidence of GATA3 mutations in ILC and lower GATA3 mRNA and protein expression suggest that in LumA ILC tumors there is a preferential occupancy of ER in FOXA1 bounded sites.	('GATA3', 'Gene', '2625', (56, 61))	('FOXA1', 'Gene', '3169', (165, 170))	('ILC ', 'Gene', (111, 115))	('GATA3', 'Gene', '2625', (23, 28))	('GATA3', 'Gene', (56, 61))	('LumA', 'Gene', (106, 110))	('FOXA1', 'Gene', (165, 170))	('GATA3', 'Gene', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('ILC ', 'Gene', '10850', (42, 46))	('lower', 'NegReg', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (29, 38))	('tumors', 'Disease', (115, 121))	('LumA', 'Gene', '79188', (106, 110))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('ILC ', 'Gene', '10850', (111, 115))	('ILC ', 'Gene', (42, 46))	('tumors', 'Disease', 'MESH:D009369', (115, 121))
47954	26451490	Intriguingly, five acetylation sites have been identified in the wings of the fork-head domain; three of them in W2 (K264, K267 and K270) where most of our newly observed FOXA1 mutations cluster.	('K264', 'Var', (117, 121))	('FOXA1', 'Gene', '3169', (171, 176))	('K270', 'Var', (132, 136))	('K267', 'Var', (123, 127))	('FOXA1', 'Gene', (171, 176))
47955	26451490	These observations lead to the hypothesis that FOXA1 mutations could alter EP300 dependent acetylation of FOXA1 without affecting EP300 modulation of ER.	('EP300', 'Gene', (75, 80))	('EP300', 'Gene', '2033', (75, 80))	('FOXA1', 'Gene', (106, 111))	('acetylation', 'MPA', (91, 102))	('EP300', 'Gene', (130, 135))	('FOXA1', 'Gene', '3169', (47, 52))	('FOXA1', 'Gene', '3169', (106, 111))	('mutations', 'Var', (53, 62))	('alter', 'Reg', (69, 74))	('FOXA1', 'Gene', (47, 52))	('EP300', 'Gene', '2033', (130, 135))
47956	26451490	While a rigorous evaluation of the role of EP300 in breast cancer and how FOXA1 mutations interfere with it goes beyond the scope of this study, FOXA1 mutations, its correlation with FOXA1 expression and lack of DNA methylation at its binding sites, and exclusivity with GATA3 mutations support these as events activating FOXA1 function and, thus, ER transcriptional program.	('function', 'MPA', (328, 336))	('GATA3', 'Gene', '2625', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('FOXA1', 'Gene', (183, 188))	('binding', 'molecular_function', 'GO:0005488', ('235', '242'))	('EP300', 'Gene', '2033', (43, 48))	('GATA3', 'Gene', (271, 276))	('FOXA1', 'Gene', '3169', (322, 327))	('mutations', 'Var', (80, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('FOXA1', 'Gene', (322, 327))	('mutations', 'Var', (151, 160))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('EP300', 'Gene', (43, 48))	('FOXA1', 'Gene', '3169', (74, 79))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('breast cancer', 'Disease', (52, 65))	('FOXA1', 'Gene', (74, 79))	('DNA methylation', 'biological_process', 'GO:0006306', ('212', '227'))	('FOXA1', 'Gene', '3169', (145, 150))	('transcriptional', 'MPA', (351, 366))	('FOXA1', 'Gene', (145, 150))	('activating', 'PosReg', (311, 321))	('FOXA1', 'Gene', '3169', (183, 188))
47978	26451490	Distances between of FOXA1 mutations have been determined from the tertiary structure of FOXA3 fork-head domain (PDB ID: 1VTN).	('mutations', 'Var', (27, 36))	('FOXA1', 'Gene', (21, 26))	('PDB ID', 'Disease', (113, 119))	('FOXA3', 'Gene', (89, 94))	('FOXA3', 'Gene', '3171', (89, 94))	('PDB ID', 'Disease', 'MESH:C537985', (113, 119))	('FOXA1', 'Gene', '3169', (21, 26))
47985	26451490	ILCs show CDH1 and PTEN loss, AKT activation, and mutations in TBX3 and FOXA1.	('FOXA1', 'Gene', '3169', (72, 77))	('CDH1', 'Gene', (10, 14))	('CDH1', 'Gene', '999', (10, 14))	('mutations', 'Var', (50, 59))	('PTEN', 'Gene', (19, 23))	('FOXA1', 'Gene', (72, 77))	('AKT', 'Gene', '207', (30, 33))	('PTEN', 'Gene', '5728', (19, 23))	('TBX3', 'Gene', '6926', (63, 67))	('activation', 'PosReg', (34, 44))	('AKT', 'Gene', (30, 33))	('TBX3', 'Gene', (63, 67))	('loss', 'NegReg', (24, 28))
48062	18652707	Next the diagnostic stained tissue sections of surgical specimen demonstrated that it was, in fact, a lobular carcinoma of the breast (Figures 3a, b, c), with this immunoassaying profile ER + (figure 3d) (60%); PR + (40%); Ki67: 5%; human epidermal growth factor receptor 2 (Her-2) (DAKO) negative.	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (110, 133))	('human', 'Species', '9606', (233, 238))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (102, 119))	('Her-2', 'Gene', (275, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('lobular carcinoma of the breast', 'Disease', 'MESH:D018275', (102, 133))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('239', '262'))	('lobular carcinoma of the breast', 'Disease', (102, 133))	('epidermal growth factor receptor 2', 'Gene', (239, 273))	('epidermal growth factor receptor 2', 'Gene', '2064', (239, 273))	('ER +', 'Var', (187, 191))	('Her-2', 'Gene', '2064', (275, 280))
48122	30332649	Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast.	('Cdh1', 'Gene', (0, 4))	('invasive lobular carcinoma', 'Disease', (163, 189))	('Pik3ca', 'Gene', '18706', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('Mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (111, 117))	('Lobular Carcinoma', 'Phenotype', 'HP:0030076', (70, 87))	('Carcinoma of the Breast', 'Phenotype', 'HP:0100013', (78, 101))	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (163, 189))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (172, 189))	('Lobular Carcinoma', 'Disease', (70, 87))	('Carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Pik3ca', 'Gene', (9, 15))	('CDH1', 'Gene', (102, 106))	('Lobular Carcinoma', 'Disease', 'MESH:D018275', (70, 87))	('Induce', 'Reg', (39, 45))	('Cdh1', 'Gene', '12550', (0, 4))
48124	30332649	Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('Pik3ca', 'Gene', (67, 73))	('leads to', 'Reg', (126, 134))	('mice', 'Species', '10090', (120, 124))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('activation', 'PosReg', (53, 63))	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('gene expression', 'biological_process', 'GO:0010467', ('209', '224'))	('rat', 'Species', '10116', (190, 193))	('IR-ILC-like', 'Disease', (148, 159))	('deletion', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Cdh1', 'Gene', (33, 37))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
48137	30332649	For example, deletion of Cdh1 and Tp53 in mammary epithelium leads to the development of pleomorphic ILC, an aggressive but relatively rare non-classical ILC subtype.	('leads to', 'Reg', (61, 69))	('Cdh1', 'Gene', (25, 29))	('Tp53', 'Gene', (34, 38))	('pleomorphic ILC', 'Disease', (89, 104))	('Tp53', 'Gene', '22059', (34, 38))	('deletion', 'Var', (13, 21))
48138	30332649	The same group reported that deletion of Cdh1 and Pten in mammary epithelium leads to tumors with more classical ILC-like features.	('deletion', 'Var', (29, 37))	('Pten', 'Gene', (50, 54))	('Cdh1', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Pten', 'Gene', '19211', (50, 54))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('leads to', 'Reg', (77, 85))
48140	30332649	In this study, we describe a genetically modified mouse model based on mutations in the two most commonly mutated genes from human ILC: Cdh1 and Pik3ca.	('human', 'Species', '9606', (125, 130))	('Pik3ca', 'Gene', (145, 151))	('mutations', 'Var', (71, 80))	('mouse', 'Species', '10090', (50, 55))	('Cdh1', 'Gene', (136, 140))
48141	30332649	As noted above, the two most common alterations in human ILC are CDH1 loss-of-function mutations and activating gain-of-function mutations in PIK3CA.	('CDH1', 'Gene', (65, 69))	('gain-of-function', 'PosReg', (112, 128))	('mutations', 'Var', (129, 138))	('rat', 'Species', '10116', (40, 43))	('human', 'Species', '9606', (51, 56))	('loss-of-function', 'NegReg', (70, 86))	('PIK3CA', 'Gene', (142, 148))	('activating', 'PosReg', (101, 111))	('mutations', 'Var', (87, 96))
48142	30332649	Indeed, approximately 50% of CDH1 mutant tumors have activating mutations in PIK3CA, suggesting that these gene mutations may well cooperate to transform mammary epithelial cells.	('PIK3CA', 'Gene', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('CDH1', 'Gene', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('transform', 'Reg', (144, 153))	('rat', 'Species', '10116', (136, 139))	('activating', 'MPA', (53, 63))	('mutant', 'Var', (34, 40))
48143	30332649	To model ILC of this genotype, we bred mice with a Cre-conditional mutant allele of Cdh1 (Cdh1loxP/loxP) to Cre-conditional transgenics for activated mouse Pik3ca (R26-LSL-Pik3caE545K and R26-LSL-Pik3caH1047R) and to mice with a mammary epithelial specific Wap-Cre transgene.	('Cdh1loxP/loxP', 'Gene', (90, 103))	('Wap', 'Gene', '22373', (257, 260))	('mice', 'Species', '10090', (217, 221))	('Cdh1loxP/loxP', 'Gene', '12550', (90, 103))	('R26-LSL-Pik3caE545K', 'Var', (164, 183))	('R26-LSL-Pik3caH1047R', 'Var', (188, 208))	('mutant', 'Var', (67, 73))	('Wap', 'Gene', (257, 260))	('Cdh1', 'Gene', (84, 88))	('mice', 'Species', '10090', (39, 43))	('mouse', 'Species', '10090', (150, 155))
48150	30332649	The mean number of mammary tumors per female mouse increased from approximately 4.0 in R26-LSL-Pik3caE545K; Wap-Cre cohort mice to greater than 8.7 in Cdh1loxP/loxP;R26-LSL-Pik3caE545K;Wap-Cre animals (p = 7.137 3 10 10), whereas the number of mammary tumors per mouse was not altered by Cdh1 deletion in Pik3caH1047R mutant cohorts (approximately 7.5 mammary tumors formed in female mice from R26-LSL-Pik3caH1047R;Wap-Cre and Cdh1loxP/loxP;R26-LSL-Pik3caH1047R Wap-Cre cohorts) (data not shown).	('Wap', 'Gene', '22373', (108, 111))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('mice', 'Species', '10090', (123, 127))	('mammary tumors', 'Disease', 'MESH:D001943', (244, 258))	('deletion', 'Var', (293, 301))	('mammary tumors', 'Disease', (244, 258))	('mammary tumors', 'Disease', 'MESH:D001943', (19, 33))	('mammary tumors', 'Disease', (19, 33))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('R26-LSL-Pik3caH1047R', 'Var', (394, 414))	('Wap', 'Gene', (108, 111))	('Cdh1', 'Gene', (288, 292))	('Wap', 'Gene', '22373', (462, 465))	('mice', 'Species', '10090', (384, 388))	('mammary tumors', 'Disease', 'MESH:D001943', (352, 366))	('tumors', 'Phenotype', 'HP:0002664', (360, 366))	('Cdh1loxP/loxP', 'Gene', '12550', (151, 164))	('mammary tumors', 'Disease', (352, 366))	('Cdh1loxP/loxP', 'Gene', (151, 164))	('mouse', 'Species', '10090', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('Wap', 'Gene', '22373', (415, 418))	('Wap', 'Gene', '22373', (185, 188))	('Cdh1loxP/loxP', 'Gene', (427, 440))	('Cdh1loxP/loxP', 'Gene', '12550', (427, 440))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Wap', 'Gene', (462, 465))	('mouse', 'Species', '10090', (263, 268))	('Wap', 'Gene', (415, 418))	('Wap', 'Gene', (185, 188))
48151	30332649	For Pik3caH1047R mice, we observed a sizable reduction in mammary tumor-free survival (MTFS) with deletion of Cdh1 (p = 1.02 x 10 -11).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mice', 'Species', '10090', (17, 21))	('Cdh1', 'Gene', (110, 114))	('tumor', 'Disease', (66, 71))	('deletion', 'Var', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('reduction', 'NegReg', (45, 54))
48152	30332649	In contrast, for Pik3caE545K mice, Cdh1 deletion did not significantly affect MTFS at 18 months (p = 0.264).	('deletion', 'Var', (40, 48))	('Cdh1', 'Gene', (35, 39))	('affect', 'Reg', (71, 77))	('mice', 'Species', '10090', (29, 33))	('E545K', 'Mutation', 'rs104886003', (23, 28))	('MTFS', 'MPA', (78, 82))
48153	30332649	However, at 150 and 250 days, deletion of Cdh1 had a dramatic effect on MTFS of Pik3caE5454K cohort mice (p = 6.78 x 10 -6 and p = 8.58 x 10 -3, respectively).	('effect', 'Reg', (62, 68))	('MTFS', 'CPA', (72, 76))	('mice', 'Species', '10090', (100, 104))	('Cdh1', 'Gene', (42, 46))	('deletion', 'Var', (30, 38))
48160	30332649	The vast majority of lesions that formed in Cdh1loxP/loxP;R26-LSL-Pik3camut;Wap-Cre double-mutant mice were scirrhous tumors (Figures 1B and S1A).	('Wap', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('scirrhous tumors', 'Disease', 'MESH:D002293', (108, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('Wap', 'Gene', '22373', (76, 79))	('mice', 'Species', '10090', (98, 102))	('Cdh1loxP/loxP', 'Gene', (44, 57))	('Cdh1loxP/loxP', 'Gene', '12550', (44, 57))	('double-mutant', 'Var', (84, 97))	('scirrhous tumors', 'Disease', (108, 124))
48162	30332649	The Pik3caE545K single mutant induced mostly adenosquamous carcinomas (ASCs) (78%), with a number of other histotypes seen in a small percentage of tumors (Figures 1C and S1B).	('mostly adenosquamous carcinomas', 'Disease', (38, 69))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('induced', 'Reg', (30, 37))	('Pik3caE545K single', 'Var', (4, 22))	('E545K', 'Mutation', 'rs104886003', (10, 15))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('mostly adenosquamous carcinomas', 'Disease', 'MESH:D018196', (38, 69))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
48164	30332649	Results from these control cohorts are consistent with a published report on transgenic models for E545K- and H1047R-induced mammary tumors.	('mammary tumors', 'Disease', 'MESH:D001943', (125, 139))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('E545K', 'Mutation', 'rs104886003', (99, 104))	('H1047R', 'SUBSTITUTION', 'None', (110, 116))	('mammary tumors', 'Disease', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('E545K-', 'Var', (99, 105))	('H1047R', 'Var', (110, 116))
48165	30332649	Thus, both hotspot mutant alleles of Pik3ca cooperate with Cdh1 loss-of-function mutations to induce ILC-like tumors in mice (unpublished data and see below).	('mice', 'Species', '10090', (120, 124))	('Pik3ca', 'Gene', (37, 43))	('Cdh1', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('mutant', 'Var', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (81, 90))	('rat', 'Species', '10116', (49, 52))	('loss-of-function', 'NegReg', (64, 80))
48167	30332649	To this end, we tested for E-cadherin expression and PI3K activation and confirmed dramatically reduced E-cadherin accumulation as well as Akt activation in the H1047R mutant model (Figure S1C).	('tested', 'Reg', (16, 22))	('Akt', 'Gene', '11651', (139, 142))	('Akt', 'Gene', (139, 142))	('H1047R', 'Var', (161, 167))	('E-cadherin accumulation', 'MPA', (104, 127))	('activation', 'PosReg', (143, 153))	('cadherin', 'molecular_function', 'GO:0008014', ('106', '114'))	('H1047R', 'SUBSTITUTION', 'None', (161, 167))	('PI3K', 'molecular_function', 'GO:0016303', ('53', '57'))	('cadherin', 'molecular_function', 'GO:0008014', ('29', '37'))	('reduced', 'NegReg', (96, 103))
48172	30332649	Tumors that formed in Cdh1;Pik3ca double-mutant mice had less connective tissue than in human lobular BC.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Cdh1;Pik3ca', 'Gene', (22, 33))	('double-mutant', 'Var', (34, 47))	('mice', 'Species', '10090', (48, 52))	('less', 'NegReg', (57, 61))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('human', 'Species', '9606', (88, 93))
48182	30332649	Both receptors were expressed in double-mutant tumors (Figures 2G and 2H).	('double-mutant', 'Var', (33, 46))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
48189	30332649	Gene expression profiles among Cdh1loxP/loxP; R26-LSL-Pik3caH1047R double-mutant tumors were highly correlated (centroid correlation > 0.9), and all ten assayed tumors clustered together without interruption by even a single tumor from any of the other models.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', (161, 167))	('tumor', 'Disease', (225, 230))	('tumors clustered', 'Disease', (161, 177))	('Gene expression', 'MPA', (0, 15))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (81, 86))	('Cdh1loxP/loxP', 'Gene', '12550', (31, 44))	('tumors clustered', 'Disease', 'MESH:D003027', (161, 177))	('Cdh1loxP/loxP', 'Gene', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('double-mutant', 'Var', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
48191	30332649	Tumors with the greatest similarity to those from Cdh1loxP/loxP;R26-LSL-Pik3caH1047R;Wap-Cre mice were from Stat1-/- , MMTV-ATX, and R26-LSL-Pik3caH1047R;MMTV-Cre mice, all of which are ERalpha+.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Wap', 'Gene', '22373', (85, 88))	('Stat1', 'Gene', (108, 113))	('Stat1', 'Gene', '20846', (108, 113))	('Wap', 'Gene', (85, 88))	('R26-LSL-Pik3caH1047R', 'Var', (133, 153))	('Cdh1loxP/loxP', 'Gene', (50, 63))	('Cdh1loxP/loxP', 'Gene', '12550', (50, 63))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('MMTV', 'Species', '11757', (119, 123))	('mice', 'Species', '10090', (93, 97))	('mice', 'Species', '10090', (163, 167))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MMTV', 'Species', '11757', (154, 158))
48217	30332649	Concordant with single-gene profiling, we saw low expression of signatures for cell cycle progression pathways in Cdh1loxP/loxP;R26-LSL-Pik3caH1047R tumors and human ILC.	('low', 'NegReg', (46, 49))	('cell cycle progression pathways', 'Pathway', (79, 110))	('cell cycle', 'biological_process', 'GO:0007049', ('79', '89'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Cdh1loxP/loxP', 'Gene', (114, 127))	('Cdh1loxP/loxP', 'Gene', '12550', (114, 127))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('R26-LSL-Pik3caH1047R', 'Var', (128, 148))	('expression', 'MPA', (50, 60))	('human', 'Species', '9606', (160, 165))
48225	30332649	Next, we compared our model with other recently described models for Cdh1-/-;Pten-/- ILC as well as for ILC induced by Cdh1 deletion together with oncogenic insertions associated with sleeping beauty transposon mobilization.	('Pten', 'Gene', (77, 81))	('Pten', 'Gene', '19211', (77, 81))	('deletion', 'Var', (124, 132))	('Cdh1', 'Gene', (119, 123))	('ILC', 'Disease', (104, 107))
48233	30332649	To test for tumor cell dependence on altered signaling, we performed mitochondrial activity assays (MTT) on tumorsphere and control mammosphere cultures treated with inhibitors of PI3K (BKM120 and BYL719), Rac1 (NSC23766), or Yap1 (verteporfin).	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('verteporfin', 'Chemical', 'MESH:D000077362', (232, 243))	('BKM120', 'Var', (186, 192))	('Yap1', 'Gene', (226, 230))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (12, 17))	('mitochondrial activity assays', 'MPA', (69, 98))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('MTT', 'Chemical', '-', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('Yap1', 'Gene', '22601', (226, 230))	('NSC23766', 'Var', (212, 220))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (108, 114))	('BKM120', 'Chemical', 'MESH:C571178', (186, 192))	('PI3K', 'Gene', (180, 184))	('PI3K', 'molecular_function', 'GO:0016303', ('180', '184'))	('Rac1', 'Gene', (206, 210))	('tumors', 'Disease', 'MESH:D009369', (108, 114))
48246	30332649	These included CD11blo MHCIIhi CD24hi dendritic cells, MHCII Ly6G+ granulocytes, MHCIIlo Ly6Chi monocytes and MHCII CD24hi SiglecF+ cells resembling alveolar macrophages (not shown).	('SiglecF', 'Gene', '233186', (123, 130))	('Ly6G', 'Gene', '546644', (61, 65))	('Ly6C', 'Gene', '17067', (89, 93))	('CD24', 'Gene', '12484', (31, 35))	('CD24', 'Gene', (31, 35))	('Ly6G', 'Gene', (61, 65))	('CD24', 'Gene', (116, 120))	('SiglecF', 'Gene', (123, 130))	('CD24', 'Gene', '12484', (116, 120))	('CD11blo', 'Var', (15, 22))	('Ly6C', 'Gene', (89, 93))
48254	30332649	Finally, PD1+ regulatory T cells in tumor MG samples also expressed higher levels of the CD25 cytokine receptor (Figure S7C), providing further evidence that they were activated.	('PD1+', 'Var', (9, 13))	('higher', 'PosReg', (68, 74))	('CD25', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('levels', 'MPA', (75, 81))	('CD25', 'Gene', '16184', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
48255	30332649	Collectively these data suggest that development of MG tumors in this model is accompanied by generation of an immune suppressive micro-environment in which CD11chi CD49Fhi macrophages as well as PD1hi cytotoxic and regulatory T cells are more prevalent than in the normal MG.	('PD1hi', 'Var', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MG tumors', 'Disease', 'MESH:D000080343', (52, 61))	('CD49F', 'Gene', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('rat', 'Species', '10116', (98, 101))	('CD49F', 'Gene', '16403', (165, 170))	('MG tumors', 'Disease', (52, 61))
48258	30332649	Here we report that homozygous deletion of Cdh1 cooperates with Pik3caH1047R to induce mouse mammary tumors with a dramatically reduced latency, in comparison with tumor formation induced by Pik3caH1047R alone (note that Cdh1 deletion by itself does not induce mammary tumor formation).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Disease', (164, 169))	('formation', 'biological_process', 'GO:0009058', ('275', '284'))	('mouse', 'Species', '10090', (87, 92))	('deletion', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('mammary tumors', 'Disease', 'MESH:D001943', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('mammary tumors', 'Disease', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('induce', 'PosReg', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('Cdh1', 'Gene', (43, 47))	('formation', 'biological_process', 'GO:0009058', ('170', '179'))	('rat', 'Species', '10116', (53, 56))	('latency', 'MPA', (136, 143))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (269, 274))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
48260	30332649	During the first ~8 months (250 days), Pik3caE545K cooperates with Cdh1 deletion to induce mammary tumor formation at a higher rate.	('tumor', 'Disease', (99, 104))	('rat', 'Species', '10116', (56, 59))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('rat', 'Species', '10116', (127, 130))	('E545K', 'Mutation', 'rs104886003', (45, 50))	('induce', 'PosReg', (84, 90))	('Cdh1', 'Gene', (67, 71))	('Pik3caE545K', 'Var', (39, 50))	('deletion', 'Var', (72, 80))
48262	30332649	The exact reason for this difference between alleles is unclear, although PIK3CAE545K mutants are mostly found in slow-growing luminal A breast tumors, whereas PIK3CAH1047R mutations are common in both luminal A and luminal B.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('breast tumor', 'Phenotype', 'HP:0100013', (137, 149))	('PIK3CAE545K', 'Var', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('found', 'Reg', (105, 110))	('breast tumors', 'Disease', (137, 150))	('breast tumors', 'Disease', 'MESH:D001943', (137, 150))	('slow-growing', 'CPA', (114, 126))	('PIK3CAH1047R', 'Gene', (160, 172))	('PIK3CAH1047R', 'Gene', '18706', (160, 172))	('breast tumors', 'Phenotype', 'HP:0100013', (137, 150))
48263	30332649	Perhaps this is related to inefficient activation of Akt by p110aE545K, as opposed to p110aH1047R, or to the differential dependence of helical (E545K) versus kinase domain (H1047R) mutant proteins on Ras-GTP and tyrosine kinase signaling, respectively.	('proteins', 'Protein', (189, 197))	('activation', 'PosReg', (39, 49))	('E545K', 'Mutation', 'rs104886003', (65, 70))	('Akt', 'Gene', '11651', (53, 56))	('H1047R', 'Var', (91, 97))	('H1047R', 'Var', (174, 180))	('H1047R', 'SUBSTITUTION', 'None', (91, 97))	('E545K', 'Mutation', 'rs104886003', (145, 150))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('Akt', 'Gene', (53, 56))	('E545K', 'Var', (145, 150))	('H1047R', 'SUBSTITUTION', 'None', (174, 180))	('tyrosine kinase signaling', 'MPA', (213, 238))	('p110aE545K', 'Var', (60, 70))
48269	30332649	Transcriptional profiling also revealed a number of gene expression programs and signaling pathways that show shared activation in Cdh1loxP/loxP;R26-LSL-Pik3caH1047R tumors and human IR-ILC; this includes Rac1, Yap, Oct4, Hif1a, Shh, and Notch.	('signaling pathways', 'Pathway', (81, 99))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('human', 'Species', '9606', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))	('Hif1a', 'Gene', '3091', (222, 227))	('Oct4', 'Gene', (216, 220))	('Shh', 'Gene', (229, 232))	('Hif1a', 'Gene', (222, 227))	('tumors', 'Disease', (166, 172))	('Shh', 'Gene', '6469', (229, 232))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('activation', 'PosReg', (117, 127))	('R26-LSL-Pik3caH1047R', 'Var', (145, 165))	('Cdh1loxP/loxP', 'Gene', (131, 144))	('Oct4', 'Gene', '5460', (216, 220))	('Cdh1loxP/loxP', 'Gene', '12550', (131, 144))	('gene expression programs', 'Gene', (52, 76))
48271	30332649	Also, mouse IR-ILC tumor cells show sensitivity to PI3K, Rac1, and Yap inhibitors.	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('PI3K', 'Var', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('sensitivity', 'MPA', (36, 47))	('mouse', 'Species', '10090', (6, 11))
48275	30332649	For example, tissue resident macrophages were reduced in number, while a new CD11b+, CD11cHi (Itgax), and CD49F (Itga6)Hi macrophage compartment was present.	('Itga6', 'Gene', '16403', (113, 118))	('tissue resident macrophages', 'CPA', (13, 40))	('CD49F', 'Gene', (106, 111))	('CD11cHi', 'Var', (85, 92))	('Itga6', 'Gene', (113, 118))	('CD49F', 'Gene', '16403', (106, 111))	('reduced', 'NegReg', (46, 53))	('CD11b+', 'Var', (77, 83))	('Itgax', 'Gene', '16411', (94, 99))	('Itgax', 'Gene', (94, 99))
48287	30332649	Ultimately, combination therapies can be developed with this model, on the basis of signaling defects (e.g., PI3K and Rac1), as well as on activation of effective immune clearance of tumor.	('Rac1', 'Gene', (118, 122))	('activation', 'PosReg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('PI3K', 'molecular_function', 'GO:0016303', ('109', '113'))	('immune clearance', 'CPA', (163, 179))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('PI3K', 'Var', (109, 113))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))
48309	30332649	AlexaFluor488 anti-mouse (Invitrogen A21202), AlexaFluor488 anti-rat (Invitrogen A11006) and AlexaFluor594 anti-rabbit (Invitrogen A21442).	('AlexaFluor488', 'Chemical', '-', (0, 13))	('rat', 'Species', '10116', (65, 68))	('rabbit', 'Species', '9986', (112, 118))	('AlexaFluor488', 'Chemical', '-', (46, 59))	('mouse', 'Species', '10090', (19, 24))	('AlexaFluor488 anti-rat', 'Var', (46, 68))	('AlexaFluor594 anti-rabbit', 'Var', (93, 118))	('AlexaFluor594', 'Chemical', '-', (93, 106))
48314	30332649	Cells were incubated with a lineage antibody cocktail (anti-mouse TER-119, eBioscience, #14-5921; anti-mouse CD45, eBioscience, #14-0451; anti-mouse CD140a, eBioscience, #14-1401; anti-mouse CD31, eBioscience, #14-0311) for 30 minutes (4 C), then with Goat anti-rat IgG microbeads (Miltenyi Biotec, #120-000-290) for 15 minutes (4 C).	('mouse', 'Species', '10090', (103, 108))	('antibody', 'molecular_function', 'GO:0003823', ('36', '44'))	('Biotec', 'Chemical', '-', (291, 297))	('rat', 'Species', '10116', (262, 265))	('CD31', 'Gene', (191, 195))	('antibody', 'cellular_component', 'GO:0042571', ('36', '44'))	('mouse', 'Species', '10090', (143, 148))	('CD45', 'Gene', '19264', (109, 113))	('anti-mouse', 'Var', (138, 148))	('TER-119', 'Gene', '104231', (66, 73))	('CD140a', 'Gene', '18595', (149, 155))	('TER', 'cellular_component', 'GO:0097047', ('66', '69'))	('antibody', 'cellular_component', 'GO:0019815', ('36', '44'))	('CD45', 'Gene', (109, 113))	('mouse', 'Species', '10090', (60, 65))	('mouse', 'Species', '10090', (185, 190))	('CD140a', 'Gene', (149, 155))	('Goat', 'Species', '9925', (252, 256))	('antibody', 'cellular_component', 'GO:0019814', ('36', '44'))	('CD31', 'Gene', '18613', (191, 195))	('TER-119', 'Gene', (66, 73))
