title: FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer.
abstract: Amplification of fibroblast growth factor receptor 1 (FGFR1) occurs in approximately 10% of breast cancers and is associated with poor prognosis. However, it is uncertain whether overexpression of FGFR1 is causally linked to the poor prognosis of amplified cancers. Here, we show that FGFR1 overexpression is robustly associated with FGFR1 amplification in two independent series of breast cancers. Breast cancer cell lines with FGFR1 overexpression and amplification show enhanced ligand-dependent signaling, with increased activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase-AKT signaling pathways in response to FGF2, but also show basal ligand-independent signaling, and are dependent on FGFR signaling for anchorage-independent growth. FGFR1-amplified cell lines show resistance to 4-hydroxytamoxifen, which is reversed by small interfering RNA silencing of FGFR1, suggesting that FGFR1 overexpression also promotes endocrine therapy resistance. FGFR1 signaling suppresses progesterone receptor (PR) expression in vitro, and likewise, amplified cancers are frequently PR negative, identifying a potential biomarker for FGFR1 activity. Furthermore, we show that amplified cancers have a high proliferative rate assessed by Ki67 staining and that FGFR1 amplification is found in 16% to 27% of luminal B-type breast cancers. Our data suggest 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.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. nicholas.turner@icr.ac.uk
authors.forename: Nicholas
authors.initials: N
authors.lastname: Turner
authors.forename: Alex
authors.initials: A
authors.lastname: Pearson
authors.forename: Rachel
authors.initials: R
authors.lastname: Sharpe
authors.forename: Maryou
authors.initials: M
authors.lastname: Lambros