48319	30332649	Different concentrations of the following inhibitors were added the next day: BKM120 dissolved in DMSO, BYL719 dissolved in DMSO, Verteporfin dissolved in DMSO (TOCRIS 5305) and NSC23766 dissolved in ddH2O (Millipore Sigma 553502).	('DMSO', 'Chemical', 'MESH:D004121', (155, 159))	('ddH2O', 'Chemical', '-', (200, 205))	('BKM120', 'Chemical', 'MESH:C571178', (78, 84))	('BKM120', 'Gene', (78, 84))	('NSC23766', 'Var', (178, 186))	('DMSO', 'Chemical', 'MESH:D004121', (98, 102))	('rat', 'Species', '10116', (17, 20))	('Verteporfin', 'Chemical', 'MESH:D000077362', (130, 141))	('DMSO', 'Chemical', 'MESH:D004121', (124, 128))	('BYL719', 'Gene', (104, 110))
48357	30332649	Development of mouse model for lobular BC with deletion of Cdh1 and Pik3ca activation Mouse model shows gene expression signature akin to human immune-related lobular tumors Tumors show enhanced Rac and Yap signaling, with tumorsphere sensitivity to inhibitors Immune suppression and exhaustion in mouse model linked to myeloid and T cell anomalies	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('Tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumors', 'Disease', (223, 229))	('mouse', 'Species', '10090', (15, 20))	('T cell anomalies', 'Phenotype', 'HP:0002843', (332, 348))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('Mouse', 'Species', '10090', (86, 91))	('Tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Cdh1', 'Gene', (59, 63))	('Tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('myeloid and T cell anomalies', 'Disease', 'MESH:D016399', (320, 348))	('deletion', 'Var', (47, 55))	('Pik3ca', 'Gene', (68, 74))	('Rac', 'Gene', '11651', (195, 198))	('signaling', 'biological_process', 'GO:0023052', ('207', '216'))	('Tumors', 'Disease', 'MESH:D009369', (174, 180))	('lobular tumors', 'Disease', 'MESH:D018275', (159, 173))	('lobular tumors', 'Disease', (159, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('mouse', 'Species', '10090', (298, 303))	('Rac', 'Gene', (195, 198))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('human', 'Species', '9606', (138, 143))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('enhanced', 'PosReg', (186, 194))	('tumors', 'Disease', (167, 173))
48416	23971832	Pharmacologic reversion of epigenetic silencing of the PRKD1 promoter blocks breast tumor cell invasion and metastasis DNA methylation-induced silencing of genes encoding tumor suppressors is common in many types of cancer, but little is known about how such epigenetic silencing can contribute to tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (298, 314))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('contribute', 'Reg', (284, 294))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancer', 'Disease', (216, 222))	('PRKD1', 'Gene', '5587', (55, 60))	('tumor', 'Disease', (298, 303))	('tumor metastasis', 'Disease', (298, 314))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('DNA methylation', 'biological_process', 'GO:0006306', ('119', '134'))	('methylation-induced', 'Var', (123, 142))	('breast tumor', 'Disease', 'MESH:D001943', (77, 89))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('PRKD1', 'Gene', (55, 60))	('breast tumor', 'Phenotype', 'HP:0100013', (77, 89))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (171, 176))	('breast tumor', 'Disease', (77, 89))
48421	23971832	Using an animal model, we show that reversion of PRKD1 promoter methylation with the DNA methyltransferase inhibitor decitabine restores PKD1 expression and blocks tumor spread and metastasis to the lung in a PKD1-dependent fashion.	('PKD1 expression', 'MPA', (137, 152))	('PRKD1', 'Gene', '5587', (49, 54))	('PRKD1', 'Gene', (49, 54))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('decitabine', 'Chemical', 'MESH:D000077209', (117, 127))	('reversion', 'Var', (36, 45))	('blocks tumor', 'Disease', (157, 169))	('restores', 'PosReg', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('blocks tumor', 'Disease', 'MESH:D006327', (157, 169))
48422	23971832	Our data suggest that the status of epigenetic regulation of the PRKD1 promoter can provide valid information on the invasiveness of breast tumors and therefore could serve as an early diagnostic marker.	('breast tumors', 'Phenotype', 'HP:0100013', (133, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('breast tumor', 'Phenotype', 'HP:0100013', (133, 145))	('regulation', 'biological_process', 'GO:0065007', ('47', '57'))	('epigenetic regulation', 'Var', (36, 57))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('invasiveness of breast tumors', 'Disease', 'MESH:D001943', (117, 146))	('PRKD1', 'Gene', '5587', (65, 70))	('PRKD1', 'Gene', (65, 70))	('invasiveness of breast tumors', 'Disease', (117, 146))
48430	23971832	In breast cancer, PKD1 may be a key protein that inhibits the invasive phenotype, since a knockdown of PKD1 expression by reverse genetics has been shown to increase the invasiveness of the non- or minimally motile MCF-7 cells.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('knockdown', 'Var', (90, 99))	('MCF-7', 'CellLine', 'CVCL:0031', (215, 220))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('inhibits', 'NegReg', (49, 57))	('breast cancer', 'Disease', (3, 16))	('PKD1', 'Gene', (103, 107))	('invasiveness of', 'CPA', (170, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('increase', 'PosReg', (157, 165))
48435	23971832	Aberrant epigenetic regulation of genes is one of the earliest and most frequent alteration in cancer cells and can lead to dramatic changes in cell phenotype and contribute to breast carcinogenesis .	('breast carcinogenesis', 'Disease', (177, 198))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (177, 198))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('Aberrant epigenetic', 'Var', (0, 19))	('cell phenotype', 'MPA', (144, 158))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('lead to', 'Reg', (116, 123))	('changes', 'Reg', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('contribute', 'Reg', (163, 173))
48437	23971832	In contrast to genetic mutations, epigenetic modifications such as DNA methylation are reversible and represent very promising therapeutic targets for breast cancer treatment.	('DNA methylation', 'biological_process', 'GO:0006306', ('67', '82'))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('epigenetic', 'Var', (34, 44))	('breast cancer', 'Disease', (151, 164))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
48438	23971832	The goal of this study was to determine if epigenetic silencing of PRKD1 occurs in invasive cancer and whether this can be a driver of breast cancer cell metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('PRKD1', 'Gene', '5587', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('invasive cancer', 'Disease', (83, 98))	('PRKD1', 'Gene', (67, 72))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast cancer', 'Disease', (135, 148))	('invasive cancer', 'Disease', 'MESH:D009362', (83, 98))	('epigenetic silencing', 'Var', (43, 63))
48441	23971832	By comparing control to PKD1-knockdown cells in an orthotopic animal model, we demonstrate that local invasion and breast cancer metastasis to the lung are specific to loss of PKD1 and can be blocked with decitabine.	('breast cancer metastasis to the lung', 'Disease', (115, 151))	('loss', 'Var', (168, 172))	('decitabine', 'Chemical', 'MESH:D000077209', (205, 215))	('local invasion', 'CPA', (96, 110))	('breast cancer metastasis to the lung', 'Disease', 'MESH:D009362', (115, 151))	('PKD1', 'Var', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
48469	23971832	Biospecimens were obtained and processed from the Mayo Clinic Tissues Registry under protocols 09-001642, 09-001599, 09-000530 and 11-001638 and approved by the Mayo Clinic Institutional Review Board (IRB) and the Institutional Biosafety Committee.	('Mayo', 'Species', '162683', (50, 54))	('09-000530', 'Var', (117, 126))	('Mayo', 'Species', '162683', (161, 165))	('09-001599', 'Var', (106, 115))
48500	23971832	In human samples of IDC, PKD1 is downregulated at its protein level, but the mechanisms underlying how this is achieved are unknown .	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('human', 'Species', '9606', (3, 8))	('IDC', 'Gene', '4000', (20, 23))	('PKD1', 'Var', (25, 29))	('IDC', 'Gene', (20, 23))	('downregulated', 'NegReg', (33, 46))
48501	23971832	So far, the only mutation in the PRKD1 gene found for breast cancer does not explain the loss of its expression , and it is conceivable that downregulation of PKD1 expression is due to epigenetic modifications such as DNA methylation of its promoter .	('DNA methylation', 'biological_process', 'GO:0006306', ('218', '233'))	('breast cancer', 'Disease', (54, 67))	('DNA', 'cellular_component', 'GO:0005574', ('218', '221'))	('expression', 'MPA', (164, 174))	('PRKD1', 'Gene', '5587', (33, 38))	('PRKD1', 'Gene', (33, 38))	('downregulation', 'NegReg', (141, 155))	('DNA methylation', 'Var', (218, 233))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('PKD1', 'Gene', (159, 163))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
48505	23971832	Hypermethylation of the PRKD1 promoter in breast cancer cell lines directly correlated with a loss of PRKD1 gene expression (Figure  1C).	('expression', 'MPA', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Hypermethylation', 'Var', (0, 16))	('loss', 'NegReg', (94, 98))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('PRKD1', 'Gene', '5587', (102, 107))	('breast cancer', 'Disease', (42, 55))	('gene expression', 'biological_process', 'GO:0010467', ('108', '123'))	('PRKD1', 'Gene', (102, 107))	('PRKD1', 'Gene', '5587', (24, 29))	('PRKD1', 'Gene', (24, 29))
48507	23971832	Next, to confirm bisulfite sequencing analyses, we designed sets of primers that allow distinguishing between methylated and unmethylated PRKD1 promoter (shown in Figure  1A).	('methylated', 'Var', (110, 120))	('PRKD1', 'Gene', '5587', (138, 143))	('PRKD1', 'Gene', (138, 143))	('bisulfite', 'Chemical', 'MESH:C042345', (17, 26))
48508	23971832	Using these primers sets in MSP-PCR, we confirmed that DNA methylation of the PRKD1 promoter was present only in the highly invasive breast cancer cell lines, whereas it was unmethylated in the non- or minimally invasive cells (Figure  1E).	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('PRKD1', 'Gene', '5587', (78, 83))	('invasive breast cancer', 'Disease', (124, 146))	('DNA methylation', 'biological_process', 'GO:0006306', ('55', '70'))	('methylation', 'Var', (59, 70))	('PRKD1', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('invasive breast cancer', 'Disease', 'MESH:D001943', (124, 146))
48509	23971832	PRKD1 promoter methylation directly correlated with loss of PKD1 expression in highly invasive cells (Figure  1F).	('methylation', 'Var', (15, 26))	('loss', 'NegReg', (52, 56))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('PRKD1', 'Gene', '5587', (0, 5))	('expression', 'MPA', (65, 75))	('PRKD1', 'Gene', (0, 5))	('PKD1', 'Gene', (60, 64))
48511	23971832	Taken together, using different methods, we show that the methylation status of the gene promoter directly correlates not only with the loss of PKD1 expression but also with the invasive potential of breast cancer cells.	('invasive potential', 'CPA', (178, 196))	('PKD1', 'Gene', (144, 148))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('methylation', 'Var', (58, 69))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('expression', 'MPA', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Disease', (200, 213))	('loss', 'NegReg', (136, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))
48519	23971832	In contrast, the percentage of tumor cells positive for methylated PRKD1 promoter significantly increased in samples from patients with ER+/HER2- IDC (average of 26.9%) and even more in HER2+ (average of 55.4%) or triple-negative (average of 59.7%) samples.	('increased', 'PosReg', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('HER2', 'Gene', (186, 190))	('tumor', 'Disease', (31, 36))	('HER2', 'Gene', '2064', (186, 190))	('PRKD1', 'Gene', '5587', (67, 72))	('methylated', 'Var', (56, 66))	('patients', 'Species', '9606', (122, 130))	('HER2', 'Gene', '2064', (140, 144))	('PRKD1', 'Gene', (67, 72))	('HER2', 'Gene', (140, 144))	('IDC', 'Gene', '4000', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('IDC', 'Gene', (146, 149))
48520	23971832	Methylation of the PRKD1 promoter correlated with loss of PKD1 protein expression in the same tissue (Additional file 4: Figure S3).	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('Methylation', 'Var', (0, 11))	('PRKD1', 'Gene', '5587', (19, 24))	('loss', 'NegReg', (50, 54))	('PRKD1', 'Gene', (19, 24))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('PKD1', 'Gene', (58, 62))
48522	23971832	As predicted for invasive cancer, we detected a high percentage of positive tumor cells for methylated PRKD1 promoter in both samples.	('PRKD1', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('invasive cancer', 'Disease', (17, 32))	('PRKD1', 'Gene', '5587', (103, 108))	('invasive cancer', 'Disease', 'MESH:D009362', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('methylated', 'Var', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
48525	23971832	In these samples, we observed a significant increase in the percentage of positive cells for PRKD1 promoter methylation in primary tumors (average 71.1%) and a further increase in lymph node metastasis (average 89.1%) compared to adjacent "normal" tissue (average 22.2%).	('increase', 'PosReg', (168, 176))	('primary tumors', 'Disease', (123, 137))	('PRKD1', 'Gene', '5587', (93, 98))	('PRKD1', 'Gene', (93, 98))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('primary tumors', 'Disease', 'MESH:D009369', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('increase', 'PosReg', (44, 52))	('lymph node metastasis', 'Disease', 'MESH:D009362', (180, 201))	('lymph node metastasis', 'Disease', (180, 201))	('methylation', 'Var', (108, 119))
48526	23971832	Hypermethylation of the PRKD1 promoter correlated with loss of PKD1 expression in the same tissue (Additional file 5: Figure S4).	('loss', 'NegReg', (55, 59))	('expression', 'MPA', (68, 78))	('PKD1', 'Gene', (63, 67))	('Hypermethylation', 'Var', (0, 16))	('PRKD1', 'Gene', '5587', (24, 29))	('PRKD1', 'Gene', (24, 29))
48529	23971832	This suggests that both PKD1 expression and methylation of its promoter could serve to determine the invasive potential of breast tumors.	('methylation', 'Var', (44, 55))	('breast tumor', 'Phenotype', 'HP:0100013', (123, 135))	('breast tumors', 'Phenotype', 'HP:0100013', (123, 136))	('determine', 'Reg', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('breast tumors', 'Disease', 'MESH:D001943', (123, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('breast tumors', 'Disease', (123, 136))
48530	23971832	On the basis of the preceding experiments, we hypothesized that inhibition of methylation of the PRKD1 promoter with DNA methyltransferase inhibitors can lead to reexpression of PKD1 and reversion of the invasive phenotype.	('PKD1', 'Enzyme', (178, 182))	('PRKD1', 'Gene', '5587', (97, 102))	('PRKD1', 'Gene', (97, 102))	('invasive phenotype', 'CPA', (204, 222))	('inhibition', 'Var', (64, 74))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('reexpression', 'MPA', (162, 174))	('methylation', 'MPA', (78, 89))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
48532	23971832	Decitabine induced the demethylation of the PRKD1 promoter, and this correlated with the reexpression of PKD1 at the transcriptional level (Figure  3B) and at the protein level without affecting the levels of expression of PKD2 and PKD3 (Figure  3C).	('PKD2', 'Gene', '5311', (223, 227))	('scr', 'Gene', '109559', (121, 124))	('PKD3', 'Gene', (232, 236))	('demethylation', 'biological_process', 'GO:0070988', ('23', '36'))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('demethylation', 'MPA', (23, 36))	('PKD2', 'Gene', (223, 227))	('Decitabine', 'Chemical', 'MESH:D000077209', (0, 10))	('PRKD1', 'Gene', '5587', (44, 49))	('scr', 'Gene', (121, 124))	('PRKD1', 'Gene', (44, 49))	('PKD3', 'Gene', '5312', (232, 236))	('PKD1', 'Var', (105, 109))
48534	23971832	Inhibition of methyltransferases can lead to induction of multiple genes in cancer, including the estrogen receptor .	('methyltransferases', 'Enzyme', (14, 32))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Inhibition', 'Var', (0, 10))	('induction', 'MPA', (45, 54))	('estrogen receptor', 'Gene', (98, 115))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('estrogen receptor', 'Gene', '2099', (98, 115))
48535	23971832	To distinguish between decitabine-induced PKD1-dependent and PKD1-independent effects, we next compared control MDA-MB-231 cells (scrambled shRNA control) to cells previously infected with shRNA targeting PKD1 (PKD1-shRNA 1 or PKD1-shRNA 2).	('scr', 'Gene', (130, 133))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))	('scr', 'Gene', '109559', (130, 133))	('PKD1', 'Var', (205, 209))	('decitabine', 'Chemical', 'MESH:D000077209', (23, 33))
48536	23971832	Expression of shRNA specific for PKD1 in these cells blocks decitabine-induced reexpression of PKD1 as compared to parental or control cells.	('blocks', 'NegReg', (53, 59))	('decitabine-induced reexpression', 'MPA', (60, 91))	('decitabine', 'Chemical', 'MESH:D000077209', (60, 70))	('PKD1', 'Var', (33, 37))
48539	23971832	This suggests that the inhibitory effects of decitabine on cell invasion are due in part to PRKD1 promoter demethylation and reexpression of PKD1.	('cell invasion', 'CPA', (59, 72))	('decitabine', 'Chemical', 'MESH:D000077209', (45, 55))	('PRKD1', 'Gene', '5587', (92, 97))	('PRKD1', 'Gene', (92, 97))	('demethylation', 'Var', (107, 120))	('demethylation', 'biological_process', 'GO:0070988', ('107', '120'))
48550	23971832	When we analyzed tumor edges and connections to the mouse mammary tissue in control cells, we observed a reduced local invasion in the tumors treated with decitabine and reexpressing PKD1.	('tumor', 'Disease', (17, 22))	('local invasion', 'CPA', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('mouse', 'Species', '10090', (52, 57))	('decitabine', 'Chemical', 'MESH:D000077209', (155, 165))	('tumor', 'Disease', (135, 140))	('PKD1', 'Var', (183, 187))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('reduced', 'NegReg', (105, 112))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
48551	23971832	However, cells expressing shRNA targeting PKD1, thus not allowing decitabine-induced reexpression, showed local invasion similar to that of untreated cells (Figure  5A).	('local invasion', 'CPA', (106, 120))	('decitabine', 'Chemical', 'MESH:D000077209', (66, 76))	('PKD1', 'Var', (42, 46))
48562	23971832	Moreover, despite some heterogeneity, mice with tumors formed by cells containing PKD1 shRNA showed no statistical differences in the number of lung metastases or in their size, regardless of the treatment.	('mice', 'Species', '10090', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('PKD1 shRNA', 'Var', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('lung metastases', 'Disease', (144, 159))	('lung metastases', 'Disease', 'MESH:D009362', (144, 159))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
48565	23971832	In prostate and breast tissue, PKD1 contributes to maintenance of the epithelial phenotype by inhibiting EMT and upregulating E-cadherin expression .	('expression', 'MPA', (137, 147))	('E-cadherin', 'Gene', (126, 136))	('EMT', 'CPA', (105, 108))	('E-cadherin', 'Gene', '999', (126, 136))	('PKD1', 'Var', (31, 35))	('inhibiting', 'NegReg', (94, 104))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('cadherin', 'molecular_function', 'GO:0008014', ('128', '136'))	('upregulating', 'PosReg', (113, 125))
48566	23971832	In addition, active PKD1 negatively impacts cell migration and invasion through inhibition of actin reorganization processes at the leading edge , as well as downregulation of expression of MMPs .	('active PKD1', 'Var', (13, 24))	('impacts', 'Reg', (36, 43))	('negatively', 'NegReg', (25, 35))	('inhibition', 'NegReg', (80, 90))	('actin', 'Protein', (94, 99))	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('downregulation', 'NegReg', (158, 172))	('expression', 'MPA', (176, 186))	('invasion', 'CPA', (63, 71))	('cell migration', 'CPA', (44, 58))	('MMPs', 'Gene', '4318', (190, 194))	('MMPs', 'Gene', (190, 194))
48568	23971832	Moreover, loss of PKD1 has been associated with increased invasiveness and risk of metastases in gastric cancer and osteosarcoma .	('invasiveness', 'CPA', (58, 70))	('increased', 'PosReg', (48, 57))	('gastric cancer', 'Disease', (97, 111))	('loss', 'Var', (10, 14))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('metastases', 'Disease', (83, 93))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('metastases', 'Disease', 'MESH:D009362', (83, 93))	('PKD1', 'Gene', (18, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('osteosarcoma', 'Disease', (116, 128))
48569	23971832	We previously have shown the importance of PKD1 for breast cancer cell invasion by demonstrating that a knockdown of PKD1 in the low invasive breast cancer cell line MCF-7 led to an increase of its invasive potential, and reexpression of a constitutively active PKD1 in highly invasive MDA-MB-231 cells impaired their invasive phenotype .	('increase', 'PosReg', (182, 190))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('invasive phenotype', 'CPA', (318, 336))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (286, 296))	('low invasive breast cancer', 'Disease', (129, 155))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('MCF-7', 'CellLine', 'CVCL:0031', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('PKD1', 'Gene', (117, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('low invasive breast cancer', 'Disease', 'MESH:D001943', (129, 155))	('invasive potential', 'CPA', (198, 216))	('impaired', 'NegReg', (303, 311))	('knockdown', 'Var', (104, 113))
48570	23971832	We now show that breast cancer cell lines can be divided into cells that express PKD1 and cells that do not express PKD1 (Figure  1).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('PKD1', 'Var', (81, 85))	('breast cancer', 'Disease', (17, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))
48575	23971832	Recent studies have identified missense mutations in the coding sequence of the PRKD1 gene in human colorectal and breast cancers .	('PRKD1', 'Gene', '5587', (80, 85))	('breast cancers', 'Phenotype', 'HP:0003002', (115, 129))	('PRKD1', 'Gene', (80, 85))	('missense mutations', 'Var', (31, 49))	('human', 'Species', '9606', (94, 99))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal and breast cancers', 'Disease', 'MESH:D015179', (100, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
48576	23971832	However, these mutations do not explain the loss of PKD1 expression during the invasive progression of breast cancer, suggesting another type of regulation.	('mutations', 'Var', (15, 24))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('PKD1', 'Gene', (52, 56))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('regulation', 'biological_process', 'GO:0065007', ('145', '155'))
48577	23971832	Epigenetic alterations such as promoter-specific DNA methylation promote dramatic changes in gene expression and have been shown to play a critical role during tumorigenesis .	('DNA methylation', 'biological_process', 'GO:0006306', ('49', '64'))	('gene expression', 'biological_process', 'GO:0010467', ('93', '108'))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('changes', 'Reg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('gene expression', 'MPA', (93, 108))	('tumor', 'Disease', (160, 165))	('DNA methylation', 'Var', (49, 64))	('play', 'Reg', (132, 136))
48578	23971832	Herein we demonstrate that the silencing of PKD1 observed in invasive breast cancer cell lines, as well as in IDC, is also linked to hypermethylation of its promoter (Figures  1 and 2).	('silencing', 'MPA', (31, 40))	('invasive breast cancer', 'Disease', 'MESH:D001943', (61, 83))	('IDC', 'Gene', '4000', (110, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('invasive breast cancer', 'Disease', (61, 83))	('IDC', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypermethylation', 'Var', (133, 149))	('PKD1', 'Gene', (44, 48))	('linked', 'Reg', (123, 129))
48583	23971832	Our studies also show that the silencing of PRKD1 caused by the hypermethylation of its promoter occurs in IDC, but not in ILC (Figure  2C).	('PRKD1', 'Gene', '5587', (44, 49))	('PRKD1', 'Gene', (44, 49))	('IDC', 'Gene', '4000', (107, 110))	('hypermethylation', 'Var', (64, 80))	('silencing', 'NegReg', (31, 40))	('IDC', 'Gene', (107, 110))
48588	23971832	However, it is possible that PKD1 in this subtype of breast cancer may be regulated in its kinase activity.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('regulated', 'Reg', (74, 83))	('kinase activity', 'MPA', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('kinase activity', 'molecular_function', 'GO:0016301', ('91', '106'))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('PKD1', 'Var', (29, 33))	('breast cancer', 'Disease', (53, 66))
48589	23971832	Combining the knowledge gained from cell culture studies and data obtained with patient specimens (Figures  1 and 2), a strategy to prevent an invasive phenotype and metastasis of breast cancer cells may be reactivation of PKD1.	('metastasis of breast cancer', 'Disease', (166, 193))	('reactivation', 'Var', (207, 219))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('metastasis of breast cancer', 'Disease', 'MESH:D009362', (166, 193))	('patient', 'Species', '9606', (80, 87))
48598	23971832	Cells reexpressing PKD1 formed not only less but also much smaller tumor colonies in the lungs (Figure  6C, D).	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('smaller', 'NegReg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('PKD1', 'Var', (19, 23))
48599	23971832	Therefore, it is likely that PKD1 not only affects the ability of cancer cells to escape from the primary tumor and invades through the surrounding matrix and enter the bloodstream but also may impact their ability to adapt to their new environment.	('adapt to their new environment', 'CPA', (218, 248))	('impact', 'Reg', (194, 200))	('cancer', 'Disease', (66, 72))	('escape', 'CPA', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('affects', 'Reg', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('PKD1', 'Var', (29, 33))	('tumor', 'Disease', (106, 111))	('invades', 'CPA', (116, 123))
48602	23971832	Interestingly, normal cells were less sensitive to drug-induced gene activation, suggesting that DNA methylation is more easily reversed in the targeted tumor cells, in which abnormally methylated CpG islands are responsible for the silencing of tumor suppressor genes .	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor suppressor', 'biological_process', 'GO:0051726', ('246', '262'))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('246', '262'))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('DNA methylation', 'biological_process', 'GO:0006306', ('97', '112'))	('abnormally', 'Var', (175, 185))	('tumor', 'Disease', (246, 251))	('silencing', 'NegReg', (233, 242))
48605	23971832	Taken together, our data suggest a role for PRKD1 promoter silencing by methylation as a measure of how the invasive potential of breast tumors is achieved or increased.	('breast tumors', 'Phenotype', 'HP:0100013', (130, 143))	('promoter', 'PosReg', (50, 58))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('breast tumor', 'Phenotype', 'HP:0100013', (130, 142))	('breast tumors', 'Disease', 'MESH:D001943', (130, 143))	('PRKD1', 'Gene', '5587', (44, 49))	('breast tumors', 'Disease', (130, 143))	('PRKD1', 'Gene', (44, 49))	('methylation', 'Var', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
48606	23971832	They also suggest that reexpression of PRKD1, for example, by using DNA methyltransferase inhibitors such as the FDA-approved drug decitabine, could be an effective strategy to prevent tumor metastasis.	('decitabine', 'Chemical', 'MESH:D000077209', (131, 141))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('tumor metastasis', 'Disease', 'MESH:D009362', (185, 201))	('PRKD1', 'Gene', '5587', (39, 44))	('PRKD1', 'Gene', (39, 44))	('tumor metastasis', 'Disease', (185, 201))	('reexpression', 'Var', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
48612	23971832	This work was supported by grants from the National Institutes of Health (GM086435 and CA140182) and the Bankhead-Coley Program of the Florida Department of Health (1BG11) to PS, as well as a pilot project grant from the Mayo Clinic Breast Cancer SPORE (CA116201-03DR4) to PS, an R21 NS070117 grant to PZA, a grant from the Breast Cancer Research Foundation to EAP and partial support from the 26.2 with Donna Foundation to EAT.	('EAT', 'Disease', 'None', (424, 427))	('Breast Cancer', 'Disease', 'MESH:D001943', (324, 337))	('Cancer', 'Phenotype', 'HP:0002664', (331, 337))	('Breast Cancer', 'Phenotype', 'HP:0003002', (233, 246))	('Breast Cancer', 'Disease', (324, 337))	('Mayo', 'Species', '162683', (221, 225))	('Breast Cancer', 'Phenotype', 'HP:0003002', (324, 337))	('Breast Cancer', 'Disease', (233, 246))	('Cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Breast Cancer', 'Disease', 'MESH:D001943', (233, 246))	('EAP', 'Gene', '6146', (361, 364))	('EAP', 'Gene', (361, 364))	('EAT', 'Disease', (424, 427))	('CA140182', 'Var', (87, 95))
48615	32022473	Multifocal breast cancers are more prevalent in BRCA2 versus BRCA1 mutation carriers Multifocal (MF)/multicentric (MC) breast cancer is generally considered to be where two or more breast tumours are present within the same breast, and is seen in ~10% of breast cancer cases.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('BRCA1', 'Gene', (61, 66))	('prevalent', 'Reg', (35, 44))	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('breast cancer', 'Disease', (255, 268))	('BRCA2', 'Gene', (48, 53))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('mutation', 'Var', (67, 75))	('breast tumours', 'Disease', (181, 195))	('breast cancer', 'Disease', (119, 132))	('Multifocal breast cancers', 'Disease', 'MESH:D001943', (0, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancers', 'Phenotype', 'HP:0003002', (11, 25))	('BRCA2', 'Gene', '675', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('Multifocal', 'Disease', (85, 95))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('breast tumours', 'Disease', 'MESH:D001943', (181, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('Multifocal breast cancers', 'Disease', (0, 25))	('BRCA1', 'Gene', '672', (61, 66))	('Multifocal breast cancers', 'Phenotype', 'HP:0006625', (0, 25))
48616	32022473	This study investigates the prevalence of multifocality/multicentricity in a cohort of BRCA1/2 mutation carriers with breast cancer from Northern Ireland via cross-sectional analysis.	('BRCA1/2', 'Gene', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BRCA1/2', 'Gene', '672;675', (87, 94))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('mutation', 'Var', (95, 103))
48617	32022473	Data from 211 women with BRCA1/2 mutations (BRCA1-91, BRCA2-120) and breast cancer were collected including age, tumour focality, size, type, grade and receptor profile.	('BRCA1', 'Gene', (44, 49))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('BRCA1', 'Gene', '672', (25, 30))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('BRCA1/2', 'Gene', '672;675', (25, 32))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('BRCA1', 'Gene', (25, 30))	('BRCA2', 'Gene', (54, 59))	('tumour', 'Disease', (113, 119))	('breast cancer', 'Disease', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('women', 'Species', '9606', (14, 19))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA1/2', 'Gene', (25, 32))	('BRCA2', 'Gene', '675', (54, 59))
48618	32022473	The prevalence of multifocality/multicentricity within this group was 25% but, within subgroups, prevalence amongst BRCA2 carriers was more than double that of BRCA1 carriers (p = 0.001).	('BRCA1', 'Gene', (160, 165))	('BRCA2', 'Gene', (116, 121))	('BRCA1', 'Gene', '672', (160, 165))	('carriers', 'Var', (122, 130))	('BRCA2', 'Gene', '675', (116, 121))
48620	32022473	These observations are likely to be driven by the higher BRCA2 mutation prevalence observed within this cohort.	('BRCA2', 'Gene', (57, 62))	('BRCA2', 'Gene', '675', (57, 62))	('mutation', 'Var', (63, 71))
48623	32022473	This confirmed a significantly higher prevalence of MF/MC tumours amongst BRCA2 mutation carriers compared with BRCA1 mutation carriers.	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA2', 'Gene', (74, 79))	('BRCA2', 'Gene', '675', (74, 79))	('BRCA1', 'Gene', '672', (112, 117))	('MF/MC tumours', 'Disease', 'MESH:D009369', (52, 65))	('mutation', 'Var', (80, 88))	('BRCA1', 'Gene', (112, 117))	('MF/MC tumours', 'Disease', (52, 65))
48634	32022473	Germline mutations in these genes predispose female carriers to a significantly increased risk of breast and ovarian cancer, with up to 80% lifetime risk of breast cancer.	('Germline mutations', 'Var', (0, 18))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (98, 123))	('predispose', 'Reg', (34, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))
48636	32022473	Surprisingly, despite biological plausibility for the existence of an association between BRCA1/2 mutations and MF/MC tumours, at the time of writing, there were no studies investigating this.	('BRCA1/2', 'Gene', (90, 97))	('MF/MC tumours', 'Disease', 'MESH:D009369', (112, 125))	('BRCA1/2', 'Gene', '672;675', (90, 97))	('mutations', 'Var', (98, 107))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('MF/MC tumours', 'Disease', (112, 125))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))
48637	32022473	Therefore, this study aimed to investigate the prevalence of MF/MC breast cancer in BRCA1/2 mutation carriers, with exploration of the clinicopathological characteristics of all tumours occurring in these patients.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('patients', 'Species', '9606', (205, 213))	('mutation', 'Var', (92, 100))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('BRCA1/2', 'Gene', (84, 91))	('MF/MC breast cancer', 'Disease', 'MESH:D001943', (61, 80))	('tumours', 'Disease', (178, 185))	('BRCA1/2', 'Gene', '672;675', (84, 91))	('MF/MC breast cancer', 'Disease', (61, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
48638	32022473	Data from 252 women with a known pathogenic germline BRCA1/2 mutation diagnosed with breast cancer (1994-2017) were retrospectively extracted from a database containing all known female BRCA1/2 mutation carriers in Northern Ireland (Figure 1).	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('mutation', 'Var', (61, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('BRCA1/2', 'Gene', (186, 193))	('BRCA1/2', 'Gene', (53, 60))	('women', 'Species', '9606', (14, 19))	('BRCA1/2', 'Gene', '672;675', (186, 193))	('BRCA1/2', 'Gene', '672;675', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
48642	32022473	For validation of the findings in the Northern Ireland patient cohort, a second cohort of breast cancer patients with known germline BRCA1/2 mutations was identified.	('BRCA1/2', 'Gene', '672;675', (133, 140))	('mutations', 'Var', (141, 150))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('patient', 'Species', '9606', (104, 111))	('BRCA1/2', 'Gene', (133, 140))	('breast cancer', 'Disease', (90, 103))	('patient', 'Species', '9606', (55, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('patients', 'Species', '9606', (104, 112))
48650	32022473	Of the 211 BRCA1/2 carriers diagnosed with breast cancer (with MF/MC information available) in Northern Ireland between 1994 and 2017, 90 (42.7%) women had a BRCA1 mutation and 121 (57.3%) a BRCA2 mutation.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('BRCA1', 'Gene', '672', (11, 16))	('BRCA1', 'Gene', (158, 163))	('BRCA1/2', 'Gene', '672;675', (11, 18))	('BRCA2', 'Gene', (191, 196))	('BRCA1', 'Gene', (11, 16))	('mutation', 'Var', (164, 172))	('BRCA2', 'Gene', '675', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('BRCA1/2', 'Gene', (11, 18))	('BRCA1', 'Gene', '672', (158, 163))	('women', 'Species', '9606', (146, 151))
48654	32022473	The prevalence of MF/MC disease was 13.3% in BRCA1 mutation carriers and 33.1% in BRCA2 mutation carriers.	('BRCA1', 'Gene', '672', (45, 50))	('BRCA2', 'Gene', (82, 87))	('MF/MC disease', 'Disease', (18, 31))	('MF/MC disease', 'Disease', 'MESH:D003141', (18, 31))	('BRCA1', 'Gene', (45, 50))	('mutation', 'Var', (51, 59))	('BRCA2', 'Gene', '675', (82, 87))
48655	32022473	Therefore, the prevalence of MF/MC disease in BRCA2 carriers was 2.5-fold greater than in BRCA1 carriers (p = 0.001).	('BRCA2', 'Gene', (46, 51))	('carriers', 'Var', (52, 60))	('BRCA1', 'Gene', '672', (90, 95))	('BRCA2', 'Gene', '675', (46, 51))	('BRCA1', 'Gene', (90, 95))	('MF/MC disease', 'Disease', 'MESH:D003141', (29, 42))	('MF/MC disease', 'Disease', (29, 42))	('greater', 'PosReg', (74, 81))
48660	32022473	Of the 52 women diagnosed with MF/MC disease, 23.1% (n = 12) had a BRCA1 mutation and 76.9% (n = 40) a BRCA2 mutation.	('BRCA2', 'Gene', '675', (103, 108))	('MF/MC disease', 'Disease', 'MESH:D003141', (31, 44))	('MF/MC disease', 'Disease', (31, 44))	('women', 'Species', '9606', (10, 15))	('BRCA1', 'Gene', '672', (67, 72))	('mutation', 'Var', (73, 81))	('BRCA2', 'Gene', (103, 108))	('BRCA1', 'Gene', (67, 72))
48661	32022473	50% (n = 6) of women with a BRCA1 mutation were oestrogen receptor positive whilst 82.5% (n = 33) women with a BRCA2 mutation were oestrogen receptor positive (p = 0.039).	('BRCA1', 'Gene', '672', (28, 33))	('BRCA2', 'Gene', (111, 116))	('women', 'Species', '9606', (15, 20))	('BRCA1', 'Gene', (28, 33))	('women', 'Species', '9606', (98, 103))	('mutation', 'Var', (34, 42))	('BRCA2', 'Gene', '675', (111, 116))	('oestrogen', 'Protein', (48, 57))
48662	32022473	The unadjusted odds of breast cancer being MF/MC in BRCA2 mutation carriers were 3.2 times greater than in BRCA1 mutation carriers (CI: 1.57-6.57, p = 0.001).	('BRCA2', 'Gene', (52, 57))	('breast cancer', 'Disease', (23, 36))	('BRCA1', 'Gene', '672', (107, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('BRCA2', 'Gene', '675', (52, 57))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('mutation', 'Var', (58, 66))	('BRCA1', 'Gene', (107, 112))	('greater', 'PosReg', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
48663	32022473	After adjusting for age, the odds of a BRCA2 mutation carrier developing MF/MC breast cancer were 3.7-fold greater than in BRCA1 mutation carriers (CI: 1.77-7.78, p = 0.001) (Table 2).	('BRCA1', 'Gene', '672', (123, 128))	('BRCA2', 'Gene', (39, 44))	('BRCA1', 'Gene', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('MF/MC breast cancer', 'Disease', 'MESH:D001943', (73, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('greater', 'PosReg', (107, 114))	('mutation', 'Var', (45, 53))	('BRCA2', 'Gene', '675', (39, 44))	('MF/MC breast cancer', 'Disease', (73, 92))	('carrier', 'molecular_function', 'GO:0005215', ('54', '61'))
48665	32022473	Similarly, there was no difference in survival between MF/MC or unifocal tumours in BRCA1 mutation carriers (Figure 2B) or BRCA2 mutation carriers (Figure 2C), nor was there a difference in all-cause survival between women with unifocal versus MF/MC disease (Figure 2D).	('unifocal tumours', 'Disease', (64, 80))	('BRCA2', 'Gene', '675', (123, 128))	('mutation', 'Var', (129, 137))	('BRCA1', 'Gene', '672', (84, 89))	('unifocal versus MF/MC disease', 'Disease', 'MESH:D006086', (228, 257))	('unifocal versus MF/MC disease', 'Disease', (228, 257))	('unifocal tumours', 'Disease', 'MESH:D009369', (64, 80))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('women', 'Species', '9606', (217, 222))	('BRCA2', 'Gene', (123, 128))	('BRCA1', 'Gene', (84, 89))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('mutation', 'Var', (90, 98))	('MF/MC', 'Disease', (55, 60))
48666	32022473	There were 338 germline BRCA mutation carriers in the POSH study breast cancer cohort; focality data were missing in 37 cases, leaving 180 women with a BRCA1 mutation and 121 with a BRCA2 mutation for analysis.	('BRCA', 'Gene', '672', (182, 186))	('women', 'Species', '9606', (139, 144))	('BRCA', 'Gene', '672', (24, 28))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('BRCA', 'Gene', (182, 186))	('BRCA2', 'Gene', '675', (182, 187))	('BRCA', 'Gene', (24, 28))	('POSH', 'Gene', (54, 58))	('BRCA1', 'Gene', '672', (152, 157))	('breast cancer', 'Disease', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('POSH', 'Gene', '57630', (54, 58))	('mutation', 'Var', (158, 166))	('BRCA', 'Gene', '672', (152, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('BRCA1', 'Gene', (152, 157))	('BRCA', 'Gene', (152, 156))	('BRCA2', 'Gene', (182, 187))
48670	32022473	MF/MC breast cancer was identified in 26.9% of BRCA1/2 mutation carriers who developed breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('BRCA1/2', 'Gene', '672;675', (47, 54))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('MF/MC breast cancer', 'Disease', (0, 19))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('BRCA1/2', 'Gene', (47, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('mutation', 'Var', (55, 63))	('MF/MC breast cancer', 'Disease', 'MESH:D001943', (0, 19))
48671	32022473	The prevalence of MF/MC disease was 13.3% amongst BRCA1 mutation carriers diagnosed with breast cancer, and 47.1% amongst BRCA2 mutation carriers diagnosed with breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('BRCA1', 'Gene', (50, 55))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (161, 174))	('breast cancer', 'Disease', (89, 102))	('MF/MC disease', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('MF/MC disease', 'Disease', 'MESH:D003141', (18, 31))	('BRCA2', 'Gene', (122, 127))	('mutation', 'Var', (56, 64))	('BRCA1', 'Gene', '672', (50, 55))	('BRCA2', 'Gene', '675', (122, 127))
48672	32022473	Therefore, the prevalence of MF/MC disease in BRCA2 mutation carriers was 3.5-fold greater than in BRCA1 mutation carriers in this independent cohort of BRCA1/2 carriers (p < 0.001).	('BRCA2', 'Gene', (46, 51))	('BRCA1', 'Gene', (99, 104))	('BRCA1/2', 'Gene', (153, 160))	('BRCA1', 'Gene', '672', (153, 158))	('greater', 'PosReg', (83, 90))	('BRCA2', 'Gene', '675', (46, 51))	('BRCA1/2', 'Gene', '672;675', (153, 160))	('MF/MC disease', 'Disease', 'MESH:D003141', (29, 42))	('mutation', 'Var', (52, 60))	('BRCA1', 'Gene', (153, 158))	('MF/MC disease', 'Disease', (29, 42))	('BRCA1', 'Gene', '672', (99, 104))
48673	32022473	BRCA1/2 mutation carriers with MF/MC disease were more likely to be oestrogen receptor positive (74.1%) than those with unifocal disease (41.4%).	('BRCA1/2', 'Gene', '672;675', (0, 7))	('MF/MC disease', 'Disease', 'MESH:D003141', (31, 44))	('oestrogen receptor', 'Protein', (68, 86))	('MF/MC disease', 'Disease', (31, 44))	('mutation', 'Var', (8, 16))	('BRCA1/2', 'Gene', (0, 7))
48674	32022473	Similarly, BRCA1/2 mutation carriers with MF/MC disease were less likely to be triple receptor negative (18.5%) compared to those with unifocal disease (42.3%).	('mutation', 'Var', (19, 27))	('MF/MC disease', 'Disease', (42, 55))	('triple receptor', 'Protein', (79, 94))	('BRCA1/2', 'Gene', '672;675', (11, 18))	('MF/MC disease', 'Disease', 'MESH:D003141', (42, 55))	('less', 'NegReg', (61, 65))	('BRCA1/2', 'Gene', (11, 18))	('negative', 'NegReg', (95, 103))
48675	32022473	When data from women who developed MF/MC breast cancer were analysed in isolation, the prevalence of oestrogen receptor positivity was 85% amongst BRCA2 mutation carriers but only 15% in BRCA1 mutation carriers.	('MF/MC breast cancer', 'Disease', 'MESH:D001943', (35, 54))	('BRCA2', 'Gene', '675', (147, 152))	('women', 'Species', '9606', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('BRCA1', 'Gene', '672', (187, 192))	('MF/MC breast cancer', 'Disease', (35, 54))	('BRCA1', 'Gene', (187, 192))	('BRCA2', 'Gene', (147, 152))	('mutation', 'Var', (153, 161))	('oestrogen receptor', 'Protein', (101, 119))
48676	32022473	The unadjusted odds (in binary logistic regression analysis) of a breast cancer being MF/MC in BRCA2 mutation carriers was 5.8 times greater than in a BRCA1 mutation carrier who developed breast cancer (CI: 3.31-10.12) (p < 0.001) (Table 2).	('greater', 'PosReg', (133, 140))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('BRCA2', 'Gene', '675', (95, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('breast cancer', 'Disease', (188, 201))	('BRCA1', 'Gene', '672', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('BRCA1', 'Gene', (151, 156))	('carrier', 'molecular_function', 'GO:0005215', ('166', '173'))	('breast cancer', 'Disease', (66, 79))	('BRCA2', 'Gene', (95, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('mutation', 'Var', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
48677	32022473	Adjustment for oestrogen receptor status gave odds of a BRCA2 mutation carrier developing MF/MC breast cancer 4.2 times greater than a BRCA1 mutation carrier (CI: 2.12-8.19) (p < 0.001).	('greater', 'PosReg', (120, 127))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA2', 'Gene', '675', (56, 61))	('MF/MC breast cancer', 'Disease', 'MESH:D001943', (90, 109))	('BRCA1', 'Gene', '672', (135, 140))	('MF/MC breast cancer', 'Disease', (90, 109))	('carrier', 'molecular_function', 'GO:0005215', ('150', '157'))	('carrier', 'molecular_function', 'GO:0005215', ('71', '78'))	('mutation', 'Var', (62, 70))	('BRCA1', 'Gene', (135, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('BRCA2', 'Gene', (56, 61))
48681	32022473	Nevertheless, and in contrast, the prevalence of multifocality/multicentricity in the Northern Ireland cohort of 211 BRCA1/2 mutation carriers was 24.6%, more than double that reported by Vera-Badillo et al for sporadic breast cancer 1.	('BRCA1/2', 'Gene', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('sporadic breast cancer', 'Disease', (211, 233))	('BRCA1/2', 'Gene', '672;675', (117, 124))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (211, 233))	('mutation', 'Var', (125, 133))
48682	32022473	This finding is supported by a strikingly similar prevalence of 26.9% in the larger cohort of BRCA1/2 mutation carriers from the multicentre POSH study.	('BRCA1/2', 'Gene', (94, 101))	('POSH', 'Gene', (141, 145))	('mutation', 'Var', (102, 110))	('POSH', 'Gene', '57630', (141, 145))	('BRCA1/2', 'Gene', '672;675', (94, 101))
48683	32022473	Our study found that the prevalence of multifocality/multicentricity in BRCA2 mutation carriers was at least double that in BRCA1 mutation carriers in both reported patient cohorts - a finding mirrored in a small-scale study by Bergthorsson et al 16.	('BRCA2', 'Gene', (72, 77))	('mutation', 'Var', (78, 86))	('BRCA1', 'Gene', '672', (124, 129))	('BRCA2', 'Gene', '675', (72, 77))	('patient', 'Species', '9606', (165, 172))	('BRCA1', 'Gene', (124, 129))
48684	32022473	The odds of a woman who had developed breast cancer exhibiting MF/MC disease were over three times greater if she had a BRCA2 mutation compared to a BRCA1 mutation.	('MF/MC disease', 'Disease', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('BRCA2', 'Gene', '675', (120, 125))	('MF/MC disease', 'Disease', 'MESH:D003141', (63, 76))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('mutation', 'Var', (126, 134))	('breast cancer', 'Disease', (38, 51))	('BRCA2', 'Gene', (120, 125))	('woman', 'Species', '9606', (14, 19))	('BRCA1', 'Gene', '672', (149, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('BRCA1', 'Gene', (149, 154))
48687	32022473	These findings are in keeping with numerous studies documenting significantly higher rates of oestrogen receptor positivity amongst BRCA2 carriers compared with BRCA1 mutation carriers.	('carriers', 'Var', (138, 146))	('BRCA1', 'Gene', (161, 166))	('higher', 'PosReg', (78, 84))	('BRCA2', 'Gene', (132, 137))	('BRCA2', 'Gene', '675', (132, 137))	('oestrogen receptor', 'Protein', (94, 112))	('BRCA1', 'Gene', '672', (161, 166))
48690	32022473	Similarly, although ILC was seen more commonly in BRCA2 mutation carriers than in BRCA1 carriers in the Northern Ireland patient cohort, the significant increase in prevalence of MF/MC disease in BRCA2 carriers persisted even when ILC cases were excluded from the analysis, suggesting that it is not the lobular phenotype which drives the increased prevalence of multifocality/multicentricity.	('BRCA1', 'Gene', (82, 87))	('mutation carriers', 'Var', (56, 73))	('MF/MC disease', 'Disease', (179, 192))	('MF/MC disease', 'Disease', 'MESH:D003141', (179, 192))	('BRCA2', 'Gene', '675', (196, 201))	('BRCA2', 'Gene', (50, 55))	('increase', 'PosReg', (153, 161))	('ILC', 'Disease', (20, 23))	('BRCA1', 'Gene', '672', (82, 87))	('BRCA2', 'Gene', '675', (50, 55))	('patient', 'Species', '9606', (121, 128))	('BRCA2', 'Gene', (196, 201))	('carriers', 'Var', (65, 73))
48692	32022473	Recent evidence suggests that BRCA1-related breast cancer is driven by aberrant RANK/RANKL signalling in BRCA1 heterozygous luminal progenitor cells, coupled with increased DNA damage/defective DNA repair in these cells, resulting in development of basal breast cancers 19.	('DNA repair', 'biological_process', 'GO:0006281', ('194', '204'))	('BRCA1', 'Gene', (30, 35))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('luminal', 'Chemical', 'MESH:D010634', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('driven by', 'Reg', (61, 70))	('increased', 'PosReg', (163, 172))	('RANKL', 'Gene', '8600', (85, 90))	('basal breast cancers 19', 'Disease', 'MESH:C000657245', (249, 272))	('BRCA1', 'Gene', '672', (105, 110))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('aberrant', 'Var', (71, 79))	('BRCA1', 'Gene', (105, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('signalling', 'biological_process', 'GO:0023052', ('91', '101'))	('basal breast cancers 19', 'Disease', (249, 272))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancers', 'Phenotype', 'HP:0003002', (255, 269))	('breast cancer', 'Disease', (44, 57))	('RANKL', 'Gene', (85, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('BRCA1', 'Gene', '672', (30, 35))	('DNA damage/defective', 'MPA', (173, 193))
48696	32022473	Moreover, given the apparent predominant development of synchronous but distinct cancers in BRCA2 mutation carriers, the contribution of genomic instability at a single cell level also needs to be investigated.	('carriers', 'Reg', (107, 115))	('mutation', 'Var', (98, 106))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('development', 'PosReg', (41, 52))	('cancers', 'Disease', (81, 88))	('BRCA2', 'Gene', (92, 97))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BRCA2', 'Gene', '675', (92, 97))
48697	32022473	Finally, given recent data demonstrating activation of cell intrinsic innate immune responses to the loss of BRCA1/2, the role of early immunoediting in control of tumours in BRCA1 versus BRCA2 carriers needs to be investigated 21.	('BRCA2', 'Gene', '675', (188, 193))	('BRCA1', 'Gene', (109, 114))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('BRCA1', 'Gene', (175, 180))	('loss', 'Var', (101, 105))	('BRCA1', 'Gene', '672', (175, 180))	('BRCA1/2', 'Gene', (109, 116))	('BRCA2', 'Gene', (188, 193))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('tumours', 'Disease', (164, 171))	('activation', 'PosReg', (41, 51))	('BRCA1', 'Gene', '672', (109, 114))	('BRCA1/2', 'Gene', '672;675', (109, 116))
48701	32022473	Additionally, the presence of a large, independent cohort of BRCA1/2 mutation carriers in the validation cohort provides strong evidence to support the increased prevalence of MF/MC tumours in BRCA2 mutation carriers.	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('MF/MC tumours', 'Disease', (176, 189))	('BRCA2', 'Gene', (193, 198))	('tumours', 'Phenotype', 'HP:0002664', (182, 189))	('mutation', 'Var', (199, 207))	('mutation', 'Var', (69, 77))	('BRCA1/2', 'Gene', (61, 68))	('BRCA2', 'Gene', '675', (193, 198))	('BRCA1/2', 'Gene', '672;675', (61, 68))	('MF/MC tumours', 'Disease', 'MESH:D009369', (176, 189))
48703	32022473	Other groups have reported worse 10 year survival in BRCA1 mutation carriers as compared with BRCA2 carriers, ascribing this difference to tumour biology 23.	('tumour', 'Disease', (139, 145))	('worse', 'NegReg', (27, 32))	('BRCA2', 'Gene', (94, 99))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('BRCA2', 'Gene', '675', (94, 99))	('mutation', 'Var', (59, 67))	('BRCA1', 'Gene', '672', (53, 58))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('BRCA1', 'Gene', (53, 58))
48704	32022473	However, the cohort of young patients from the POSH study, which form the validation cohort for this study, did not demonstrate a significant difference in overall survival between either BRCA1 or BRCA2 mutation carriers and non-mutation carriers, despite showing a similar increase in multifocality/multicentricity prevalence in BRCA2 mutation carriers 13.	('patients', 'Species', '9606', (29, 37))	('BRCA2', 'Gene', (330, 335))	('BRCA1', 'Gene', (188, 193))	('BRCA2', 'Gene', (197, 202))	('BRCA2', 'Gene', '675', (330, 335))	('mutation', 'Var', (203, 211))	('POSH', 'Gene', '57630', (47, 51))	('POSH', 'Gene', (47, 51))	('BRCA2', 'Gene', '675', (197, 202))	('BRCA1', 'Gene', '672', (188, 193))
48714	32022473	In conclusion, we report a higher than anticipated prevalence of multifocality/multicentricity amongst female BRCA1/2 mutation carriers diagnosed with breast cancer.	('BRCA1/2', 'Gene', (110, 117))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('BRCA1/2', 'Gene', '672;675', (110, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('mutation', 'Var', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
48715	32022473	This finding was seen in a cohort of patients from Northern Ireland and is validated in the independent cohort of BRCA1/2 mutation carriers from the POSH study.	('BRCA1/2', 'Gene', (114, 121))	('POSH', 'Gene', '57630', (149, 153))	('mutation', 'Var', (122, 130))	('POSH', 'Gene', (149, 153))	('patients', 'Species', '9606', (37, 45))	('BRCA1/2', 'Gene', '672;675', (114, 121))
48726	27499907	We evaluated the number of mutated genes with somatic non-silent mutations in different subgroups of breast cancer based on clinico-pathological, including immunohistochemical and tumour characteristics.	('non-silent mutations', 'Var', (54, 74))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('tumour', 'Disease', (180, 186))
48728	27499907	The number of mutated genes was strongly positively associated with higher tumour grade (p = 1.4e-14) and with the different immunohistochemical and PAM50 molecular subtypes of breast cancer (p = 1.4e-10 and p = 4.3e-10, respectively).	('mutated genes', 'Var', (14, 27))	('breast cancer', 'Disease', (177, 190))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))
48731	27499907	Multivariate analysis for overall survival (OS) revealed a worse survival for patients with high numbers of mutated genes (hazard ratio = 4.6, 95% CI: 1.0 - 20.0, p = 0.044).	('high numbers', 'Var', (92, 104))	('worse', 'NegReg', (59, 64))	('mutated genes', 'Var', (108, 121))	('patients', 'Species', '9606', (78, 86))
48732	27499907	Here, we report a strong association of the number of mutated genes with immunohistochemical and PAM50 subtypes and tumour grade in breast cancer.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Disease', (116, 122))	('mutated', 'Var', (54, 61))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
48743	27499907	In this context, it is worth recalling that just as the molecular phenotype, the morphological phenotype of the tumour, including tumour grade and tumour size is essentially a result of accumulated genetic aberrations over time, thereby reflecting tumour evolution at the phenotypic level.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Disease', (248, 254))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('recalling', 'Disease', 'MESH:D008569', (29, 38))	('tumour', 'Disease', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', (130, 136))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('genetic aberrations', 'Var', (198, 217))	('tumour', 'Disease', 'MESH:D009369', (248, 254))	('recalling', 'Disease', (29, 38))	('tumour', 'Disease', (147, 153))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
48750	27499907	Structural rearrangements, aneuploidy, translocations or duplications as well as silent mutations were excluded from the analysis.	('aneuploidy', 'Disease', 'MESH:D000782', (27, 37))	('duplications', 'Var', (57, 69))	('translocations', 'Var', (39, 53))	('aneuploidy', 'Disease', (27, 37))
48754	27499907	For visualization, fold changes (FC) between highly mutated tumours (22 or more mutations) and lowly mutated tumours (21 or less mutations) were calculated.	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('mutations', 'Var', (80, 89))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('tumours', 'Disease', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
48757	27499907	First, we correlated the number of mutated genes with the clinico-pathological characteristics of the tumour (Table 2, Figure 1).	('mutated', 'Var', (35, 42))	('tumour', 'Disease', (102, 108))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (102, 108))
48758	27499907	The number of mutated genes was strongly associated with tumour grade increasing from a median of 23 mutated genes in G1 tumors via 27 in G2 tumors to 43 in G3 tumours (p = 1.4e-14).	('G1 tumors', 'Disease', (118, 127))	('G3 tumours', 'Disease', 'MESH:D009369', (157, 167))	('tumour', 'Disease', (160, 166))	('tumour', 'Disease', (57, 63))	('mutated', 'Var', (14, 21))	('tumour', 'Disease', 'MESH:D009369', (57, 63))	('tumors', 'Disease', (121, 127))	('G3 tumours', 'Disease', (157, 167))	('tumors', 'Disease', (141, 147))	('tumour', 'Disease', 'MESH:D009369', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('G1 tumors', 'Disease', 'MESH:C564173', (118, 127))
48759	27499907	When analysing the three components of tumour grade, nuclear pleomorphism (atypia) showed the strongest association with the number of mutated genes (p = 5.5e-11), but mitotic count and the degree of tubule formation also contributed significantly (p = 4.8e-08 and p = 1.4e-03, respectively).	('mitotic count', 'CPA', (168, 181))	('nuclear', 'Var', (53, 60))	('formation', 'biological_process', 'GO:0009058', ('207', '216'))	('tumour', 'Disease', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))
48760	27499907	In addition, the number of mutated genes was strongly associated with the molecular subtype of breast cancer as determined by routine immunohistochemistry and the PAM50 classifier (p = 1.4e-10 and p = 4.3e-10, respectively).	('number', 'Var', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutated genes', 'Var', (27, 40))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('associated', 'Reg', (54, 64))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
48764	27499907	Interestingly, ILC of any grade shared a high burden of mutated PIK3CA with G1-G3 NST.	('PIK3CA', 'Gene', (64, 70))	('mutated', 'Var', (56, 63))	('PIK3CA', 'Gene', '5290', (64, 70))
48766	27499907	54.6% of NST G1 showed mutated PIK3CA, followed by MAP3K1 (16.4%), GATA3 (14.6%), MAP2K4 (10.4%), and FOXP1 and TP53 (3.6% each).	('NST G1', 'Gene', (9, 15))	('MAP3K1', 'Gene', '4214', (51, 57))	('FOXP1', 'Gene', '27086', (102, 107))	('MAP3K', 'molecular_function', 'GO:0004709', ('51', '56'))	('MAP2K', 'molecular_function', 'GO:0004708', ('82', '87'))	('FOXP1', 'Gene', (102, 107))	('GATA3', 'Gene', (67, 72))	('PIK3CA', 'Gene', (31, 37))	('mutated', 'Var', (23, 30))	('PIK3CA', 'Gene', '5290', (31, 37))	('TP53', 'Gene', '7157', (112, 116))	('MAP3K1', 'Gene', (51, 57))	('MAP2K4', 'Gene', '6416', (82, 88))	('GATA3', 'Gene', '2625', (67, 72))	('MAP2K4', 'Gene', (82, 88))	('TP53', 'Gene', (112, 116))
48767	27499907	With higher tumour grades, NST tumours with mutated MAP2K4 (G2: 5.0%, G3:1.8%), MAP3K1 (G2: 10.5%, G3: 3.2%) and GATA3 (G2: 14.2%, G3: 5.6%) decreased while cases with TP53 mutations strongly increased (G2: 19.7%, G3: 52.6%).	('NST tumours', 'Disease', (27, 38))	('GATA3', 'Gene', (113, 118))	('MAP3K1', 'Gene', (80, 86))	('MAP2K', 'molecular_function', 'GO:0004708', ('52', '57'))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('NST tumours', 'Disease', 'MESH:D009369', (27, 38))	('MAP3K1', 'Gene', '4214', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (12, 18))	('TP53', 'Gene', '7157', (168, 172))	('tumour', 'Disease', (12, 18))	('mutated', 'Var', (44, 51))	('MAP2K4', 'Gene', '6416', (52, 58))	('MAP2K4', 'Gene', (52, 58))	('decreased', 'NegReg', (141, 150))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('TP53', 'Gene', (168, 172))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('MAP3K', 'molecular_function', 'GO:0004709', ('80', '85'))	('tumour', 'Disease', (31, 37))	('GATA3', 'Gene', '2625', (113, 118))
48769	27499907	The median number of mutated genes in node positive (N+) tumours was 30 compared with 34 in N0 tumours.	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('N0 tumours', 'Disease', (92, 102))	('tumours', 'Disease', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('N0 tumours', 'Disease', 'MESH:D009369', (92, 102))	('mutated', 'Var', (21, 28))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
48777	27499907	Second, we correlated the number of mutated genes with the mutation status of each of the 23 genes that were reported by TCGA 2 as recurrently mutated in breast cancer (Figure 2, supplementary material Table S1).	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('mutated', 'Var', (143, 150))
48778	27499907	It turned out that the number of mutated genes was strongly associated with the mutation status of the tumour suppressor gene TP53 (median of the number of mutated genes 47 in TP53-mutated tumours versus 27 in TP53 wild-type tumours; p = 3.8e-21), while it was not associated with the mutation status of the oncogene PIK3CA (p = 0.36).	('TP53', 'Gene', (126, 130))	('tumours', 'Disease', (225, 232))	('TP53', 'Gene', '7157', (176, 180))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('TP53', 'Gene', (210, 214))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('TP53', 'Gene', '7157', (126, 130))	('PIK3CA', 'Gene', '5290', (317, 323))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', (225, 231))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('TP53', 'Gene', (176, 180))	('tumour', 'Disease', (103, 109))	('mutation', 'Var', (80, 88))	('TP53', 'Gene', '7157', (210, 214))	('associated', 'Reg', (60, 70))	('tumours', 'Disease', (189, 196))	('PIK3CA', 'Gene', (317, 323))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('tumours', 'Disease', 'MESH:D009369', (189, 196))
48786	27499907	Taken together, in the overall cohort as well as in HR+ -driven tumours, we found especially upregulated cell cycle and proliferation-related genes to be associated with higher numbers of mutated genes.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('HR', 'Gene', '3164', (52, 54))	('proliferation-related', 'CPA', (120, 141))	('tumours', 'Disease', (64, 71))	('cell cycle', 'biological_process', 'GO:0007049', ('105', '115'))	('upregulated', 'PosReg', (93, 104))	('mutated', 'Var', (188, 195))	('cell cycle', 'Gene', (105, 115))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
48792	27499907	Further, we found a strong association between CDH1 mutation status and the histopathological subtype, where 56.1% of the lobular cancers had CHD1 mutations (G1: 57.9%, G2: 56.3%, G3: 50.0%) compared with only 2.1% of NST/other cancers (G1: 1.8%, G2: 2.1%, G3: 2.1%).	('lobular cancers', 'Disease', 'MESH:D013274', (122, 137))	('mutations', 'Var', (147, 156))	('CDH1', 'Gene', '999', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('lobular cancers', 'Disease', (122, 137))	('CHD1', 'Gene', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('mutation', 'Var', (52, 60))	('CDH1', 'Gene', (47, 51))	('CHD1', 'Gene', '1105', (142, 146))	('NST/other cancers', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('NST/other cancers', 'Disease', 'MESH:D009369', (218, 235))
48793	27499907	Finally, we detected a moderate, but significant association of mutated MLL3 (p = 0.00046) and FOXA1 (p = 0.00097) with patient age.	('FOXA1', 'Gene', (95, 100))	('MLL3', 'Gene', '58508', (72, 76))	('patient', 'Species', '9606', (120, 127))	('FOXA1', 'Gene', '3169', (95, 100))	('association', 'Interaction', (49, 60))	('mutated', 'Var', (64, 71))	('MLL3', 'Gene', (72, 76))
48796	27499907	Mutations in BRCA1 were detected only in the basal-like molecular subtype (in 3.9% of these tumours), but absent in all other PAM50 subtypes (p = 0.053).	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('BRCA1', 'Gene', (13, 18))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('Mutations', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA1', 'Gene', '672', (13, 18))
48797	27499907	BRCA2 mutations were found in the HER2-enriched subtype (8.3%) in the basal subtype (3.9%) and in the luminal A subtype (1.2%), but absent in the other PAM50 subtypes (p = 0.032).	('BRCA2', 'Gene', '675', (0, 5))	('BRCA2', 'Gene', (0, 5))	('HER2', 'Gene', (34, 38))	('found', 'Reg', (21, 26))	('HER2', 'Gene', '2064', (34, 38))	('mutations', 'Var', (6, 15))
48809	27499907	Mutations frequently affected transcription factors of the ER pathway (GATA3, FOXA1 and RUNX1) and the PI3K cascade with mutations in PIK3CA as the most frequent genetic aberration followed by mutually exclusive mutations in PIK3R1, AKT and PTEN.	('mutations', 'Var', (121, 130))	('FOXA1', 'Gene', '3169', (78, 83))	('GATA3', 'Gene', '2625', (71, 76))	('transcription', 'biological_process', 'GO:0006351', ('30', '43'))	('FOXA1', 'Gene', (78, 83))	('GATA3', 'Gene', (71, 76))	('PI3K cascade', 'biological_process', 'GO:0014065', ('103', '115'))	('PIK3CA', 'Gene', '5290', (134, 140))	('affected', 'Reg', (21, 29))	('PIK3R1', 'Gene', (225, 231))	('AKT', 'Gene', (233, 236))	('PTEN', 'Gene', (241, 245))	('RUNX1', 'Gene', (88, 93))	('RUNX1', 'Gene', '861', (88, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('103', '107'))	('PIK3CA', 'Gene', (134, 140))	('ER pathway', 'Pathway', (59, 69))	('PTEN', 'Gene', '5728', (241, 245))	('AKT', 'Gene', '207', (233, 236))	('PIK3R1', 'Gene', '5295', (225, 231))
48811	27499907	TP53 mutations occurred in approx.	('occurred', 'Reg', (15, 23))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
48814	27499907	They are primarily characterized by genomic instability that is putatively caused by the loss of function of three tumour suppressor genes and cell-cycle regulators by mutations or deletions: TP53 (75%), RB1 (4%), and BRCA1/2 (7.9%).	('BRCA1/2', 'Gene', '672;675', (218, 225))	('loss of function', 'NegReg', (89, 105))	('TP53', 'Gene', '7157', (192, 196))	('cell-cycle', 'biological_process', 'GO:0007049', ('143', '153'))	('tumour', 'Disease', (115, 121))	('deletions', 'Var', (181, 190))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('RB1', 'Gene', (204, 207))	('BRCA1/2', 'Gene', (218, 225))	('genomic instability', 'CPA', (36, 55))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('RB1', 'Gene', '5925', (204, 207))	('TP53', 'Gene', (192, 196))	('mutations', 'Var', (168, 177))
48816	27499907	In accord with these observations, extended analysis of the whole cohort showed a significantly high prevalence of mutated TP53 in TNBC and HER2-enriched breast cancer, while mutated CDH1 and GATA3 occur significantly more frequently in the HR+ subtype and the HR+/HER2- subtype, respectively.	('HER2', 'Gene', (265, 269))	('HER2-enriched breast cancer', 'Disease', 'MESH:D001943', (140, 167))	('TNBC', 'Chemical', '-', (131, 135))	('HER2-enriched breast cancer', 'Disease', (140, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('HER2', 'Gene', '2064', (265, 269))	('CDH1', 'Gene', (183, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('mutated', 'Var', (115, 122))	('HR', 'Gene', '3164', (241, 243))	('HR', 'Gene', '3164', (261, 263))	('CDH1', 'Gene', '999', (183, 187))	('GATA3', 'Gene', '2625', (192, 197))	('GATA3', 'Gene', (192, 197))	('HER2', 'Gene', (140, 144))	('TP53', 'Gene', '7157', (123, 127))	('HER2', 'Gene', '2064', (140, 144))	('TP53', 'Gene', (123, 127))
48817	27499907	We also noted that while PIK3CA and CDH1 mutations were significantly enriched in tumours with lower tumour grades, TP53 and CDKN1B were significantly associated with higher tumour grades.	('tumours', 'Disease', (82, 89))	('PIK3CA', 'Gene', '5290', (25, 31))	('CDH1', 'Gene', '999', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('mutations', 'Var', (41, 50))	('CDKN1B', 'Gene', '1027', (125, 131))	('TP53', 'Gene', (116, 120))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('associated', 'Reg', (151, 161))	('tumour', 'Disease', (101, 107))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('CDH1', 'Gene', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('PIK3CA', 'Gene', (25, 31))	('tumour', 'Disease', (82, 88))	('TP53', 'Gene', '7157', (116, 120))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('CDKN1B', 'Gene', (125, 131))	('tumour', 'Disease', (174, 180))
48819	27499907	As already reported by other investigators 2, 44, 45, mutated CDH1 occured almost exclusively in lobular breast cancer.	('lobular breast cancer', 'Phenotype', 'HP:0006625', (97, 118))	('CDH1', 'Gene', (62, 66))	('CDH1', 'Gene', '999', (62, 66))	('occured', 'Reg', (67, 74))	('mutated', 'Var', (54, 61))	('lobular breast cancer', 'Disease', (97, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lobular breast cancer', 'Disease', 'MESH:D013274', (97, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
48822	27499907	As expected, non-silent mutations in TP53 and RB1, which have been causally linked to genomic instability of tumours 46, 47, are strongly correlated with the number of mutated genes in breast cancer.	('TP53', 'Gene', (37, 41))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('linked', 'Reg', (76, 82))	('correlated', 'Reg', (138, 148))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('RB1', 'Gene', (46, 49))	('breast cancer', 'Disease', (185, 198))	('tumours', 'Disease', (109, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('RB1', 'Gene', '5925', (46, 49))	('TP53', 'Gene', '7157', (37, 41))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
48823	27499907	Moreover, our data show that high numbers of mutated genes are strongly associated with mutant NCOR1, which is mutated in ~4% of breast cancer cases 2.	('breast cancer', 'Disease', (129, 142))	('NCOR1', 'Gene', '9611', (95, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('associated', 'Reg', (72, 82))	('NCOR1', 'Gene', (95, 100))	('mutant', 'Var', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
48825	27499907	Pointing towards a similar direction, the mutant variant of PTPRD (genetic aberrations in ~7% of breast cancers 2) encoding the protein tyrosine phosphatase receptor type delta was also strongly associated with high numbers of mutated genes in breast cancer.	('associated', 'Reg', (195, 205))	('mutant', 'Var', (42, 48))	('PTPRD', 'Gene', '5789', (60, 65))	('PTPRD', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('breast cancer', 'Disease', 'MESH:D001943', (244, 257))	('breast cancers 2', 'Disease', 'MESH:D001943', (97, 113))	('breast cancer', 'Disease', (244, 257))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('breast cancers 2', 'Disease', (97, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancers', 'Phenotype', 'HP:0003002', (97, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('phosphatase', 'molecular_function', 'GO:0016791', ('145', '156'))
48827	27499907	Last but not least, the mutated variant of the putative breast cancer oncogene NF1 (genetic alterations in ~5% of breast cancers 2) correlated with a high abundance of mutated genes in our study.	('mutated', 'Var', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancers 2', 'Disease', 'MESH:D001943', (114, 130))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancers', 'Phenotype', 'HP:0003002', (114, 128))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancers 2', 'Disease', (114, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('NF1', 'Gene', (79, 82))	('breast cancer', 'Disease', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
48828	27499907	Neurofibromin1 acts as a negative regulator of RAS by stimulating GTPase activity of RAS 52 and impaired NF1 function has been linked to increased mutations frequencies in mice 53.	('mutations', 'Var', (147, 156))	('stimulating', 'PosReg', (54, 65))	('activity', 'MPA', (73, 81))	('NF1', 'Gene', (105, 108))	('GTPase activity', 'molecular_function', 'GO:0003924', ('66', '81'))	('GTPase', 'Enzyme', (66, 72))	('mice', 'Species', '10090', (172, 176))	('Neurofibromin', 'Gene', '4763', (0, 13))	('Neurofibromin', 'Gene', (0, 13))	('function', 'MPA', (109, 117))	('impaired', 'NegReg', (96, 104))
48834	27499907	These data suggest that the link between proliferation and abundant mutations is largely restricted to HR+ tumours and does not pertain to HR- tumours.	('HR- tumours', 'Disease', 'MESH:D009369', (139, 150))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('HR+ tumours', 'Disease', (103, 114))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('HR+ tumours', 'Disease', 'MESH:D009369', (103, 114))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (68, 77))	('HR- tumours', 'Disease', (139, 150))
48836	27499907	Remarkably, we found that tumour grade, that is, phenotypes indicating the degree of cellular differentiation, but not the two main breast cancer types, that is, NST and ILC, are strongly associated with different numbers of mutated genes.	('associated', 'Reg', (188, 198))	('cellular differentiation', 'CPA', (85, 109))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('ILC', 'Disease', (170, 173))	('tumour', 'Disease', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mutated genes', 'Var', (225, 238))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('NST', 'Disease', (162, 165))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
48837	27499907	Additionally, we identified a significant but comparably weaker correlation of the mutational load with two other measures reflecting the temporal development of the tumour, that is, age at diagnosis and tumour size.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('weaker', 'NegReg', (57, 63))	('tumour', 'Disease', (204, 210))	('tumour', 'Disease', (166, 172))	('mutational load', 'Var', (83, 98))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
48842	27499907	Hence, our data may suggest that the abundance of mutated genes has a certain relation with metastatic progression ultimately leading to tumour-related death 55, 56, 57.	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('mutated genes', 'Var', (50, 63))	('leading to', 'Reg', (126, 136))	('tumour', 'Disease', (137, 143))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', (152, 157))	('metastatic progression', 'CPA', (92, 114))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
48846	27499907	Interestingly, the increasing abundance of mutated genes displayed strong correlations with increasing tumour grades and also with tumour size and age at diagnosis albeit to a lower degree.	('tumour', 'Disease', (131, 137))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('mutated', 'Var', (43, 50))	('tumour', 'Disease', (103, 109))
48857	34001921	The mortality from other causes was found to be lower amongst the IDC patients using metformin (HR 0.64, 95% CI 0.45-0.89), but amongst ILC patients the evidence was inconclusive (HR 1.22, 95% CI 0.64-2.32).	('IDC', 'Disease', (66, 69))	('patients', 'Species', '9606', (70, 78))	('mortality', 'Disease', 'MESH:D003643', (4, 13))	('metformin', 'Var', (85, 94))	('lower', 'NegReg', (48, 53))	('metformin', 'Chemical', 'MESH:D008687', (85, 94))	('mortality', 'Disease', (4, 13))	('patients', 'Species', '9606', (140, 148))
48863	34001921	Oestrogen receptor (ER) positivity is more common in ILC, whereas human epidermal growth factor receptor 2 (HER2) overexpression is rare in this tumour type.	('HER2', 'Gene', (108, 112))	('tumour', 'Disease', (145, 151))	('HER2', 'Gene', '2064', (108, 112))	('positivity', 'Var', (24, 34))	('ER', 'Gene', '2069', (109, 111))	('epidermal growth factor receptor 2', 'Gene', (72, 106))	('human', 'Species', '9606', (66, 71))	('epidermal growth factor receptor 2', 'Gene', '2064', (72, 106))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('72', '95'))	('ILC', 'Disease', (53, 56))	('ER', 'Gene', '2069', (20, 22))	('common', 'Reg', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))
48910	34001921	In the IDC patients, mortality from other causes of death was found to be lower amongst the metformin users (HR 0.64, 95% CI 0.45-0.89) compared to the users of other oral ADM. Amongst the ILC patients, the result was inconclusive: mortality from other causes appeared to be higher in metformin users (HR 1.22, 95% CI 0.64-2.32), but the wide confidence interval was also statistically compatible with the result in IDC patients.	('mortality', 'Disease', 'MESH:D003643', (232, 241))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (420, 428))	('metformin', 'Chemical', 'MESH:D008687', (92, 101))	('mortality', 'Disease', (232, 241))	('mortality', 'Disease', 'MESH:D003643', (21, 30))	('death', 'Disease', 'MESH:D003643', (52, 57))	('metformin', 'Var', (285, 294))	('death', 'Disease', (52, 57))	('ADM', 'Chemical', '-', (172, 175))	('mortality', 'Disease', (21, 30))	('higher', 'PosReg', (275, 281))	('metformin', 'Chemical', 'MESH:D008687', (285, 294))
48919	34001921	In the IDC patients, mortality from other causes of death was found to be lower amongst metformin users compared to other oral ADM users.	('metformin', 'Chemical', 'MESH:D008687', (88, 97))	('mortality', 'Disease', 'MESH:D003643', (21, 30))	('death', 'Disease', 'MESH:D003643', (52, 57))	('death', 'Disease', (52, 57))	('ADM', 'Chemical', '-', (127, 130))	('patients', 'Species', '9606', (11, 19))	('lower', 'NegReg', (74, 79))	('metformin', 'Var', (88, 97))	('mortality', 'Disease', (21, 30))	('IDC', 'Disease', (7, 10))
48926	34001921	Preclinical studies have suggested that metformin could inhibit the growth of BC cells via indirect and direct pathways by reducing the level of blood glucose and insulin, which involves AMPK-dependent and -independent mechanisms.	('reducing', 'NegReg', (123, 131))	('blood glucose and insulin', 'Disease', 'MESH:D007022', (145, 170))	('AMPK', 'molecular_function', 'GO:0047322', ('187', '191'))	('metformin', 'Chemical', 'MESH:D008687', (40, 49))	('indirect', 'Pathway', (91, 99))	('AMPK', 'molecular_function', 'GO:0004691', ('187', '191'))	('insulin', 'molecular_function', 'GO:0016088', ('163', '170'))	('AMPK', 'molecular_function', 'GO:0050405', ('187', '191'))	('AMPK', 'Gene', (187, 191))	('growth of BC cells', 'CPA', (68, 86))	('direct pathways', 'Pathway', (104, 119))	('AMPK', 'Gene', '5562', (187, 191))	('inhibit', 'NegReg', (56, 63))	('metformin', 'Var', (40, 49))
48931	34001921	There are epidemiological data that show that BC patients with T2D treated with insulin alone or sulphonylurea monotherapy had increased BC mortality.	('insulin', 'molecular_function', 'GO:0016088', ('80', '87'))	('insulin', 'Gene', '3630', (80, 87))	('mortality', 'Disease', 'MESH:D003643', (140, 149))	('sulphonylurea', 'Chemical', 'MESH:D013453', (97, 110))	('mortality', 'Disease', (140, 149))	('T2D', 'Var', (63, 66))	('patients', 'Species', '9606', (49, 57))	('increased', 'PosReg', (127, 136))	('insulin', 'Gene', (80, 87))
48956	34001921	No sufficient evidence could be found for metformin use being associated with a lower BC mortality compared with the use of other oral ADM in either the IDC or the ILC groups.	('mortality', 'Disease', 'MESH:D003643', (89, 98))	('ADM', 'Chemical', '-', (135, 138))	('metformin', 'Var', (42, 51))	('mortality', 'Disease', (89, 98))	('lower', 'NegReg', (80, 85))	('metformin', 'Chemical', 'MESH:D008687', (42, 51))
48977	32586354	ILC is also commonly characterized by pathological features that are usually associated with a good prognosis, such as hormone receptor (HR) positivity, human epidermal growth factor receptor (HER2/neu) negativity, low proliferative rate, and low histological grade, yet it has been described to have a higher propensity for late distant metastases compared to IDC tumors of similar grade and hormone receptor status.	('metastases', 'Disease', (338, 348))	('HER2/neu', 'Gene', '2064', (193, 201))	('HER2/neu', 'Gene', (193, 201))	('IDC tumors', 'Disease', (361, 371))	('metastases', 'Disease', 'MESH:D009362', (338, 348))	('IDC tumors', 'Disease', 'MESH:D009369', (361, 371))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('epidermal growth factor receptor', 'Gene', (159, 191))	('positivity', 'Var', (141, 151))	('tumors', 'Phenotype', 'HP:0002664', (365, 371))	('human', 'Species', '9606', (153, 158))	('ILC', 'Disease', (0, 3))	('negativity', 'Var', (203, 213))	('epidermal growth factor receptor', 'Gene', '1956', (159, 191))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('159', '182'))
49153	22933976	During preoperative evaluation, she was found to have evidence of mitral valve regurgitation due to a flail mitral valve posterior leaflet, and subsequently underwent mitral valve repair.	('mitral valve regurgitation', 'Disease', (66, 92))	('flail', 'Var', (102, 107))	('mitral valve regurgitation', 'Phenotype', 'HP:0001653', (66, 92))	('mitral valve', 'Phenotype', 'HP:0011564', (167, 179))	('mitral valve regurgitation', 'Disease', 'MESH:D008944', (66, 92))	('mitral valve', 'Phenotype', 'HP:0011564', (66, 78))	('mitral valve', 'Phenotype', 'HP:0011564', (108, 120))
49198	22933976	The Alberta study showed that there was no significant difference in survival rates between cancer patients who had implants and those without implants.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('patients', 'Species', '9606', (99, 107))	('implants', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
49220	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))	('NAC', 'cellular_component', 'GO:0005854', ('174', '177'))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('MFT', 'Var', (255, 258))
49245	28705168	Two patients (1.9%) were operated in the context of BRCA2 gene mutations.	('mutations', 'Var', (63, 72))	('BRCA2', 'Gene', '675', (52, 57))	('BRCA2', 'Gene', (52, 57))	('patients', 'Species', '9606', (4, 12))
49264	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))
49285	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))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('mutation', 'Var', (124, 132))	('BRCA2', 'Gene', '675', (118, 123))	('patient', 'Species', '9606', (103, 110))
49339	26962366	In recent years, microRNAs (miRs) were described as potential prognosticators and predictors for breast cancer.	('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))	('microRNAs', 'Var', (17, 26))
49342	26962366	This panel of de-regulated miRs correlated with known clinical and biological features such as hormonal receptor status, tumor size, lymph node status, vascular invasion, proliferation index, and p53.	('proliferation index', 'CPA', (171, 190))	('miRs', 'Var', (27, 31))	('lymph node status', 'CPA', (133, 150))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('vascular invasion', 'CPA', (152, 169))	('de-regulated', 'NegReg', (14, 26))	('tumor', 'Disease', (121, 126))	('clinical', 'Species', '191496', (54, 62))	('rat', 'Species', '10116', (178, 181))	('p53', 'Gene', (196, 199))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
49348	26962366	In the pilot study, five miRs showed a significant fold change between relapse patients and their controls (linear models for microarray analysis (LIMMA), raw p value <0.05): hsa-miR-362-3p, hsa-miR-660, hsa-miR-375, hsa-miR-223, and hsa-miR-125a-3p.	('hsa-miR-125a-3p', 'Var', (234, 249))	('hsa-miR-375', 'Gene', (204, 215))	('hsa-miR-223', 'Gene', (217, 228))	('hsa-miR-223', 'Gene', '407008', (217, 228))	('change', 'Reg', (56, 62))	('hsa-miR-375', 'Gene', '494324', (204, 215))	('hsa-miR-660', 'Gene', (191, 202))	('patients', 'Species', '9606', (79, 87))	('hsa-miR-362', 'Gene', (175, 186))	('hsa-miR-362', 'Gene', '574030', (175, 186))	('hsa-miR-660', 'Gene', '724030', (191, 202))
49390	26962366	Its re-expression reverses both Tamoxifen resistance and accompanying epithelial-mesenchymal transition (EMT)-like properties in breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('70', '103'))	('reverses', 'NegReg', (18, 26))	('Tamoxifen resistance', 'MPA', (32, 52))	('Tamoxifen', 'Chemical', 'MESH:D013629', (32, 41))	('re-expression', 'Var', (4, 17))	('EMT', 'biological_process', 'GO:0001837', ('105', '108'))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
49433	26962366	In summary, we could show that high levels of hsa-miR-375 are associated with a significantly higher probability of local relapse, especially in ER-alpha-positive patients.	('patients', 'Species', '9606', (163, 171))	('local relapse', 'CPA', (116, 129))	('ER-alpha', 'Gene', '2099', (145, 153))	('hsa-miR-375', 'Gene', (46, 57))	('high', 'Var', (31, 35))	('hsa-miR-375', 'Gene', '494324', (46, 57))	('ER-alpha', 'Gene', (145, 153))
49555	25971426	While most IDC patients were ER+/HER2- (45/74, 61%), a substantial portion were HER2+ (16/74, 22%) or triple negative (11/74, 15%).	('patients', 'Species', '9606', (15, 23))	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('HER2', 'Gene', (33, 37))	('triple negative', 'Var', (102, 117))	('HER2', 'Gene', '2064', (33, 37))	('IDC', 'Disease', (11, 14))
49693	19116033	Furthermore, ILC molecular subtypes were reported to include the typical and IDC-like ILCs, yet the CDH1 mutation and/or underexpression was common but not universal to ILCs in general.	('mutation', 'Var', (105, 113))	('CDH1', 'Gene', (100, 104))	('IDC', 'Gene', (77, 80))	('CDH1', 'Gene', '999', (100, 104))	('ILC', 'Disease', (13, 16))	('IDC', 'Gene', '4000', (77, 80))	('ILCs', 'Disease', (86, 90))
49694	19116033	Low-grade breast tumors were generally characterized by ER(+), PR(+) and with limited genomic aberrations whereas high grade tumors were generally ER(-) and PR(-) and had complex karyotypic changes.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('ER(+', 'Var', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('breast tumors', 'Phenotype', 'HP:0100013', (10, 23))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('PR(+', 'Var', (63, 67))	('ER(-', 'Var', (147, 151))	('breast tumor', 'Phenotype', 'HP:0100013', (10, 22))	('breast tumors', 'Disease', (10, 23))	('breast tumors', 'Disease', 'MESH:D001943', (10, 23))	('PR(-', 'Var', (157, 161))
49711	19116033	Breast tumor subtype classification remains a complicated issue due to difficulties associated with the presence of multiple interacting factors such as the presence or absence of node-filtration, ER-positivity, metastatic potential, different degrees of genomic instability, and tumor cell origin.	('Breast tumor', 'Phenotype', 'HP:0100013', (0, 12))	('ER-positivity', 'Var', (197, 210))	('tumor', 'Disease', (7, 12))	('Breast tumor', 'Disease', 'MESH:D001943', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('Breast tumor', 'Disease', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Disease', (280, 285))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('metastatic potential', 'CPA', (212, 232))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
49725	19116033	suggested that the expression of ID4 in the mammary duct epithelium may be regulated by estrogen depending on the differential expression pattern of ID4 in ER(+) and ER(-) breast tumors.	('expression', 'MPA', (19, 29))	('ID4', 'Gene', '3400', (149, 152))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('ER(+', 'Var', (156, 160))	('ID4', 'Gene', (33, 36))	('breast tumors', 'Phenotype', 'HP:0100013', (172, 185))	('ID4', 'Gene', '3400', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('breast tumor', 'Phenotype', 'HP:0100013', (172, 184))	('breast tumors', 'Disease', 'MESH:D001943', (172, 185))	('ID4', 'Gene', (149, 152))	('breast tumors', 'Disease', (172, 185))
49727	19116033	In previous studies, loss of SFRP1 was found to be associated with cancer progression and poor prognosis in breast cancer.	('loss', 'Var', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('associated', 'Reg', (51, 61))	('SFRP1', 'Gene', '6422', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('SFRP1', 'Gene', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('breast cancer', 'Disease', (108, 121))
49851	23299541	Neoadjuvant chemotherapy results in lower rates of clinical benefit, including less downstaging, more positive margins and fewer breast-conserving surgeries in ER-positive ILC compared with ER-positive IDC.	('positive margins', 'CPA', (102, 118))	('IDC', 'Gene', '4000', (202, 205))	('ER-positive', 'Var', (160, 171))	('IDC', 'Gene', (202, 205))	('ILC', 'Disease', (172, 175))	('downstaging', 'CPA', (84, 95))	('fewer', 'NegReg', (123, 128))	('less', 'NegReg', (79, 83))
49874	23299541	Oestrogen receptor and PR positivity were defined as nuclear staining >=10% and HER2 positivity was defined as 3+ staining on immunohistochemistry or gene amplification by FISH.	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('Oestrogen receptor', 'Protein', (0, 18))	('PR', 'Gene', '5241', (23, 25))	('gene amplification', 'Var', (150, 168))
49887	23299541	In univariate analysis, multifocal tumour, higher tumour size, node-positive status and lower nuclear grade were also significantly associated with lower pCR rates.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('multifocal tumour', 'Disease', 'None', (24, 41))	('tumour', 'Disease', (50, 56))	('multifocal tumour', 'Disease', (24, 41))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('lower', 'NegReg', (148, 153))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('node-positive status', 'Var', (63, 83))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('lower', 'NegReg', (88, 93))	('pCR', 'Disease', (154, 157))	('tumour', 'Disease', (35, 41))
49990	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', 'molecular_function', 'GO:0008181', ('145', '161'))	('tumor suppressor', 'Gene', (145, 161))	('DNA methylation', 'biological_process', 'GO:0006306', ('14', '29'))	('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))	('tumor suppressor', 'biological_process', 'GO:0051726', ('145', '161'))	('breast cancer', 'Disease', (80, 93))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('silencing', 'NegReg', (127, 136))
49992	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))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('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))
50010	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))	('HER2', 'Gene', (135, 139))	('TP53', 'Gene', (220, 224))	('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))
50017	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))
50020	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))
50035	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.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('86', '109'))	('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))	('transmembrane', 'cellular_component', 'GO:0044214', ('25', '38'))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('HER2', 'Gene', '2064', (53, 57))	('transmembrane', 'cellular_component', 'GO:0016021', ('25', '38'))	('epidermal growth factor receptor', 'Gene', '1956', (86, 118))
50036	19452229	The HER2 + subtype essentially results from gene amplification within the ERBB2 amplicon at 17q12-q22.	('ERBB2', 'Gene', (74, 79))	('gene amplification', 'Var', (44, 62))	('results from', 'Reg', (31, 43))	('HER2', 'Gene', (4, 8))	('HER2', 'Gene', '2064', (4, 8))	('ERBB2', 'Gene', '2064', (74, 79))
50039	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))	('upregulation', 'PosReg', (17, 29))	('transcription factor', 'molecular_function', 'GO:0000981', ('170', '190'))	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('YBX1', 'Gene', (191, 195))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('Y box binding protein 1', 'Gene', (197, 220))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('EGFR', 'Gene', '1956', (12, 16))	('binding', 'molecular_function', 'GO:0005488', ('203', '210'))	('YBX1', 'Gene', '4904', (191, 195))	('transcriptional', 'MPA', (137, 152))	('EGFR', 'Gene', (12, 16))	('transcription', 'biological_process', 'GO:0006351', ('170', '183'))
50040	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))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('115', '131'))	('EGFR', 'molecular_function', 'GO:0005006', ('5', '9'))	('EGFR', 'Gene', '1956', (101, 105))	('gefitinib', 'Chemical', 'MESH:D000077156', (80, 89))	('EGFR', 'Gene', (101, 105))	('EGFR', 'Gene', '1956', (5, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('sensitivity', 'MPA', (65, 76))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('drug uptake/efflux transporters', 'MPA', (150, 181))	('uptake', 'biological_process', 'GO:0098657', ('155', '161'))	('efflux', 'biological_process', 'GO:0140115', ('162', '168'))	('uptake', 'biological_process', 'GO:0098739', ('155', '161'))	('efflux', 'biological_process', 'GO:0140352', ('162', '168'))	('EGFR', 'Gene', (5, 9))	('mutations', 'Var', (21, 30))
50041	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))	('EGFR', 'Gene', (102, 106))	('gefitinib', 'Chemical', 'MESH:D000077156', (128, 137))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('EGFR', 'Gene', '1956', (102, 106))	('suppression', 'NegReg', (143, 154))	('YBX1', 'Gene', (158, 162))
50042	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))
50044	19452229	In situ carcinomas as well as certain benign proliferative lesions also exhibit ESR1 amplification, suggesting that this mechanism is an early event in luminal breast cancer progression.	('situ carcinomas', 'Disease', 'MESH:D002278', (3, 18))	('situ carcinomas', 'Disease', (3, 18))	('ESR1', 'Gene', '2099', (80, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('luminal breast cancer', 'Disease', (152, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (8, 18))	('amplification', 'Var', (85, 98))	('ESR1', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('luminal breast cancer', 'Disease', 'MESH:D001943', (152, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))
50045	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))	('amplification', 'Var', (126, 139))	('survival', 'MPA', (16, 24))	('luminal breast cancer', 'Disease', 'MESH:D001943', (94, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('women', 'Species', '9606', (52, 57))	('ESR1', 'Gene', '2099', (121, 125))
50046	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))
50054	19452229	Moreover, it has been amply demonstrated that hypermethylation of CpG islands associated with TSGs is closely associated with their silencing.	('associated', 'Reg', (78, 88))	('CpG islands', 'Gene', (66, 77))	('TSG', 'Gene', (94, 97))	('TSG', 'Gene', '57045', (94, 97))	('associated', 'Reg', (110, 120))	('silencing', 'MPA', (132, 141))	('hypermethylation', 'Var', (46, 62))
50056	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))
50059	19452229	Thus, in this review, we focus on gene hypermethylation as a marker for epigenetic gene silencing in breast cancer.	('gene silencing', 'biological_process', 'GO:0016458', ('83', '97'))	('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))
50060	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))	('methylation', 'biological_process', 'GO:0032259', ('212', '223'))	('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))
50062	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))
50065	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))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('WIF1', 'Gene', '11197', (77, 81))	('SOCS1', 'Gene', '8651', (96, 101))	('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))	('methylation', 'biological_process', 'GO:0032259', ('167', '178'))	('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))	('methylation', 'biological_process', 'GO:0032259', ('315', '326'))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('TFPI2', 'Gene', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
50068	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))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (267, 285))	('mucinous carcinoma', 'Disease', (267, 285))	('methylation', 'Var', (223, 234))	('breast tumor', 'Disease', (86, 98))	('methylation', 'biological_process', 'GO:0032259', ('223', '234'))	('IDC', 'Disease', (253, 256))	('breast tumor', 'Phenotype', 'HP:0100013', (86, 98))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
50070	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))
50071	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))
50073	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))	('methylation', 'biological_process', 'GO:0032259', ('199', '210'))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('ER', 'Gene', '2099', (146, 148))	('methylation', 'Var', (104, 115))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))
50074	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))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))
50075	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))	('ER', 'Gene', '2099', (230, 232))	('hormone receptor', 'Gene', '3164', (140, 156))	('PGR', 'Gene', '5241', (179, 182))	('methylation', 'biological_process', 'GO:0032259', ('183', '194'))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('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))
50077	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))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('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))
50079	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))	('loss of heterozygosity', 'Var', (176, 198))	('BRCA1', 'Gene', (24, 29))	('BRCA1', 'Gene', '672', (213, 218))	('methylation', 'biological_process', 'GO:0032259', ('147', '158'))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('BRCA1', 'Gene', (213, 218))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
50080	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', 'biological_process', 'GO:0032259', ('6', '17'))	('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))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
50081	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))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('breast tumors', 'Disease', (9, 22))	('mutations', 'Var', (50, 59))	('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))
50083	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))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('reduced', 'NegReg', (46, 53))	('BRCA1', 'Gene', '672', (0, 5))
50085	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))	('regulation', 'biological_process', 'GO:0065007', ('151', '161'))	('BRCA1', 'Gene', '672', (165, 170))	('expression', 'MPA', (92, 102))
50089	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))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('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))
50091	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))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('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))
50095	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))	('gene expression', 'biological_process', 'GO:0010467', ('16', '31'))	('breast cancer', 'Disease', (138, 151))	('contribute', 'Reg', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
50096	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))
50098	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))
50100	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))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('RASSF1A', 'Gene', '11186', (77, 84))	('promoter', 'MPA', (24, 32))	('RASSF1A', 'Gene', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Epigenetic silencing', 'Var', (0, 20))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
50104	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))	('invasive growth', 'biological_process', 'GO:0044412', ('167', '182'))	('invasive growth', 'biological_process', 'GO:0001404', ('167', '182'))	('RASSF1A', 'Gene', (27, 34))	('RASSF1A', 'Gene', '11186', (133, 140))	('invasive growth', 'biological_process', 'GO:0051831', ('167', '182'))	('invasive growth', 'biological_process', 'GO:0044409', ('167', '182'))	('invasive growth', 'biological_process', 'GO:0007125', ('167', '182'))	('RASSF1A', 'Gene', '11186', (27, 34))	('methylation', 'Var', (141, 152))	('methylation', 'biological_process', 'GO:0032259', ('141', '152'))	('invasive growth', 'biological_process', 'GO:0036267', ('167', '182'))
50105	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))	('TSG', 'Gene', (19, 22))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('TP53', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (71, 75))	('breast cancer', 'Disease', (118, 131))	('TSG', 'Gene', '57045', (19, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('cell-cycle control', 'biological_process', 'GO:1901987', ('35', '53'))
50106	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))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('hyperplasia', 'Disease', 'MESH:D006965', (81, 92))
50111	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))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('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))
50112	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))	('cytologic abnormality', 'MPA', (78, 99))	('breast cancer', 'Disease', (175, 188))	('methylation', 'biological_process', 'GO:0032259', ('160', '171'))	('RARB', 'Gene', '5915', (155, 159))	('RARB', 'Gene', (13, 17))	('methylation', 'Var', (18, 29))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('RARB', 'Gene', '5915', (13, 17))
50114	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))	('IDC', 'Gene', (208, 211))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('85', '105'))	('cystatin E', 'Gene', '1474', (9, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('silenced', 'NegReg', (158, 166))	('degrade', 'NegReg', (73, 80))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inhibits', 'NegReg', (22, 30))	('cystatin', 'molecular_function', 'GO:0004869', ('9', '17'))	('tumor suppressor', 'Gene', (116, 132))	('methylation', 'Var', (179, 190))	('CST6', 'Gene', (149, 153))	('DCIS', 'Gene', (199, 203))	('CST6', 'Gene', '1474', (149, 153))	('DCIS', 'Phenotype', 'HP:0030075', (199, 203))	('lysosomal cysteine proteases', 'Enzyme', (35, 63))	('cystatin E', 'Gene', (9, 19))	('tumor suppressor', 'Gene', '7248', (116, 132))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))
50116	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))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('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))
50119	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))
50121	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))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('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))
50122	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', '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))	('breast tumor', 'Phenotype', 'HP:0100013', (94, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('epigenetically silenced', 'Var', (59, 82))	('breast tumors', 'Phenotype', 'HP:0100013', (94, 107))	('TSG', 'Gene', (55, 58))	('DCIS', 'Disease', (119, 123))	('SCGB3A1', 'Gene', (0, 7))
50123	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))	('SCGB3A1', 'Gene', '92304', (52, 59))	('RASSF1A', 'Gene', '11186', (61, 68))	('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))
50127	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))
50130	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))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('cancer', 'Disease', (246, 252))	('women', 'Species', '9606', (260, 265))	('methylation', 'biological_process', 'GO:0032259', ('173', '184'))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('women', 'Species', '9606', (134, 139))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('led to', 'Reg', (217, 223))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))
50132	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))	('aberrant', 'Var', (6, 14))	('NAF', 'Gene', (47, 50))	('DCIS', 'Disease', (80, 84))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('NAF', 'Gene', '3576', (47, 50))	('DCIS', 'Phenotype', 'HP:0030075', (80, 84))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('I cancer', 'Disease', 'MESH:D009369', (94, 102))	('patients', 'Species', '9606', (66, 74))	('I cancer', 'Disease', (94, 102))
50140	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))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('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))
50141	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', 'biological_process', 'GO:0032259', ('6', '17'))	('methylation', 'Var', (6, 17))	('BRCA1', 'Gene', '672', (0, 5))	('mammary atypia', 'Disease', (82, 96))
50142	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))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('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))
50147	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))	('APC', 'cellular_component', 'GO:0005680', ('74', '77'))	('Aberrant methylation', 'Var', (0, 20))	('RASSF1A', 'Gene', '11186', (65, 72))	('positive', 'Reg', (90, 98))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('DAPK1', 'Gene', (79, 84))	('invasive breast cancer', 'Disease', (160, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
50148	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))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('patients', 'Species', '9606', (109, 117))	('RASSF1A', 'Gene', '11186', (13, 20))	('primary', 'Disease', (123, 130))	('methylation', 'Var', (21, 32))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))
50150	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))	('GSTP1', 'Gene', (107, 112))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('RASSF1A', 'Gene', '11186', (114, 121))	('APC', 'Disease', 'MESH:D011125', (102, 105))	('APC', 'Disease', (102, 105))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('RASSF1A', 'Gene', (114, 121))	('breast cancer', 'Disease', (237, 250))	('RARB', 'Gene', (127, 131))	('RARB', 'Gene', '5915', (127, 131))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('women', 'Species', '9606', (27, 32))	('GSTP1', 'Gene', '2950', (107, 112))	('APC', 'cellular_component', 'GO:0005680', ('102', '105'))
50153	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))	('gene silencing', 'biological_process', 'GO:0016458', ('51', '65'))	('propel', 'PosReg', (110, 116))
50154	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.	('epigenetic analysis', 'Var', (93, 112))	('undergo', 'Reg', (19, 26))	('promoter methylation', 'MPA', (27, 47))	('TSG', 'Gene', (8, 11))	('improve', 'PosReg', (185, 192))	('TSG', 'Gene', '57045', (8, 11))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))
50188	33435562	Most of the patients with thyroid cancer received radioisotopes, while not the external beam radiation (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (12, 20))	('radioisotopes', 'Var', (50, 63))	('thyroid cancer', 'Phenotype', 'HP:0002890', (26, 40))	('radioisotope', 'Chemical', 'MESH:D011868', (50, 62))	('thyroid cancer', 'Disease', (26, 40))	('thyroid cancer', 'Disease', 'MESH:D013964', (26, 40))
50191	33435562	Owing to the limitations of Fine and Gray models, the proportional sub-distribution hazard assumption in the competing risk model is often impossible to hold over a long time of follow-up, thus in some multivariable models, Cox models were utilized to calculate the effect sizes of radiotherapy vs. no radiotherapy.	('Cox', 'Gene', '1351', (224, 227))	('radiotherapy', 'Var', (282, 294))	('Cox', 'Gene', (224, 227))
50210	33435562	In the PSM-adjusted population, according to the outcomes of the survival analysis (Kaplan-Meier) considering the competing-risks in event occurrence, the results could be divided into two groups: (I) Patients receiving radiotherapy were associated with more SPMs and (II) Patients who received radiotherapy showed similar SPM incidences.	('radiotherapy', 'Var', (220, 232))	('SPMs', 'Disease', (259, 263))	('Patients', 'Species', '9606', (273, 281))	('Patients', 'Species', '9606', (201, 209))
50427	28057031	This relationship between pathological response and outcome is stronger in aggressive subtypes such as the triple-negative (TN) BCs than in estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) BCs.	('estrogen receptor', 'Gene', (140, 157))	('estrogen receptor', 'Gene', '2099', (140, 157))	('BC', 'Phenotype', 'HP:0003002', (229, 231))	('BCs', 'Disease', (128, 131))	('HER2', 'Gene', (222, 226))	('HER2', 'Gene', '2064', (222, 226))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('173', '196'))	('stronger', 'PosReg', (63, 71))	('epidermal growth factor receptor 2', 'Gene', '2064', (173, 207))	('human', 'Species', '9606', (167, 172))	('triple-negative', 'Var', (107, 122))	('epidermal growth factor receptor 2', 'Gene', (173, 207))	('BC', 'Phenotype', 'HP:0003002', (128, 130))
50474	28057031	Patient age was not associated with SUV parameters, MATV, and textural features, for the different subgroups tested (<=40y vs. >40y and <=50y vs. >50y) (Table 2).	('<=40y', 'Var', (117, 122))	('Patient', 'Species', '9606', (0, 7))	('<=50y vs.', 'Var', (136, 145))	('MATV', 'Species', '908873', (52, 56))
50587	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))
50627	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))
50708	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))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('E-cadherin', 'Gene', (17, 27))	('ILC', 'Disease', (120, 123))	('E-cadherin', 'Gene', '999', (17, 27))
50732	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))	('mutation', 'Var', (38, 46))	('TP53', 'Gene', (33, 37))
50737	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))	('HER2', 'Gene', (64, 68))	('negative', 'NegReg', (69, 77))	('mutation', 'Var', (144, 152))	('TP53', 'Gene', '7157', (139, 143))	('CK5/6', 'Gene', (16, 21))	('HER2', 'Gene', '2064', (64, 68))	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', '1956', (29, 33))	('TP53', 'Gene', (139, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))
50743	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))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('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))
50755	33616307	Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1 Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E-cadherin.	('carcinoma', 'Disease', 'MESH:D009369', (118, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('carcinoma', 'Disease', 'MESH:D009369', (36, 45))	('LOXL1', 'Var', (95, 100))	('breast cancer', 'Disease', (187, 200))	('Invasive lobular carcinoma', 'Disease', 'MESH:D018275', (101, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('carcinoma', 'Disease', (118, 127))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (28, 45))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('70', '90'))	('cadherin', 'molecular_function', 'GO:0008014', ('239', '247'))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('Invasive lobular carcinoma', 'Disease', (101, 127))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (110, 127))	('carcinoma', 'Disease', (36, 45))
50760	33616307	Treatment with the pan LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling.	('decreased', 'NegReg', (165, 174))	('silencing', 'Var', (46, 55))	('ECM', 'MPA', (138, 141))	('decrease tumor', 'Disease', (76, 90))	('disrupting', 'NegReg', (127, 137))	('LOXL1', 'Gene', '4016', (59, 64))	('invasion', 'CPA', (99, 107))	('LOXL1', 'Gene', (59, 64))	('ER', 'Gene', '2069', (175, 177))	('decrease tumor', 'Disease', 'MESH:D002303', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BAPN', 'Chemical', 'MESH:D000629', (37, 41))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))
50780	33616307	Cytogenetically, ILCs are more likely to be diploid than non-ILC tumors (Arpino et al, 2004).	('tumors', 'Disease', (65, 71))	('diploid', 'Var', (44, 51))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('ILCs', 'Disease', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
50781	33616307	Elegant genetically engineered mouse models carrying various mutations in conjunction with CDH1 deletion, mimic different aspects of the disease (Derksen et al, 2006; Boelens et al, 2016; Tenhagen et al, 2016; An et al, 2018) and of particular subtypes, such as the classic (Boelens et al, 2016) or inflammatory ILC (An et al, 2018).	('inflammatory ILC', 'Disease', (299, 315))	('mimic', 'Reg', (106, 111))	('mouse', 'Species', '10090', (31, 36))	('mutations', 'Var', (61, 70))	('classic', 'Disease', (266, 273))	('deletion', 'Var', (96, 104))	('CDH1', 'Gene', (91, 95))
50784	33616307	We have recently shown that the notoriously low take rates of ER+ BC xenografts of both cell lines and patient-derived tumor cells can be markedly improved by grafting the cells to the milk ducts of immunocompromised mice (Sflomos et al, 2016), a finding that extends to androgen receptor-positive, molecular apocrine BCs (Farmer et al, 2005; Richard et al, 2016).	('tumor', 'Disease', (119, 124))	('grafting', 'Var', (159, 167))	('BC', 'Phenotype', 'HP:0003002', (318, 320))	('mice', 'Species', '10090', (217, 221))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('androgen receptor', 'Gene', '11835', (271, 288))	('ER', 'Gene', '2069', (62, 64))	('patient', 'Species', '9606', (103, 110))	('BC', 'Phenotype', 'HP:0003002', (66, 68))	('androgen receptor', 'Gene', (271, 288))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('improved', 'PosReg', (147, 155))
50786	33616307	Here, we show that the ER+ ILC-derived cell lines, MDA-MB-134-VI (MM134) and SUM-44 PE (SUM44), which are both functionally inactive for p53 (Reis-Filho et al, 2006; Wasielewski et al, 2006), recapitulate many features of the disease when xenografted intraductally and provide new robust models for this understudied disease.	('MDA-MB-134-VI', 'Var', (51, 64))	('MM134', 'Gene', (66, 71))	('MM134', 'Gene', '109279911', (66, 71))	('ER', 'Gene', '2069', (23, 25))	('p53', 'Gene', (137, 140))	('p53', 'Gene', '7157', (137, 140))	('MDA-MB-134-VI', 'CellLine', 'CVCL:0617', (51, 64))
50787	33616307	Comparing lobular and non-lobular ER+ HER2- PDXs, we identify a transcriptional program underlying the lobular-specific molecular characteristics and show that extracellular matrix (ECM) modulation is a tumor cell-intrinsic characteristic and targetable feature of ILCs.	('ER', 'Gene', '2069', (39, 41))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('160', '180'))	('ER', 'Gene', '2069', (34, 36))	('modulation', 'Var', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
50792	33616307	The growth curves for MCF7 cells did not differ significantly from those for T47D cells, but differed significantly from the curves for MM134 (P < 0.03) and SUM44 (P < 0.0005) cells (Fig 1C).	('MM134', 'Gene', '109279911', (136, 141))	('differed', 'Reg', (93, 101))	('MM134', 'Gene', (136, 141))	('MCF7', 'CellLine', 'CVCL:0031', (22, 26))	('MCF7', 'Var', (22, 26))	('T47D', 'CellLine', 'CVCL:0553', (77, 81))
50794	33616307	Five months after injection, glands xenografted with MCF7 or T47D cells were enlarged and hard on palpation, whereas MM134 and SUM44 xenografts were inconspicuous.	('MM134', 'Gene', (117, 122))	('MM134', 'Gene', '109279911', (117, 122))	('MCF7', 'CellLine', 'CVCL:0031', (53, 57))	('T47D cells', 'Var', (61, 71))	('MCF7', 'Var', (53, 57))	('T47D', 'CellLine', 'CVCL:0553', (61, 65))
50803	33616307	Both MM134- and SUM44-luc2-RFP cells were first detected at distant sites 5 months after injection.	('SUM44-luc2-RFP', 'Var', (16, 30))	('MM134', 'Gene', '109279911', (5, 10))	('MM134', 'Gene', (5, 10))
50869	33616307	Next, we treated two ILC PDXs; while T125 showed a trend, T137 had a significant reduction in tumor growth (Fig 5F).	('T137', 'Var', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('reduction', 'NegReg', (81, 90))
50879	33616307	Thus, pharmacologic LOX inhibition results in disrupted collagen fibers, decreased estrogen receptor signaling activity, and decreased tumor cell proliferation and tumor progression.	('disrupted', 'NegReg', (46, 55))	('collagen', 'molecular_function', 'GO:0005202', ('56', '64'))	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('decreased tumor', 'Disease', (125, 140))	('decreased', 'NegReg', (73, 82))	('estrogen receptor', 'Gene', (83, 100))	('tumor', 'Disease', (135, 140))	('decreased estrogen receptor', 'Phenotype', 'HP:0008214', (73, 100))	('estrogen receptor', 'Gene', '2099', (83, 100))	('decreased tumor', 'Disease', 'MESH:D002303', (125, 140))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('inhibition', 'Var', (24, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('141', '159'))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('collagen', 'Protein', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
50888	33616307	As FACS sorting does not yield 100% pure GFP+ cell populations and GFP:shLOXL1 expression may inhibit growth, rare uninfected cells or cells in which expression of the viral construct is down-regulated may potentially outgrow.	('LOXL1', 'Gene', (73, 78))	('LOXL1', 'Gene', '4016', (73, 78))	('infected', 'Disease', 'MESH:D007239', (117, 125))	('CS', 'Chemical', '-', (5, 7))	('growth', 'MPA', (102, 108))	('pure', 'molecular_function', 'GO:0034023', ('36', '40'))	('expression', 'Var', (79, 89))	('infected', 'Disease', (117, 125))	('inhibit', 'NegReg', (94, 101))	('down-regulated', 'NegReg', (187, 201))
50890	33616307	Fluorescence stereomicroscopic analysis of the MM134 xenografted mammary glands (Fig 6E) revealed that the ratio of GFP/RFP signal emanating from glands engrafted with GFP:sh-scramble cells was close to 1 and decreased by a third in glands engrafted with GFP:shLOXL1 cells (Fig 6F) indicating that the presence of shLOXL1 bestows a proliferative disadvantage.	('presence', 'Var', (302, 310))	('MM134', 'Gene', '109279911', (47, 52))	('LOXL1', 'Gene', '4016', (261, 266))	('MM134', 'Gene', (47, 52))	('LOXL1', 'Gene', '4016', (316, 321))	('proliferative disadvantage', 'CPA', (332, 358))	('LOXL1', 'Gene', (316, 321))	('LOXL1', 'Gene', (261, 266))
50896	33616307	This indicates that the presence of shLOXL1 inhibits ILC cell proliferation in vivo.	('presence', 'Var', (24, 32))	('LOXL1', 'Gene', '4016', (38, 43))	('LOXL1', 'Gene', (38, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('inhibits', 'NegReg', (44, 52))	('ILC cell proliferation', 'CPA', (53, 75))
50902	33616307	Upon intraductal engraftment, MCF7 and T47D cells initially grow faster than the ILC cell lines.	('faster', 'PosReg', (65, 71))	('T47D', 'CellLine', 'CVCL:0553', (39, 43))	('MCF7', 'CellLine', 'CVCL:0031', (30, 34))	('T47D', 'Var', (39, 43))	('grow', 'CPA', (60, 64))
50905	33616307	A limitation of the two models we present here is that both MM134 and SUM44 cells have mutant TP53, which is seen only in the pleomorphic lobular carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('pleomorphic lobular carcinomas', 'Disease', (126, 156))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('mutant', 'Var', (87, 93))	('MM134', 'Gene', (60, 65))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (138, 155))	('pleomorphic lobular carcinomas', 'Disease', 'MESH:D018275', (126, 156))	('lobular carcinomas', 'Phenotype', 'HP:0030076', (138, 156))	('MM134', 'Gene', '109279911', (60, 65))
50906	33616307	The presence of TP53 mutations in the few available ILC cell lines suggests that the mutation favors in vitro establishment.	('in vitro establishment', 'CPA', (101, 123))	('favors', 'PosReg', (94, 100))	('mutation', 'Var', (85, 93))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
50984	33669749	The combination of genomic and proteomic alterations, including both inherited and acquired mutations, promotes tumor diversity and accounts for variable disease progression, therapeutic response, and clinical outcome.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('promotes', 'PosReg', (103, 111))	('tumor', 'Disease', (112, 117))	('alterations', 'Var', (41, 52))
50995	33669749	From a mechanistic standpoint, variability in patterns of genomic and proteomic alterations create a challenge in separating the key drivers of oncogenic signaling, tumor development, and progression from those mutations that are tumor-promoting but non-transforming or that do not directly contribute to tumorigenesis (i.e., passenger mutations).	('tumor', 'Disease', (230, 235))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('mutations', 'Var', (211, 220))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (305, 310))	('tumor', 'Disease', (165, 170))
50999	33669749	Over the past 20 years, beginning with the sequencing of the human genome to the more recent development of next-generation sequencing (NGS), advances in genomics, proteomics, and systems biology have allowed us to begin to catalogue, visualize, compare and dissect patterns of DNA mutations and copy number alterations, mRNA and miRNA expression patterns, protein and phosphorylated protein expression and epigenetic alterations between individual patients, across specific forms of cancer and between malignancies affecting different tissues.	('protein', 'cellular_component', 'GO:0003675', ('384', '391'))	('epigenetic', 'MPA', (407, 417))	('cancer', 'Phenotype', 'HP:0002664', (484, 490))	('patients', 'Species', '9606', (449, 457))	('protein', 'cellular_component', 'GO:0003675', ('357', '364'))	('malignancies', 'Disease', (503, 515))	('DNA', 'Gene', (278, 281))	('DNA', 'cellular_component', 'GO:0005574', ('278', '281'))	('cancer', 'Disease', 'MESH:D009369', (484, 490))	('copy number', 'Var', (296, 307))	('cancer', 'Disease', (484, 490))	('human', 'Species', '9606', (61, 66))	('mutations', 'Var', (282, 291))	('malignancies', 'Disease', 'MESH:D009369', (503, 515))
51015	33669749	Recent studies have reported that the emergence of hormone therapy resistance in ER+ breast cancers can arise through four predominant mechanisms including ESR1 mutations (18%), altered MAPK signaling (13%), MYC or transcription factor activation (9%), and other/unknown factors (60%).	('breast cancers', 'Disease', 'MESH:D001943', (85, 99))	('breast cancers', 'Disease', (85, 99))	('ESR1', 'Gene', '2099', (156, 160))	('MAPK', 'molecular_function', 'GO:0004707', ('186', '190'))	('MAPK', 'Gene', (186, 190))	('ESR1', 'Gene', (156, 160))	('breast cancers', 'Phenotype', 'HP:0003002', (85, 99))	('MAPK signaling', 'biological_process', 'GO:0000165', ('186', '200'))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('MAPK', 'Gene', '5594', (186, 190))	('MYC', 'Gene', (208, 211))	('hormone therapy', 'MPA', (51, 66))	('transcription factor', 'molecular_function', 'GO:0000981', ('215', '235'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('altered', 'Reg', (178, 185))	('MYC', 'Gene', '4609', (208, 211))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('activation', 'PosReg', (236, 246))	('mutations', 'Var', (161, 170))	('transcription', 'biological_process', 'GO:0006351', ('215', '228'))
51016	33669749	The findings of multiple clinical trials have resulted in FDA and international approval for use of the mTOR inhibitor everolimus in conjunction with exemestane for the treatment of patients with advanced or metastatic ER+, PR+, HER2-negative, PIK3CA mutant tumors.	('mTOR', 'Gene', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('mTOR', 'Gene', '2475', (104, 108))	('ER+', 'Var', (219, 222))	('PR', 'Gene', '5241', (224, 226))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('HER2', 'Gene', (229, 233))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('HER2', 'Gene', '2064', (229, 233))	('PIK3CA', 'Gene', (244, 250))	('exemestane', 'Chemical', 'MESH:C056516', (150, 160))	('everolimus', 'Chemical', 'MESH:D000068338', (119, 129))	('patients', 'Species', '9606', (182, 190))	('PIK3CA', 'Gene', '5290', (244, 250))
51019	33669749	Finally, the treatment of TNBC tumors has begun to evolve to include immune checkpoint inhibitors while patients with BRCA mutations are treated with PARP inhibitors in conjunction with chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PARP', 'Gene', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('TNBC tumors', 'Disease', 'MESH:D009369', (26, 37))	('BRCA', 'Gene', '672', (118, 122))	('PARP', 'Gene', '142', (150, 154))	('TNBC tumors', 'Disease', (26, 37))	('BRCA', 'Gene', (118, 122))	('patients', 'Species', '9606', (104, 112))	('mutations', 'Var', (123, 132))
51028	33669749	Genetically, Type I and II tumors are characterized by specific mutations: mutations common to Type I tumors include KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, and PPP2R1A, while Type II tumors have a high frequency of TP53 mutations (>95%) as well as mutation or aberrant expression of BRCA1 or BRCA2.	('KRAS', 'Gene', (117, 121))	('ERBB2', 'Gene', '2064', (129, 134))	('Type I tumors', 'Disease', 'MESH:D018761', (95, 108))	('PPP2R1A', 'Gene', (170, 177))	('mutations', 'Var', (230, 239))	('CTNNB1', 'Gene', '1499', (136, 142))	('Type II tumors', 'Disease', (185, 199))	('mutation', 'Var', (258, 266))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('BRCA2', 'Gene', (302, 307))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('PIK3CA', 'Gene', '5290', (150, 156))	('expression', 'MPA', (279, 289))	('TP53', 'Gene', (225, 229))	('II tumors', 'Disease', 'MESH:D009369', (24, 33))	('II tumors', 'Disease', 'MESH:D009369', (190, 199))	('ARID1A', 'Gene', (158, 164))	('CTNNB1', 'Gene', (136, 142))	('BRCA2', 'Gene', '675', (302, 307))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('II tumors', 'Disease', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('PTEN', 'Gene', (144, 148))	('Type II tumors', 'Disease', 'MESH:D009369', (185, 199))	('ARID1A', 'Gene', '8289', (158, 164))	('PIK3CA', 'Gene', (150, 156))	('ERBB2', 'Gene', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('KRAS', 'Gene', '3845', (117, 121))	('TP53', 'Gene', '7157', (225, 229))	('BRCA1', 'Gene', '672', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Type I tumors', 'Disease', (95, 108))	('PPP2R1A', 'Gene', '5518', (170, 177))	('BRCA1', 'Gene', (293, 298))	('PTEN', 'Gene', '5728', (144, 148))
51029	33669749	Importantly, these mutations appear to be largely confined to each subtype with Type II tumors rarely expressing Type I mutations and Type I tumors being largely wild-type for TP53, except for low-grade mucinous tumors (~25%).	('mucinous tumors', 'Disease', (203, 218))	('Type II tumors', 'Disease', (80, 94))	('mucinous tumors', 'Disease', 'MESH:D002288', (203, 218))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('TP53', 'Gene', '7157', (176, 180))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('Type II tumors', 'Disease', 'MESH:D009369', (80, 94))	('Type I tumors', 'Disease', 'MESH:D018761', (134, 147))	('TP53', 'Gene', (176, 180))	('Type I tumors', 'Disease', (134, 147))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mutations', 'Var', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
51040	33669749	Despite the inherent differences in clinical manifestation between breast and ovarian cancer, a portion of these malignancies are intrinsically linked, as women with specific inherited germline mutations including BRCA1, BRCA2, PALB2, TP53, CDH1, and PTEN have an increased lifetime risk of developing either disease.	('malignancies', 'Disease', (113, 125))	('TP53', 'Gene', (235, 239))	('PTEN', 'Gene', '5728', (251, 255))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('BRCA2', 'Gene', (221, 226))	('PALB2', 'Gene', (228, 233))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (67, 92))	('PALB2', 'Gene', '79728', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDH1', 'Gene', '999', (241, 245))	('BRCA2', 'Gene', '675', (221, 226))	('TP53', 'Gene', '7157', (235, 239))	('BRCA1', 'Gene', '672', (214, 219))	('BRCA1', 'Gene', (214, 219))	('women', 'Species', '9606', (155, 160))	('CDH1', 'Gene', (241, 245))	('mutations', 'Var', (194, 203))	('PTEN', 'Gene', (251, 255))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))
51041	33669749	BRCA1 or BRCA2 mutations are the most prevalent cause of high penetrance inherited breast or ovarian cancers and have been shown to affect patients irrespective of race or ethnicity.	('BRCA2', 'Gene', (9, 14))	('BRCA1', 'Gene', (0, 5))	('inherited breast or ovarian cancers', 'Disease', (73, 108))	('patients', 'Species', '9606', (139, 147))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('affect', 'Reg', (132, 138))	('mutations', 'Var', (15, 24))	('inherited breast or ovarian cancers', 'Disease', 'MESH:D061325', (73, 108))	('BRCA2', 'Gene', '675', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('BRCA1', 'Gene', '672', (0, 5))	('ovarian cancers', 'Phenotype', 'HP:0100615', (93, 108))	('prevalent cause', 'Reg', (38, 53))
51042	33669749	Overall, the rate for germline BRCA1 or BRCA2 mutations is relatively low with 4-6% of breast and 8-15% of ovarian tumors expressing one of these mutations.	('ovarian tumors', 'Disease', (107, 121))	('ovarian tumors', 'Phenotype', 'HP:0100615', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (46, 55))	('BRCA1', 'Gene', '672', (31, 36))	('ovarian tumors', 'Disease', 'MESH:D010051', (107, 121))	('breast', 'Disease', (87, 93))	('BRCA1', 'Gene', (31, 36))	('BRCA2', 'Gene', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian tumor', 'Phenotype', 'HP:0100615', (107, 120))	('BRCA2', 'Gene', '675', (40, 45))
51043	33669749	However, it is estimated that 39-63% of women with a BRCA1 mutation will develop ovarian cancer while 46-87% will develop breast cancer by age 70.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('age', 'Gene', (139, 142))	('breast cancer', 'Disease', (122, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('age', 'Gene', '5973', (139, 142))	('develop', 'PosReg', (73, 80))	('women', 'Species', '9606', (40, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('ovarian cancer', 'Disease', (81, 95))	('mutation', 'Var', (59, 67))	('BRCA1', 'Gene', '672', (53, 58))	('BRCA1', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
51044	33669749	Likewise, BRCA2 mutation carriers are strongly predisposed to develop ovarian (17-27%) or breast (38-84%) cancer.	('mutation', 'Var', (16, 24))	('develop', 'PosReg', (62, 69))	('BRCA2', 'Gene', '675', (10, 15))	('ovarian', 'Disease', 'MESH:D010049', (70, 77))	('ovarian', 'Disease', (70, 77))	('breast', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('predisposed', 'Reg', (47, 58))	('BRCA2', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
51055	33669749	HER2E tumors are predominantly ER negative, characterized by the amplification of the HER2 gene on chromosome 17q12, and are associated with poor prognosis and increased risk of metastasis.	('HER2', 'Gene', (86, 90))	('HER2', 'Gene', '2064', (86, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('HER2', 'Gene', '2064', (0, 4))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('HER2', 'Gene', (0, 4))	('metastasis', 'CPA', (178, 188))	('amplification', 'Var', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
51079	33669749	These tumors exhibit increased mutations in luminal genes including GATA3 and FOXA1, as well as genes belonging to the p38-JNK pathway (MAP3K1 and MAP2K4), which were mutated in a mutually exclusive manner.	('p38', 'Gene', '5594', (119, 122))	('FOXA1', 'Gene', '3169', (78, 83))	('MAP3K1', 'Gene', (136, 142))	('MAP3K1', 'Gene', '4214', (136, 142))	('JNK', 'molecular_function', 'GO:0004705', ('123', '126'))	('luminal', 'Chemical', 'MESH:D010634', (44, 51))	('FOXA1', 'Gene', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('increased', 'PosReg', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('MAP3K', 'molecular_function', 'GO:0004709', ('136', '141'))	('mutations', 'Var', (31, 40))	('JNK', 'Gene', (123, 126))	('tumors', 'Disease', (6, 12))	('p38', 'Gene', (119, 122))	('JNK', 'Gene', '5599', (123, 126))	('MAP2K4', 'Gene', '6416', (147, 153))	('GATA3', 'Gene', '2625', (68, 73))	('MAP2K4', 'Gene', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('MAP2K', 'molecular_function', 'GO:0004708', ('147', '152'))	('GATA3', 'Gene', (68, 73))
51080	33669749	PIK3CA, which is the most frequently mutated gene in breast cancer, was predominantly altered in luminal tumors and was mutated at a much higher frequency in LumA (45%) relative to LumB (29%) tumors.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', (192, 198))	('luminal tumors', 'Disease', 'MESH:D009369', (97, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('LumA', 'Gene', '79188', (158, 162))	('altered', 'Reg', (86, 93))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('PIK3CA', 'Gene', '5290', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('breast cancer', 'Disease', (53, 66))	('luminal tumors', 'Disease', (97, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('LumA', 'Gene', (158, 162))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('LumB', 'Chemical', '-', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutated', 'Var', (120, 127))
51081	33669749	Despite the high frequency of activating PIK3CA mutations in LumA subtype tumors, the PI3K/AKT signaling axis has not been shown to be consistently upregulated in these tumors.	('activating', 'PosReg', (30, 40))	('AKT', 'Gene', '207', (91, 94))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PIK3CA', 'Gene', (41, 47))	('LumA', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('AKT', 'Gene', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('AKT signaling', 'biological_process', 'GO:0043491', ('91', '104'))	('PIK3CA', 'Gene', '5290', (41, 47))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('tumors', 'Disease', (169, 175))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('mutations', 'Var', (48, 57))	('LumA', 'Gene', '79188', (61, 65))	('tumors', 'Disease', (74, 80))
51082	33669749	In contrast to LumA tumors, LumB tumors are characterized by higher inactivation of the TP53 pathway associated with a higher rate of mutation in the TP53 gene, loss of ATM2, and MDM2 amplification.	('TP53', 'Gene', (150, 154))	('LumB tumors', 'Disease', 'MESH:D009369', (28, 39))	('MDM2', 'Gene', (179, 183))	('TP53', 'Gene', '7157', (88, 92))	('LumA tumors', 'Disease', 'MESH:D009369', (15, 26))	('LumA tumors', 'Disease', (15, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('higher', 'PosReg', (61, 67))	('MDM2', 'Gene', '4193', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', '7157', (150, 154))	('ATM', 'Gene', '472', (169, 172))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('loss', 'Var', (161, 165))	('TP53', 'Gene', (88, 92))	('mutation', 'Var', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('LumB tumors', 'Disease', (28, 39))	('inactivation', 'MPA', (68, 80))	('ATM', 'Gene', (169, 172))
51089	33669749	TP53 (72%) and PIK3CA (39%) mutations are highly enriched in this subtype and show significantly higher expression and activation of receptor tyrosine kinases such as FGFR4, EGFR, and HER2.	('EGFR', 'Gene', (174, 178))	('HER2', 'Gene', (184, 188))	('higher', 'PosReg', (97, 103))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (0, 4))	('HER2', 'Gene', '2064', (184, 188))	('FGFR', 'molecular_function', 'GO:0005007', ('167', '171'))	('PIK3CA', 'Gene', '5290', (15, 21))	('EGFR', 'molecular_function', 'GO:0005006', ('174', '178'))	('activation', 'PosReg', (119, 129))	('expression', 'MPA', (104, 114))	('FGFR4', 'Gene', '2264', (167, 172))	('FGFR4', 'Gene', (167, 172))	('mutations', 'Var', (28, 37))	('PIK3CA', 'Gene', (15, 21))	('EGFR', 'Gene', '1956', (174, 178))
51090	33669749	Basal-like breast cancers represent the most heterogeneous subtype with a high frequency of TP53 mutations which are present in an overwhelming 80-90% of tumors.	('mutations', 'Var', (97, 106))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('breast cancers', 'Phenotype', 'HP:0003002', (11, 25))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancers', 'Disease', 'MESH:D001943', (11, 25))	('breast cancers', 'Disease', (11, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
51092	33669749	Increased activation of PI3K/AKT signaling, relative to other subtypes is a distinguishing feature of basal-like tumors despite a low incidence of PIK3CA (9%) mutations.	('basal-like tumors', 'Phenotype', 'HP:0002671', (102, 119))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (159, 168))	('AKT', 'Gene', '207', (29, 32))	('PIK3CA', 'Gene', (147, 153))	('PIK3CA', 'Gene', '5290', (147, 153))	('PI3K', 'molecular_function', 'GO:0016303', ('24', '28'))	('AKT signaling', 'biological_process', 'GO:0043491', ('29', '42'))	('AKT', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('activation', 'PosReg', (10, 20))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
51096	33669749	identified mutations in the E-cadherin (CDH1) gene (63% in ILC vs. 2% in IDC) which is the hallmark feature of ILCs.	('mutations', 'Var', (11, 20))	('CDH1', 'Gene', (40, 44))	('E-cadherin', 'Gene', (28, 38))	('E-cadherin', 'Gene', '999', (28, 38))	('cadherin', 'molecular_function', 'GO:0008014', ('30', '38'))	('CDH1', 'Gene', '999', (40, 44))	('ILC', 'Disease', (59, 62))
51097	33669749	In addition to CDH1 loss, mutations in PTEN, TBX3, FOXA1, and ESR1 were enriched in ILC relative to IDC tumors.	('IDC tumors', 'Disease', (100, 110))	('IDC tumors', 'Disease', 'MESH:D009369', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ILC', 'Disease', (84, 87))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('ESR1', 'Gene', (62, 66))	('TBX3', 'Gene', '6926', (45, 49))	('FOXA1', 'Gene', (51, 56))	('mutations', 'Var', (26, 35))	('PTEN', 'Gene', (39, 43))	('CDH1', 'Gene', (15, 19))	('CDH1', 'Gene', '999', (15, 19))	('PTEN', 'Gene', '5728', (39, 43))	('TBX3', 'Gene', (45, 49))	('loss', 'NegReg', (20, 24))	('FOXA1', 'Gene', '3169', (51, 56))	('ESR1', 'Gene', '2099', (62, 66))
51098	33669749	Mutations in PIK3CA were reported in 48% of ILC relative to 33% of IDC tumors which, along with loss of PTEN function, defines the significant upregulation of PI3K signaling in ILC tumors.	('ILC tumors', 'Disease', (177, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('PIK3CA', 'Gene', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('PI3K signaling', 'biological_process', 'GO:0014065', ('159', '173'))	('ILC', 'Disease', (44, 47))	('IDC tumors', 'Disease', (67, 77))	('PI3K signaling', 'Pathway', (159, 173))	('Mutations', 'Var', (0, 9))	('upregulation', 'PosReg', (143, 155))	('IDC tumors', 'Disease', 'MESH:D009369', (67, 77))	('PIK3CA', 'Gene', '5290', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('ILC tumors', 'Disease', 'MESH:D009369', (177, 187))	('PI3K', 'molecular_function', 'GO:0016303', ('159', '163'))	('PTEN', 'Gene', (104, 108))	('PTEN', 'Gene', '5728', (104, 108))
51105	33669749	Phosphoproteomic analysis informed the translational outcomes of PIK3CA mutations in breast cancer, which often are not correlated with the transcriptional signature of breast tumors.	('mutations', 'Var', (72, 81))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast tumors', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (85, 98))	('breast tumors', 'Disease', (169, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('PIK3CA', 'Gene', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast tumors', 'Phenotype', 'HP:0100013', (169, 182))	('PIK3CA', 'Gene', '5290', (65, 71))	('breast tumor', 'Phenotype', 'HP:0100013', (169, 181))
51106	33669749	These analyses resulted in the identification of 62 different phosphosites in PIK3CA mutated breast tumors, including RPS6KA5 and EIF2AK4, explaining the activation of the pathway and revealing possible druggable kinases in this pathway.	('EIF2', 'cellular_component', 'GO:0005850', ('130', '134'))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('PIK3CA', 'Gene', (78, 84))	('breast tumors', 'Disease', (93, 106))	('RPS6KA5', 'Gene', (118, 125))	('EIF2AK4', 'Gene', '440275', (130, 137))	('RPS6KA5', 'Gene', '9252', (118, 125))	('PIK3CA', 'Gene', '5290', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('breast tumors', 'Phenotype', 'HP:0100013', (93, 106))	('mutated', 'Var', (85, 92))	('breast tumor', 'Phenotype', 'HP:0100013', (93, 105))	('EIF2AK4', 'Gene', (130, 137))	('breast tumors', 'Disease', 'MESH:D001943', (93, 106))
51107	33669749	The CPTAC project highlights the need for integrating data across proteogenomic platforms to connect somatic mutations with the activation of various oncogenic signaling pathways in tumors for better therapeutic outcomes.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (182, 188))	('oncogenic signaling pathways', 'Pathway', (150, 178))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
51142	33669749	The most prominent among these is TP53 mutations which are evident in nearly all patients and are believed to arise early in the transformation process.	('patients', 'Species', '9606', (81, 89))	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))
51144	33669749	Almost half of HGSOC tumors are characterized by homologous recombination (HR) deficiency through germline or somatic mutations in BRCA1/2 (20%), BRCA1 hypermethylation (11%), and/or dysregulation of other HR genes including PTEN, ATM or ATR, RAD51C, EMSY and Fanconi anemia genes.	('RAD', 'biological_process', 'GO:1990116', ('243', '246'))	('BRCA1/2', 'Gene', (131, 138))	('BRCA1', 'Gene', '672', (146, 151))	('hypermethylation', 'Var', (152, 168))	('BRCA1', 'Gene', '672', (131, 136))	('BRCA1', 'Gene', (146, 151))	('BRCA1', 'Gene', (131, 136))	('ATM', 'Gene', (231, 234))	('PTEN', 'Gene', (225, 229))	('EMSY', 'Gene', (251, 255))	('Fanconi anemia', 'Disease', (260, 274))	('HGSOC tumors', 'Disease', (15, 27))	('HGSOC tumors', 'Disease', 'MESH:D009369', (15, 27))	('BRCA1/2', 'Gene', '672;675', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('ATR', 'Gene', '545', (238, 241))	('Fanconi anemia', 'Disease', 'MESH:D005199', (260, 274))	('(HR) deficiency', 'Disease', 'MESH:D001919', (74, 89))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('EMSY', 'Gene', '56946', (251, 255))	('homologous recombination', 'biological_process', 'GO:0035825', ('49', '73'))	('mutations', 'Var', (118, 127))	('anemia', 'Phenotype', 'HP:0001903', (268, 274))	('PTEN', 'Gene', '5728', (225, 229))	('RAD51C', 'Gene', '5889', (243, 249))	('dysregulation', 'Var', (183, 196))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (260, 274))	('ATM', 'Gene', '472', (231, 234))	('RAD51C', 'Gene', (243, 249))	('ATR', 'Gene', (238, 241))
51145	33669749	While few significant mutations are apparent in HGSOC, DNA copy number alterations are more frequent in these tumors.	('frequent', 'Reg', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('HGSOC', 'Disease', (48, 53))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('DNA copy number alterations', 'Var', (55, 82))
51146	33669749	This includes amplification of MECOM, MYC, and CCNE1 which are among the most significant focal amplifications and found in more than 20% of HGSOC cases in addition to KRAS and MAPK1 which are found in more than 10% of cases.	('HGSOC', 'Disease', (141, 146))	('MYC', 'Gene', (38, 41))	('CCNE1', 'Gene', (47, 52))	('CCNE1', 'Gene', '898', (47, 52))	('KRAS', 'Gene', '3845', (168, 172))	('MECOM', 'Gene', '2122', (31, 36))	('MAPK', 'molecular_function', 'GO:0004707', ('177', '181'))	('MAPK1', 'Gene', '5594', (177, 182))	('MAPK1', 'Gene', (177, 182))	('MECOM', 'Gene', (31, 36))	('MYC', 'Gene', '4609', (38, 41))	('KRAS', 'Gene', (168, 172))	('amplification', 'Var', (14, 27))
51147	33669749	Interestingly, while specific genes are mutated at a low frequency in HGSOC, pathway analyses incorporating orthogonal whole-exome sequencing and copy number data demonstrated that HGSOC tumors are characterized by aberrant RB1/E2F (67%), PI3K/RAS (45%), and NOTCH (22%) signaling as well as dysregulation of the FOXM1 transcription factor network (87%).	('FOXM1', 'Gene', (313, 318))	('NOTCH', 'MPA', (259, 264))	('PI3K', 'molecular_function', 'GO:0016303', ('239', '243'))	('signaling', 'biological_process', 'GO:0023052', ('271', '280'))	('RB1', 'Gene', (224, 227))	('transcription', 'biological_process', 'GO:0006351', ('319', '332'))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('RB1', 'Gene', '5925', (224, 227))	('PI3K/RAS', 'Pathway', (239, 247))	('dysregulation', 'Var', (292, 305))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('HGSOC tumors', 'Disease', (181, 193))	('FOXM1', 'Gene', '2305', (313, 318))	('transcription factor', 'molecular_function', 'GO:0000981', ('319', '339'))	('HGSOC tumors', 'Disease', 'MESH:D009369', (181, 193))
51166	33669749	Basal-like and high-grade serous ovarian tumors are enriched for BRCA1/2 inactivation and express TP53 mutations in 90-95% of tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', (41, 47))	('serous ovarian tumors', 'Disease', 'MESH:D010051', (26, 47))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BRCA1/2', 'Gene', (65, 72))	('Basal-like', 'Disease', (0, 10))	('mutations', 'Var', (103, 112))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('TP53', 'Gene', (98, 102))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('serous ovarian tumors', 'Phenotype', 'HP:0012887', (26, 47))	('BRCA1/2', 'Gene', '672;675', (65, 72))	('inactivation', 'Var', (73, 85))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('ovarian tumors', 'Phenotype', 'HP:0100615', (33, 47))	('ovarian tumor', 'Phenotype', 'HP:0100615', (33, 46))	('serous ovarian tumors', 'Disease', (26, 47))	('TP53', 'Gene', '7157', (98, 102))
51168	33669749	More recent studies have indicated that these tumors demonstrate high homologous recombination deficiency (HRD) scores, accumulation of large-scale state transitions, increased loss of heterozygosity (LOH), and telomeric allelic imbalance scar signatures.	('deficiency', 'Disease', 'MESH:D007153', (95, 105))	('homologous recombination', 'biological_process', 'GO:0035825', ('70', '94'))	('HRD', 'Disease', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('telomeric allelic imbalance', 'Var', (211, 238))	('loss', 'NegReg', (177, 181))	('homologous recombination', 'MPA', (70, 94))	('HRD', 'Disease', 'None', (107, 110))	('deficiency', 'Disease', (95, 105))	('imbalance', 'Phenotype', 'HP:0002172', (229, 238))	('scar', 'Phenotype', 'HP:0100699', (239, 243))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
51169	33669749	Clinically, these alterations have been shown to be significantly correlated with pathologic complete response and minimal residual disease in TNBC patients treated with platinum-based therapies and with a better prognosis in HGSOC.	('patients', 'Species', '9606', (148, 156))	('correlated', 'Reg', (66, 76))	('alterations', 'Var', (18, 29))	('platinum', 'Chemical', 'MESH:D010984', (170, 178))	('TNBC', 'Disease', 'None', (143, 147))	('TNBC', 'Disease', (143, 147))
51171	33669749	While PIK3CA mutations are relatively rare events in each tumor type, a number of unique alterations have emerged as contributing to aberrant signaling.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('contributing', 'Reg', (117, 129))	('aberrant signaling', 'MPA', (133, 151))	('PIK3CA', 'Gene', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PIK3CA', 'Gene', '5290', (6, 12))	('mutations', 'Var', (13, 22))
51172	33669749	In HGSOC, DNA copy number gains in PIK3CA (18%), AKT1 or AKT2 (9% combined) and to a lesser extent, homozygous deletion of PTEN (7%) are the main drivers for this pathway.	('AKT1', 'Gene', '207', (49, 53))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('AKT2', 'Gene', (57, 61))	('AKT1', 'Gene', (49, 53))	('AKT2', 'Gene', '208', (57, 61))	('PIK3CA', 'Gene', (35, 41))	('gains', 'PosReg', (26, 31))	('PTEN', 'Gene', (123, 127))	('PIK3CA', 'Gene', '5290', (35, 41))	('PTEN', 'Gene', '5728', (123, 127))	('deletion', 'Var', (111, 119))
51173	33669749	In contrast, basal-like tumors are regulated by alterations in multiple genes (EGFR, IGFR1, AKT3) that occur at a low frequency (2-4%), as well as a loss of PTEN (35%) or INPP4B (30%), SOX4 amplification and overexpression, and MAGI3-AKT3 gene fusion.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('INPP4B', 'Gene', (171, 177))	('EGFR', 'Gene', '1956', (79, 83))	('tumors', 'Disease', (24, 30))	('loss', 'NegReg', (149, 153))	('basal-like tumors', 'Phenotype', 'HP:0002671', (13, 30))	('AKT3', 'Gene', '10000', (92, 96))	('PTEN', 'Gene', '5728', (157, 161))	('MAGI3', 'Gene', (228, 233))	('SOX4', 'Gene', '6659', (185, 189))	('AKT3', 'Gene', '10000', (234, 238))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('AKT3', 'Gene', (92, 96))	('IGFR1', 'Gene', (85, 90))	('AKT3', 'Gene', (234, 238))	('overexpression', 'PosReg', (208, 222))	('EGFR', 'Gene', (79, 83))	('INPP4B', 'Gene', '8821', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('alterations', 'Var', (48, 59))	('MAGI3', 'Gene', '260425', (228, 233))	('PTEN', 'Gene', (157, 161))	('SOX4', 'Gene', (185, 189))	('IGFR1', 'Gene', '100132417', (85, 90))
51176	33669749	Basal-like breast cancers have increased altered cell cycle checkpoint regulation, DNA damage repair, MYC, and immune response signaling, while proteins associated with recurrent copy number alterations in HGSOC converge on cell migration/invasion and immune regulation pathways.	('altered', 'Reg', (41, 48))	('copy number alterations', 'Var', (179, 202))	('increased', 'PosReg', (31, 40))	('cell migration', 'biological_process', 'GO:0016477', ('224', '238'))	('MYC', 'Gene', '4609', (102, 105))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('immune response signaling', 'MPA', (111, 136))	('regulation', 'biological_process', 'GO:0065007', ('71', '81'))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancers', 'Disease', 'MESH:D001943', (11, 25))	('age', 'Gene', (90, 93))	('breast cancers', 'Disease', (11, 25))	('breast cancers', 'Phenotype', 'HP:0003002', (11, 25))	('regulation', 'biological_process', 'GO:0065007', ('259', '269'))	('cell cycle checkpoint regulation', 'MPA', (49, 81))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('age', 'Gene', '5973', (90, 93))	('MYC', 'Gene', (102, 105))	('cell migration/invasion', 'CPA', (224, 247))	('HGSOC', 'Gene', (206, 211))	('immune response', 'biological_process', 'GO:0006955', ('111', '126'))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('49', '70'))
51203	33669749	Beyond assessing the transcriptome, single-cell DNA sequencing approaches have been developed and used to identify subpopulations of cells that express unique mutational and CNA patterns in therapeutically actionable genes in a given breast tumor.	('mutational', 'Var', (159, 169))	('breast tumor', 'Disease', (234, 246))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('breast tumor', 'Phenotype', 'HP:0100013', (234, 246))	('breast tumor', 'Disease', 'MESH:D001943', (234, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
51216	33669749	Likewise, ubiquitin B (UBB) and ubiquitin C (UBC) were identified as a paralog deficiency dependency in ovarian cancers, implying the essentiality of UBC in cell lines with repressed UBB; shRNA mediated silencing of UBC in UBB repressed ovarian cancer xenograft model lead to tumor regression and prolonged survival.	('ubiquitin C', 'Gene', (32, 43))	('UBB', 'Gene', '7314', (183, 186))	('paralog deficiency dependency in ovarian cancers', 'Disease', 'MESH:D019966', (71, 119))	('ovarian cancer', 'Phenotype', 'HP:0100615', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('UBB repressed ovarian cancer', 'Disease', 'MESH:D010051', (223, 251))	('UBB', 'Gene', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('UBB', 'Gene', '7314', (223, 226))	('UBC', 'Gene', '7316', (216, 219))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('UBB', 'Gene', '7314', (23, 26))	('UBB repressed ovarian cancer', 'Disease', (223, 251))	('UBC', 'Gene', '7316', (150, 153))	('UBB', 'Gene', (223, 226))	('ovarian cancers', 'Phenotype', 'HP:0100615', (104, 119))	('ubiquitin B', 'Gene', (10, 21))	('ubiquitin', 'molecular_function', 'GO:0031386', ('10', '19'))	('UBC', 'Gene', (216, 219))	('silencing', 'Var', (203, 212))	('UBB', 'Gene', (23, 26))	('ubiquitin C', 'Gene', '7316', (32, 43))	('tumor', 'Disease', (276, 281))	('UBC', 'Gene', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('prolonged', 'PosReg', (297, 306))	('ubiquitin B', 'Gene', '7314', (10, 21))	('UBC', 'Gene', '7316', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('ubiquitin', 'molecular_function', 'GO:0031386', ('32', '41'))	('UBC', 'Gene', (45, 48))	('paralog deficiency dependency in ovarian cancers', 'Disease', (71, 119))
51220	33669749	However, biochemical and genetic-based studies as well as large-scale proteogenomic analyses have demonstrated that despite enormous tumor heterogeneity, molecular alterations often converge on a limited number of signaling networks, reflecting pathway activity levels and their role in driving tumor progression.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('enormous tumor', 'Disease', 'MESH:D009369', (124, 138))	('enormous tumor', 'Disease', (124, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('converge', 'Reg', (182, 190))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('signaling', 'biological_process', 'GO:0023052', ('214', '223'))	('alterations', 'Var', (164, 175))	('tumor', 'Disease', (295, 300))
51232	33669749	The FDA recently approved the FoundationOne Liquid CDx test, which is a circulating cell-free DNA (cfDNA) based-assay as a companion diagnostic for treatment of BRCA mutant (germline or somatic) ovarian cancer patients with the PARP inhibitor rucaparib as well as alpelisib treatment of HR+/HER2-, PIK3CA mutated breast cancer patients.	('rucaparib', 'Chemical', 'MESH:C531549', (243, 252))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('PARP', 'Gene', '142', (228, 232))	('HER2', 'Gene', (291, 295))	('ovarian cancer', 'Disease', (195, 209))	('alpelisib', 'Chemical', 'MESH:C585539', (264, 273))	('PARP', 'Gene', (228, 232))	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (195, 209))	('PIK3CA', 'Gene', (298, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (313, 326))	('patients', 'Species', '9606', (210, 218))	('BRCA', 'Gene', '672', (161, 165))	('breast cancer', 'Disease', 'MESH:D001943', (313, 326))	('breast cancer', 'Disease', (313, 326))	('mutant', 'Var', (166, 172))	('HER2', 'Gene', '2064', (291, 295))	('FoundationOne', 'Chemical', '-', (30, 43))	('patients', 'Species', '9606', (327, 335))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('CDx', 'Chemical', '-', (51, 54))	('BRCA', 'Gene', (161, 165))	('ovarian cancer', 'Disease', 'MESH:D010051', (195, 209))	('PIK3CA', 'Gene', '5290', (298, 304))
51237	33669749	Additional funding for this project was provided by New Jersey Commission for Cancer Research (DCHS-20PPC-014 to CAK and DHFS-19PPC-019 to GAM), the Cox Foundation for Cancer Research (CAK and GAM) and through a MacMillan Cancer Genetics Summer Undergraduate Research Fellowship from Rutgers University (RNM).	('CAK', 'molecular_function', 'GO:0019912', ('113', '116'))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('Cancer', 'Disease', (222, 228))	('CAK', 'Gene', (113, 116))	('Cancer', 'Disease', (78, 84))	('DHFS-19PPC-019', 'Var', (121, 135))	('CAK', 'Gene', '780', (113, 116))	('Cancer', 'Disease', 'MESH:D009369', (222, 228))	('CAK', 'Gene', '780', (185, 188))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Cancer', 'Disease', (168, 174))	('DHFS', 'Chemical', '-', (121, 125))	('CAK', 'Gene', (185, 188))	('DCHS-20PPC-014', 'Var', (95, 109))	('Cancer', 'Disease', 'MESH:D009369', (168, 174))	('Cancer', 'Phenotype', 'HP:0002664', (168, 174))	('CAK', 'molecular_function', 'GO:0019912', ('185', '188'))
51310	27172895	Using a DAKO Autostainer (DAKO, Carpinteria, CA), the slides were blocked for 30 min in horse serum and incubated with primary antibody for 1 h. Primary antibodies were matched to the RPPA platform: Caveolin-1 (1:200), E-cadherin (1:200), and RBM15 (1:1000).	('antibody', 'cellular_component', 'GO:0019815', ('127', '135'))	('1:200', 'Var', (211, 216))	('antibody', 'cellular_component', 'GO:0019814', ('127', '135'))	('cadherin', 'molecular_function', 'GO:0008014', ('221', '229'))	('antibody', 'molecular_function', 'GO:0003823', ('127', '135'))	('horse', 'Species', '9796', (88, 93))	('antibody', 'cellular_component', 'GO:0042571', ('127', '135'))	('1:200', 'Var', (231, 236))
51323	27172895	For the ER-positive/HER2-negative group, key determinants positively associated were annexin-1, collagen VI, and HSP70 and negatively associated were BAP1, phosphomyosinIIA, and PRDX1 with more modest contributions from phosphoERalpha and GATA3.	('phosphoERalpha', 'Chemical', '-', (220, 234))	('collagen', 'molecular_function', 'GO:0005202', ('96', '104'))	('ER', 'Gene', '2099', (227, 229))	('PRDX1', 'Gene', (178, 183))	('ER', 'Gene', '2099', (8, 10))	('collagen VI', 'Protein', (96, 107))	('HSP70', 'Protein', (113, 118))	('phosphomyosinIIA', 'Var', (156, 172))	('HER2', 'Gene', (20, 24))	('associated', 'Interaction', (69, 79))	('positively', 'PosReg', (58, 68))	('negatively', 'NegReg', (123, 133))	('HER2', 'Gene', '2064', (20, 24))	('annexin-1', 'Protein', (85, 94))	('ER', 'Gene', '2099', (21, 23))
51325	27172895	The Reactive subtype was also enriched in lobular cancers and thus CDH1 mutations and low-risk characteristics of breast cancers including low Nottingham grade, luminal A breast cancers, and wild-type TP53 (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancers', 'Phenotype', 'HP:0003002', (171, 185))	('lobular cancers', 'Disease', 'MESH:D013274', (42, 57))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('mutations', 'Var', (72, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('TP53', 'Gene', (201, 205))	('breast cancers', 'Disease', 'MESH:D001943', (114, 128))	('breast cancers', 'Disease', (114, 128))	('CDH1', 'Gene', '999', (67, 71))	('luminal A breast cancers', 'Disease', (161, 185))	('lobular cancers', 'Disease', (42, 57))	('breast cancers', 'Phenotype', 'HP:0003002', (114, 128))	('CDH1', 'Gene', (67, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('luminal A breast cancers', 'Disease', 'MESH:D001943', (161, 185))	('TP53', 'Gene', '7157', (201, 205))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('breast cancers', 'Disease', 'MESH:D001943', (171, 185))
51343	27172895	As expected when including triple-negative and HER2-positive cancers, poor outcomes were also highly associated with high-risk characteristics of breast cancers including tumor size, histopathology, Nottingham grade, lymph node status, and PAM50 classification (Table 2).	('HER2-positive cancers', 'Disease', 'MESH:D009369', (47, 68))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('PAM50 classification', 'Var', (240, 260))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (171, 176))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('breast cancers', 'Disease', (146, 160))	('HER2-positive cancers', 'Disease', (47, 68))
51361	27172895	S11B), the stromal cell density was higher in the Reactive breast cancer subtype of ILC cases but not for IDC cases (Fig.	('higher', 'PosReg', (36, 42))	('S11B', 'Var', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('ILC', 'Disease', (84, 87))	('S11B', 'SUBSTITUTION', 'None', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('stromal cell density', 'CPA', (11, 31))
51364	27172895	S11C, S11D, S11E, and S12).	('S11C', 'SUBSTITUTION', 'None', (0, 4))	('S11E', 'Var', (12, 16))	('S11D', 'Var', (6, 10))	('S11D', 'SUBSTITUTION', 'None', (6, 10))	('S12', 'Var', (22, 25))	('S11E', 'Mutation', 'p.S11E', (12, 16))	('S11C', 'Var', (0, 4))
51371	27172895	S14A, S14B, S14C, S14D, and S14E).	('S14D', 'Mutation', 'p.S14D', (18, 22))	('S14E', 'Var', (28, 32))	('S14C', 'Var', (12, 16))	('S14B', 'SUBSTITUTION', 'None', (6, 10))	('S14D', 'Var', (18, 22))	('S14E', 'Mutation', 'p.S14E', (28, 32))	('S14B', 'Var', (6, 10))	('S14A', 'Mutation', 'rs1214098977', (0, 4))	('S14C', 'Mutation', 'p.S14C', (12, 16))
51393	27172895	In conjunction with high stromal content, evaluation of Reactive breast cancer morphology by imaging revealed that IDC Reactive breast cancers were highly differentiated cancers often with neoplastic tubule formation as compared to RPPA luminal and basal-like cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (260, 267))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('basal-like cancers', 'Disease', (249, 267))	('basal-like cancers', 'Disease', 'MESH:D002280', (249, 267))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('formation', 'biological_process', 'GO:0009058', ('207', '216'))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('cancers', 'Disease', (135, 142))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('cancers', 'Disease', (260, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('breast cancers', 'Disease', 'MESH:D001943', (128, 142))	('breast cancers', 'Disease', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('IDC', 'Var', (115, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
51422	27172895	For triple-negative breast cancers, more late relapses might also be expected for less "basal-like" breast cancers like those observed for luminal breast cancer within the triple-negative clinical subtype, which can represent up to 25% of all triple-negative breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancers', 'Disease', 'MESH:D001943', (20, 34))	('breast cancers', 'Disease', (20, 34))	('breast cancers', 'Disease', 'MESH:D001943', (100, 114))	('breast cancers', 'Disease', (100, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (259, 273))	('luminal breast cancer', 'Disease', (139, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('luminal breast cancer', 'Disease', 'MESH:D001943', (139, 160))	('less', 'Disease', (82, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (20, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('breast cancers', 'Phenotype', 'HP:0003002', (100, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('clinical', 'Species', '191496', (188, 196))	('triple-negative', 'Var', (4, 19))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('breast cancers', 'Disease', 'MESH:D001943', (259, 273))	('breast cancers', 'Disease', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
51483	33072448	Several breast cancer risk factors preferentially promote ILC development: late age at first birth, early menarche, late age at menopause, BReast CAncer gene 2 (BRCA2) germline mutations and cadherin 1 (CDH1), the gene coding for the E-cadherin adhesion protein mutations.	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('age at menopause', 'Phenotype', 'HP:0008209', (121, 137))	('menopause', 'biological_process', 'GO:0042697', ('128', '137'))	('promote', 'PosReg', (50, 57))	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('ILC development', 'CPA', (58, 73))	('menarche', 'Disease', (106, 114))	('breast cancer', 'Disease', (8, 21))	('BRCA2', 'Gene', '675', (161, 166))	('menarche', 'Disease', 'None', (106, 114))	('CDH1', 'Gene', '999', (203, 207))	('germline', 'Var', (168, 176))	('E-cadherin', 'Gene', (234, 244))	('BReast CAncer gene 2', 'Gene', '675', (139, 159))	('E-cadherin', 'Gene', '999', (234, 244))	('BReast CAncer gene 2', 'Gene', (139, 159))	('CDH1', 'Gene', (203, 207))	('cadherin 1', 'Gene', '999', (191, 201))	('CAncer', 'Phenotype', 'HP:0002664', (146, 152))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('BReast CAncer', 'Phenotype', 'HP:0003002', (139, 152))	('cadherin', 'molecular_function', 'GO:0008014', ('236', '244'))	('cadherin', 'molecular_function', 'GO:0008014', ('191', '199'))	('BRCA2', 'Gene', (161, 166))	('menarche', 'biological_process', 'GO:0042696', ('106', '114'))	('cadherin 1', 'Gene', (191, 201))
51489	33072448	They are also associated with a higher percentage of multifocal, multicentric, and bilateral cases, lower histological grade, higher rate of hormone receptor (ER/PR) positivity, lower rate of HER2 positivity, and low tumour cell proliferation index.	('multifocal', 'CPA', (53, 63))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('histological grade', 'CPA', (106, 124))	('lower', 'NegReg', (178, 183))	('ER/PR', 'Gene', (159, 164))	('lower', 'NegReg', (100, 105))	('positivity', 'Var', (166, 176))	('HER2', 'Gene', (192, 196))	('low tumour', 'Disease', 'MESH:D009800', (213, 223))	('HER2', 'Gene', '2064', (192, 196))	('ER/PR', 'Gene', '2069;140738', (159, 164))	('low tumour', 'Disease', (213, 223))	('cell proliferation', 'biological_process', 'GO:0008283', ('224', '242'))
51516	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))
51529	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))	('growth pattern', 'biological_process', 'GO:0007150', ('17', '31'))	('necrosis', 'biological_process', 'GO:0070265', ('78', '86'))	('necrosis', 'biological_process', 'GO:0019835', ('78', '86'))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('necrosis', 'biological_process', 'GO:0001906', ('78', '86'))	('growth pattern', 'biological_process', 'GO:0040007', ('17', '31'))	('necrosis', 'Disease', 'MESH:D009336', (78, 86))	('calcifications', 'Disease', 'MESH:D002114', (91, 105))	('P-LCIS', 'Var', (107, 113))	('calcifications', 'Disease', (91, 105))	('necrosis', 'Disease', (78, 86))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (129, 153))	('necrosis', 'biological_process', 'GO:0008219', ('78', '86'))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (136, 153))	('ductal carcinoma', 'Disease', (129, 145))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (129, 145))	('P-LCIS', 'Chemical', '-', (107, 113))	('necrosis', 'biological_process', 'GO:0008220', ('78', '86'))
51530	29413653	However, the cells of P-LCIS are dyshesive, lack true cell polarity, and do not form secondary lumina.	('cell polarity', 'biological_process', 'GO:0007163', ('54', '67'))	('P-LCIS', 'Chemical', '-', (22, 28))	('lack', 'NegReg', (44, 48))	('P-LCIS', 'Var', (22, 28))
51543	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))	('chromosome', 'cellular_component', 'GO:0005694', ('227', '237'))	('extracellular', 'cellular_component', 'GO:0005576', ('140', '153'))	('CDH1', 'Gene', (261, 265))	('CDH1', 'Gene', '999', (261, 265))	('truncation mutations', 'Var', (112, 132))	('Ecadherin', 'Gene', (164, 173))
51545	29413653	In contrast, ILC and LCIS, including all LCIS variants, are characterized by loss or aberrant expression of the E-cadherin protein (Fig.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('aberrant', 'Var', (85, 93))	('LCIS', 'Disease', (21, 25))	('E-cadherin', 'Gene', (112, 122))	('E-cadherin', 'Gene', '999', (112, 122))	('ILC', 'Disease', (13, 16))	('cadherin', 'molecular_function', 'GO:0008014', ('114', '122'))	('expression', 'MPA', (94, 104))	('loss', 'NegReg', (77, 81))
51546	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))	('cadherin', 'molecular_function', 'GO:0008014', ('32', '40'))	('separating LCIS', 'Phenotype', 'HP:0006304', (131, 146))	('DCIS', 'Disease', (161, 165))
51575	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))	('patients', 'Species', '9606', (18, 26))	('invasive carcinoma', 'Disease', 'MESH:D009361', (52, 70))	('LCIS', 'Disease', (40, 44))
51591	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))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('lower', 'NegReg', (139, 144))	('invasive carcinoma', 'Disease', 'MESH:D009361', (161, 179))	('copy number', 'MPA', (90, 101))
51592	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))	('ADH', 'molecular_function', 'GO:0047636', ('196', '199'))	('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))	('ADH', 'molecular_function', 'GO:0004022', ('196', '199'))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('low grade DCIS', 'Disease', (58, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
51594	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', 'Var', (10, 14))	('invasive carcinoma', 'Disease', 'MESH:D009361', (63, 81))	('neoplastic lesions', 'Disease', (155, 173))
51595	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))
51603	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))
51604	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))	('cadherin', 'molecular_function', 'GO:0008014', ('193', '201'))	('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))
51605	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))
51606	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))
51651	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))	('patients', 'Species', '9606', (18, 26))	('invasive carcinoma', 'Disease', 'MESH:D009361', (52, 70))	('LCIS', 'Disease', (40, 44))
51652	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	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('cadherin', 'molecular_function', 'GO:0008014', ('281', '289'))	('CDH1', 'Gene', (255, 259))	('LCIS', 'Gene', (243, 247))	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('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))	('core', 'cellular_component', 'GO:0019013', ('380', '384'))	('p120', 'Gene', '1500', (125, 129))	('E-cadherin', 'Gene', (279, 289))	('E-cadherin', 'Gene', '999', (279, 289))	('p120', 'Gene', (125, 129))
51675	27650553	In addition, we established a series of long-term estrogen-deprived (LTED) endocrine-resistant variants of the ILC cell lines MDA-MB-134-VI (MM134) and SUM44PE (44PE), and examined the role of WNT4 in endocrine resistance in these models.	('endocrine-resistant', 'Disease', (75, 94))	('MM134', 'Chemical', '-', (141, 146))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (126, 136))	('variants', 'Var', (95, 103))
51684	27650553	E2, 4-OHT, ICI 182,780 (ICI), and progesterone (P4) were dissolved in ethanol; RU486 (RU, mifepristone), BMS-345541 (BMS), staurosporine (STS), endo-IWR1 (IWR), and JW 67 (JW) were dissolved in dimethyl sulfoxide.	('STS', 'Chemical', 'MESH:D019311', (138, 141))	('ICI', 'Chemical', '-', (11, 14))	('RU486', 'Var', (79, 84))	('BMS-345541', 'Var', (105, 115))	('RU486', 'Chemical', 'MESH:D015735', (79, 84))	('ICI', 'Chemical', '-', (24, 27))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (194, 212))	('4-OHT', 'Chemical', 'MESH:C032278', (4, 9))	('mifepristone', 'Chemical', 'MESH:D015735', (90, 102))	('staurosporine', 'Chemical', 'MESH:D019311', (123, 136))	('E2', 'Chemical', 'MESH:D004958', (0, 2))	('progesterone', 'Chemical', 'MESH:D011374', (34, 46))	('ethanol', 'Chemical', 'MESH:D000431', (70, 77))
51685	27650553	Cell death was assessed using CellTox Green (G8741; Promega, Madison, WI, USA) according to the manufacturer's instructions.	('death', 'Disease', (5, 10))	('Cell death', 'biological_process', 'GO:0008219', ('0', '10'))	('G8741;', 'Var', (45, 51))	('CellTox Green', 'Chemical', '-', (30, 43))	('death', 'Disease', 'MESH:D003643', (5, 10))
51686	27650553	Small interfering RNAs (siRNAs) were reverse-transfected using Lipofectamine RNAiMAX reagent (Life Technologies) according to the manufacturer's instructions.	('Lipofectamine RNAiMAX reagent', 'Chemical', '-', (63, 92))	('Small interfering', 'Var', (0, 17))	('RNAs', 'Gene', (18, 22))
51699	27650553	Antibodies were used according to the manufacturers' recommendations: ERalpha (clone 6 F11; Leica Biosystems, Buffalo Grove, IL, USA), p65 (8242; Cell Signaling Technology, Danvers, MA, USA), phospho-p65 (serine 536, CS 3033; Cell Signaling Technology), RelB (CS 4922; Cell Signaling Technology), c-Rel (CS 4727; Cell Signaling Technology), NFKB1 (p105/p50, CS 12540; Cell Signaling Technology), p21 (CS 2946; Cell Signaling Technology), DVL2 (CS 3216; Cell Signaling Technology), DVL3 (CS 3218; Cell Signaling Technology), and tubulin (T9026; Sigma-Aldrich).	('CS 3216', 'Var', (444, 451))	('RelB', 'Gene', '5971', (254, 258))	('p65', 'Gene', '5970', (135, 138))	('DVL2', 'Gene', (438, 442))	('Signaling', 'biological_process', 'GO:0023052', ('274', '283'))	('c-Rel', 'Gene', '5966', (297, 302))	('p105', 'Gene', '4790', (348, 352))	('RelB', 'Gene', (254, 258))	('Signaling', 'biological_process', 'GO:0023052', ('318', '327'))	('ERalpha', 'Gene', (70, 77))	('DVL3', 'Gene', '1857', (481, 485))	('p21', 'Gene', (396, 399))	('p50', 'Gene', '4790', (353, 356))	('DVL3', 'Gene', (481, 485))	('Signaling', 'biological_process', 'GO:0023052', ('501', '510'))	('c-Rel', 'Gene', (297, 302))	('p65', 'Gene', (200, 203))	('Signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('Signaling', 'biological_process', 'GO:0023052', ('415', '424'))	('NFKB1', 'Gene', '4790', (341, 346))	('T9026', 'Var', (537, 542))	('ERalpha', 'Gene', '2099', (70, 77))	('p50', 'Gene', (353, 356))	('p105', 'Gene', (348, 352))	('p65', 'Gene', (135, 138))	('Signaling', 'biological_process', 'GO:0023052', ('231', '240'))	('p21', 'Gene', '1026', (396, 399))	('p65', 'Gene', '5970', (200, 203))	('CS 3218', 'Var', (487, 494))	('NFKB1', 'Gene', (341, 346))	('DVL2', 'Gene', '1856', (438, 442))	('Signaling', 'biological_process', 'GO:0023052', ('458', '467'))	('Signaling', 'biological_process', 'GO:0023052', ('373', '382'))
51710	27650553	WNT4 knockdown was performed in the ILC cell lines MDA-MB-134-VI (MM134) and SUM44PE (44PE) and compared with IDC cell lines MCF-7 and HCC1428.	('MM134', 'Chemical', '-', (66, 71))	('MDA-MB-134', 'CellLine', 'CVCL:0617', (51, 61))	('SUM44PE', 'Var', (77, 84))	('MCF-7', 'CellLine', 'CVCL:0031', (125, 130))	('IDC', 'Gene', '4000', (110, 113))	('HCC1428', 'CellLine', 'CVCL:1252', (135, 142))	('IDC', 'Gene', (110, 113))
51718	27650553	On the basis of potential roles for both ER and PR in regulating WNT4 expression, we used a series of ER-positive ILC (MM134, 44PE, BCK4) and IDC (MCF-7, T47D) BCCLs to further investigate WNT4 regulation.	('T47D', 'CellLine', 'CVCL:0553', (154, 158))	('ER', 'Gene', '2099', (41, 43))	('MM134', 'Var', (119, 124))	('regulation', 'biological_process', 'GO:0065007', ('194', '204'))	('MCF-7', 'CellLine', 'CVCL:0031', (147, 152))	('IDC', 'Gene', '4000', (142, 145))	('MM134', 'Chemical', '-', (119, 124))	('IDC', 'Gene', (142, 145))	('PR', 'Gene', '5241', (48, 50))	('BCK', 'molecular_function', 'GO:0047323', ('132', '135'))	('ER', 'Gene', '2099', (102, 104))
51722	27650553	These experiments confirmed that WNT4 expression was solely ER-regulated in MM134 and 44PE; P4 and the PR antagonist RU486 had no effect, whereas WNT4 expression was E2-induced and ICI-reversed.	('PR', 'Gene', '5241', (103, 105))	('MM134', 'Chemical', '-', (76, 81))	('ICI', 'Chemical', '-', (181, 184))	('MM134', 'Var', (76, 81))	('44PE; P4', 'Var', (86, 94))	('RU486', 'Chemical', 'MESH:D015735', (117, 122))	('WNT4', 'Gene', (33, 37))	('ER', 'Gene', '2099', (60, 62))	('E2', 'Chemical', 'MESH:D004958', (166, 168))
51727	27650553	In T47D, WNT4 expression was solely PR-regulated, as P4 induced expression but E2 had no effect.	('expression', 'MPA', (64, 74))	('T47D', 'CellLine', 'CVCL:0553', (3, 7))	('WNT4', 'Gene', (9, 13))	('T47D', 'Var', (3, 7))	('PR', 'Gene', '5241', (36, 38))	('E2', 'Chemical', 'MESH:D004958', (79, 81))
51740	27650553	To model endocrine resistance during aromatase inhibitor therapy in ILC, we generated LTED variants of MM134 (134:L/A, L/B, L/D, and L/E; collectively referred to as 134:LTED) and 44PE (44:L/A and L/B; collectively referred to as 44:LTED) (Additional file 6: Figure S5a).	('MM134', 'Gene', (103, 108))	('L/D', 'Var', (124, 127))	('L/B', 'Var', (119, 122))	('L/E', 'Var', (133, 136))	('134:L/A', 'Var', (110, 117))	('MM134', 'Chemical', '-', (103, 108))
51747	27650553	Each 134:LTED cell line upregulated WNT4 vs parental MM134 cells in hormone-replete conditions (Fig.	('MM134', 'Chemical', '-', (53, 58))	('upregulated', 'PosReg', (24, 35))	('WNT4', 'Var', (36, 40))
51762	27650553	Because 44:LTED displayed maintained ER activity and WNT4 regulation, we hypothesized that siWNT4 combined with ICI may potentiate growth suppression.	('potentiate', 'PosReg', (120, 130))	('growth suppression', 'CPA', (131, 149))	('ICI', 'Chemical', '-', (112, 115))	('siWNT4', 'Var', (91, 97))	('ER', 'Gene', '2099', (37, 39))	('WNT4 regulation', 'MPA', (53, 68))	('regulation', 'biological_process', 'GO:0065007', ('58', '68'))
51767	27650553	ILC-LTED cells remained sensitive to the FGFR inhibitor PD173074, but the relative effect was equivalent with or without siWNT4 (Additional file 7: Figure S6b), suggesting that additional signaling pathways were activated during LTED to maintain viability.	('signaling pathways', 'Pathway', (188, 206))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('PD173074', 'Var', (56, 64))	('PD173074', 'Chemical', 'MESH:C115711', (56, 64))
51778	27650553	Oct-4 signaling was most strongly activated in 44:L/A but became ICI-sensitive in those cells.	('ICI', 'Chemical', '-', (65, 68))	('signaling', 'biological_process', 'GO:0023052', ('6', '15'))	('Oct-4', 'Gene', (0, 5))	('activated', 'PosReg', (34, 43))	('44:L/A', 'Var', (47, 53))	('Oct-4', 'Gene', '5460', (0, 5))
51780	27650553	Consistent with increased NF-kB activity, immunoblotting showed increased phospho-p65 and increased active NFKB1 (p50) in each ILC-LTED; notably, 134:L/E also showed increased levels of both RelB and c-Rel compared with MM134 (Fig.	('NFKB1', 'Gene', '4790', (107, 112))	('134:L/E', 'Var', (146, 153))	('increased', 'PosReg', (90, 99))	('c-Rel', 'Gene', '5966', (200, 205))	('increased', 'PosReg', (166, 175))	('p65', 'Gene', (82, 85))	('active', 'MPA', (100, 106))	('NFKB1', 'Gene', (107, 112))	('RelB', 'Gene', (191, 195))	('activity', 'MPA', (32, 40))	('increased', 'PosReg', (16, 25))	('RelB', 'Gene', '5971', (191, 195))	('p65', 'Gene', '5970', (82, 85))	('c-Rel', 'Gene', (200, 205))	('increased', 'PosReg', (64, 73))	('MM134', 'Chemical', '-', (220, 225))	('p50', 'Gene', (114, 117))	('p50', 'Gene', '4790', (114, 117))
51783	27650553	In 134:L/E, knockdown of TNF, TNFSF10 (TRAIL), NFKB2, and BCL3 had no effect on WNT4 expression (Additional file 10: Figure S9c, left); knockdown of REL, RELA, and RELB modestly suppressed WNT4 expression without reaching statistical significance (Additional file 10: Figure S9c, right), potentially due to compensation among individual Rel proteins.	('TNF', 'Gene', '7124', (30, 33))	('TNF', 'Gene', (25, 28))	('BCL3', 'Gene', (58, 62))	('NFKB2', 'Gene', (47, 52))	('RELB', 'Gene', '5971', (164, 168))	('TNFSF10', 'Gene', (30, 37))	('TRAIL', 'Gene', '8743', (39, 44))	('TNF', 'Gene', '7124', (25, 28))	('knockdown', 'Var', (136, 145))	('RELA', 'Gene', (154, 158))	('RELA', 'Gene', '5970', (154, 158))	('TNFSF10', 'Gene', '8743', (30, 37))	('TNF', 'Gene', (30, 33))	('TRAIL', 'Gene', (39, 44))	('WNT4', 'Gene', (189, 193))	('suppressed', 'NegReg', (178, 188))	('expression', 'MPA', (194, 204))	('RELB', 'Gene', (164, 168))	('NFKB2', 'Gene', '4791', (47, 52))	('BCL3', 'Gene', '602', (58, 62))
51784	27650553	However, targeting NFKB1 (siNFKB1) produced approximately 50 % suppression of WNT4 expression in 134:L/E, and this was not observed in 44:L/A (Fig.	('suppression', 'NegReg', (63, 74))	('NFKB1', 'Gene', '4790', (19, 24))	('NFKB1', 'Gene', (28, 33))	('WNT4', 'Gene', (78, 82))	('NFKB1', 'Gene', (19, 24))	('targeting', 'Var', (9, 18))	('NFKB1', 'Gene', '4790', (28, 33))
51785	27650553	The converse of this observation was not true; siWNT4 did not affect phosphorylation of p65 or activation of p100 to p52 (Fig.	('p65', 'Gene', (88, 91))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('siWNT4', 'Var', (47, 53))	('p52', 'Gene', (117, 120))	('p65', 'Gene', '5970', (88, 91))	('phosphorylation', 'MPA', (69, 84))	('p52', 'Gene', '4791', (117, 120))
51787	27650553	In examining putative NF-kB target genes, we found that CDKN1A (p21WAF1/CIP1) was strongly suppressed in ILC-LTED vs parental cells, and that siWNT4 induced CDKN1A (Fig.	('suppressed', 'NegReg', (91, 101))	('siWNT4', 'Var', (142, 148))	('p21WAF1/CIP1', 'Gene', (64, 76))	('CDKN1A', 'Gene', (157, 163))	('CDKN1A', 'Gene', (56, 62))	('p21WAF1/CIP1', 'Gene', '1026', (64, 76))
51790	27650553	The fold increase in CDKN1A upon siWNT4 was highest in cells that were growth-inhibited by siWNT4, specifically ILC vs IDC (Additional file 10: Figure S9e).	('IDC', 'Gene', '4000', (119, 122))	('increase', 'PosReg', (9, 17))	('IDC', 'Gene', (119, 122))	('siWNT4', 'Var', (91, 97))	('CDKN1A', 'Gene', (21, 27))
51791	27650553	This suggests that WNT4 suppresses CDKN1A and that the increase in CDKN1A/p21 upon WNT4 knockdown leads to the inhibition of proliferation.	('increase', 'PosReg', (55, 63))	('proliferation', 'CPA', (125, 138))	('knockdown', 'Var', (88, 97))	('p21', 'Gene', '1026', (74, 77))	('p21', 'Gene', (74, 77))	('suppresses', 'NegReg', (24, 34))	('CDKN1A', 'Gene', (35, 41))	('WNT4', 'Gene', (83, 87))	('inhibition', 'NegReg', (111, 121))
51792	27650553	6c, concurrent knockdown of CDKN1A and WNT4 partially reversed siWNT4-mediated growth inhibition in both 44PE and MM134.	('MM134', 'Chemical', '-', (114, 119))	('knockdown', 'Var', (15, 24))	('siWNT4-mediated', 'Gene', (63, 78))	('CDKN1A', 'Gene', (28, 34))
51799	27650553	Consistent with increased WNT4 expression in luminal A/PR-positive tumors, high WNT4 expression is associated with improved disease-specific survival among all ER-positive tumors and ER-positive IDCs (Fig.	('expression', 'MPA', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('WNT4', 'Gene', (80, 84))	('PR', 'Gene', '5241', (55, 57))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('high', 'Var', (75, 79))	('IDC', 'Gene', '4000', (195, 198))	('ER', 'Gene', '2099', (183, 185))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('improved', 'PosReg', (115, 123))	('disease-specific survival', 'CPA', (124, 149))	('ER', 'Gene', '2099', (160, 162))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('IDC', 'Gene', (195, 198))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
51809	27650553	Interestingly, potential ILC-specific modifiers of ER function were reported in recent large-scale genomic studies in which researchers identified differential expression and mutation of FOXA1 vs GATA3 and amplification of ESR1.	('FOXA1', 'Gene', '3169', (187, 192))	('GATA3', 'Gene', '2625', (196, 201))	('ESR1', 'Gene', (223, 227))	('mutation', 'Var', (175, 183))	('ER', 'Gene', '2099', (51, 53))	('FOXA1', 'Gene', (187, 192))	('ESR1', 'Gene', '2099', (223, 227))	('GATA3', 'Gene', (196, 201))
51810	27650553	However, we have not detected these aberrations in MM134 or 44PE (T. Du, K. Levine, M. J. Sikora, et al., unpublished manuscript; also see), and thus WNT4 regulation is likely mediated by other factors.	('regulation', 'biological_process', 'GO:0065007', ('155', '165'))	('MM134', 'Chemical', '-', (51, 56))	('44PE', 'Var', (60, 64))	('MM134', 'Var', (51, 56))
51869	22482764	They found that 30% of patients with stage I-III breast cancer harbored DTCs at diagnosis and those with DTCs had decreased disease-free survival (DFS) and overall survival (OS).	('DTCs', 'Var', (72, 76))	('patients', 'Species', '9606', (23, 31))	('overall survival', 'CPA', (156, 172))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('disease-free survival', 'CPA', (124, 145))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('decreased', 'NegReg', (114, 123))	('breast cancer', 'Disease', (49, 62))	('DTCs', 'Chemical', '-', (72, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('OS', 'Chemical', '-', (174, 176))	('DTCs', 'Chemical', '-', (105, 109))
51914	22482764	In a pooled analysis of 4703 patients, Braun and colleagues found the presence of DTCs in patients with operable breast cancer to be an independent risk factor for significantly decreased DFS and OS.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('patients', 'Species', '9606', (29, 37))	('presence', 'Var', (70, 78))	('decreased', 'NegReg', (178, 187))	('DTCs', 'Chemical', '-', (82, 86))	('breast cancer', 'Disease', (113, 126))	('DFS', 'Disease', (188, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('DTCs', 'Gene', (82, 86))	('patients', 'Species', '9606', (90, 98))	('OS', 'Chemical', '-', (196, 198))
52142	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))
52163	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))
52169	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))
52220	32403360	The mean values were 23 for Ki-67 and 25 for Top2alpha, and the medians were 18 for Ki-67 and 20 for Top2alpha.	('Top2alpha', 'Gene', (45, 54))	('Top2alpha', 'Gene', (101, 110))	('Ki-67', 'Var', (28, 33))	('Top2alpha', 'Gene', '7153', (45, 54))	('Top2alpha', 'Gene', '7153', (101, 110))
52274	32403360	We searched for discordances between tumoral foci in our patients (n = 37), and we encountered the following: 3 cases (8.1%) with histopathological mismatch, 13 (35.1%) with different grades of differentiation, 11 (29.8%) with ER status mismatch, 12 (32.4%) with PR status mismatch, 8 (21.6%) with molecular phenotype mismatch, and 17 (45.9%) cases with variable Ki-67.	('tumoral foci', 'Disease', 'MESH:C565785', (37, 49))	('patients', 'Species', '9606', (57, 65))	('tumoral foci', 'Disease', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('ER status mismatch', 'Var', (227, 245))
52365	18990752	Low levels of serotonin are clearly associated with increased frequency of migraine, and estrogen positively regulates serotonin.	('serotonin', 'MPA', (119, 128))	('serotonin', 'MPA', (14, 23))	('serotonin', 'Chemical', 'MESH:D012701', (14, 23))	('migraine', 'Disease', 'MESH:D008881', (75, 83))	('migraine', 'Disease', (75, 83))	('migraine', 'Phenotype', 'HP:0002076', (75, 83))	('serotonin', 'Chemical', 'MESH:D012701', (119, 128))	('Low', 'Var', (0, 3))
52452	16457686	Allelic imbalances of chromosomes 8p and 18q and their roles in distant relapse of early stage, node-negative breast cancer Identification of breast cancer patients at risk for postoperative distant relapse is an important clinical issue.	('Allelic imbalances', 'Var', (0, 18))	('patients', 'Species', '9606', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('imbalance', 'Phenotype', 'HP:0002172', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('imbalances', 'Phenotype', 'HP:0002172', (8, 18))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
52461	16457686	For example, cytogenetic studies have shown that the presence of an abnormal chromosome complement (aneuploidy) is associated with high tumor grade and invasive behavior, as well as with eventual disease progression.	('invasive behavior', 'CPA', (152, 169))	('aneuploidy', 'Disease', (100, 110))	('high tumor', 'Disease', (131, 141))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('abnormal chromosome', 'Phenotype', 'HP:0031411', (68, 87))	('high tumor', 'Disease', 'MESH:D009369', (131, 141))	('aneuploidy', 'Disease', 'MESH:D000782', (100, 110))	('associated', 'Reg', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('abnormal', 'Var', (68, 76))
52469	16457686	The study population consisted of lymph-node negative breast cancer patients who had received loco-regional treatment, consisting of mastectomy or tumorectomy followed by radiation therapy for T1-2N0M0 breast cancer at the University Hospital Antwerp and the general hospital Saint-Augustinus, Antwerp, Belgium between 1986 and 1992.	('breast cancer', 'Disease', (54, 67))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('breast cancer', 'Disease', (202, 215))	('patients', 'Species', '9606', (68, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('T1-2N0M0', 'Var', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
52502	16457686	Thus, it is conceivable that among the numerous genetic alterations in tumor cells, only a few events lead to the activation of oncogenes or the inactivation of TSGs, while most are random and non-specific to tumor development.	('activation', 'PosReg', (114, 124))	('TSG', 'Gene', '57045', (161, 164))	('tumor', 'Disease', (209, 214))	('alterations', 'Var', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('oncogenes', 'Protein', (128, 137))	('inactivation', 'NegReg', (145, 157))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('TSG', 'Gene', (161, 164))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('genetic alterations', 'Var', (48, 67))
52508	16457686	We hypothesized that IDC could be classified into two subtypes based on the critical TSG inactivation on either 18q or 8p (Fig.	('inactivation', 'Var', (89, 101))	('IDC', 'Gene', '4000', (21, 24))	('TSG', 'Gene', (85, 88))	('IDC', 'Gene', (21, 24))	('TSG', 'Gene', '57045', (85, 88))
52512	16457686	Moreover, the idea of distinct breast carcinogenesis pathways represented by specific allelic losses is also consistent with other CGH and LOH studies, suggesting that there is a preferential combination of genetic alterations.	('allelic losses', 'Var', (86, 100))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (31, 52))	('breast carcinogenesis', 'Disease', (31, 52))
52516	16457686	What are the putative tumor suppressor genes on 8p and 18q whose inactivation can lead to the formation of these two distinct types of IDC?	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('IDC', 'Gene', (135, 138))	('lead to', 'Reg', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('inactivation', 'Var', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('IDC', 'Gene', '4000', (135, 138))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))
52517	16457686	The identification of the TSG on 8p is an active research area in many laboratories, and linkage studies in some breast cancer families that do not have BRCA1 and BRCA2 mutations suggest that 8p12-22 is a candidate region.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('BRCA2', 'Gene', (163, 168))	('mutations', 'Var', (169, 178))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('BRCA1', 'Gene', '672', (153, 158))	('TSG', 'Gene', (26, 29))	('BRCA2', 'Gene', '675', (163, 168))	('BRCA1', 'Gene', (153, 158))	('TSG', 'Gene', '57045', (26, 29))
52518	16457686	Recently, DBC2 (deleted in breast cancer 2) was proposed as the candidate tumor suppressor gene on 8p22 because it was homozygously deleted in two breast tumors, and its expression was down-regulated in 50% of sporadic primary breast tumors.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('expression', 'MPA', (170, 180))	('tumor', 'Disease', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('DBC2', 'Gene', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('DBC2', 'Gene', '23221', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast tumors', 'Disease', (147, 160))	('breast tumors', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('breast tumors', 'Disease', (227, 240))	('breast tumors', 'Disease', 'MESH:D001943', (227, 240))	('down-regulated', 'NegReg', (185, 199))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('breast tumors', 'Phenotype', 'HP:0100013', (147, 160))	('breast cancer', 'Disease', (27, 40))	('deleted', 'Var', (132, 139))	('breast tumors', 'Phenotype', 'HP:0100013', (227, 240))
52523	16457686	Therefore, the genetic/epigenetic inactivation of MADH4 in IDC requires careful re-evaluation.	('MADH4', 'Gene', '4089', (50, 55))	('IDC', 'Gene', '4000', (59, 62))	('IDC', 'Gene', (59, 62))	('MADH4', 'Gene', (50, 55))	('genetic/epigenetic inactivation', 'Var', (15, 46))
52524	16457686	In conclusion, we feel that there may be an interesting association between LOH of 8p and 18q arms in regards to IDC cancer progression.	('IDC', 'Gene', '4000', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('LOH of 8p', 'Var', (76, 85))	('IDC', 'Gene', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('18q', 'Gene', (90, 93))
52624	14580258	Moreover, aHIF expression was associated with T3-T4 tumours and an S phase of more than 10%.	('expression', 'Var', (15, 25))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('aHIF', 'Gene', (10, 14))	('T3-T4 tumours', 'Disease', 'MESH:D005067', (46, 59))	('T3-T4 tumours', 'Disease', (46, 59))	('S phase', 'biological_process', 'GO:0051320', ('67', '74'))	('S phase', 'Disease', (67, 74))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('aHIF', 'Gene', '100750247', (10, 14))	('associated with', 'Reg', (30, 45))
52635	14580258	If we focus on HIF-1alpha, HIF-1alpha mRNA splicing variants have been shown to encode shorter forms of HIF-1alpha that could compete with the normal full-length protein.	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('HIF-1alpha', 'Gene', (27, 37))	('HIF-1alpha', 'Gene', (15, 25))	('HIF-1alpha', 'Gene', (104, 114))	('mRNA splicing', 'biological_process', 'GO:0000374', ('38', '51'))	('variants', 'Var', (52, 60))	('mRNA splicing', 'biological_process', 'GO:0000373', ('38', '51'))	('HIF-1alpha', 'Gene', '3091', (27, 37))	('mRNA splicing', 'biological_process', 'GO:0006371', ('38', '51'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('38', '51'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('38', '51'))	('HIF-1alpha', 'Gene', '3091', (104, 114))	('mRNA splicing', 'biological_process', 'GO:0000394', ('38', '51'))	('HIF-1alpha', 'Gene', '3091', (15, 25))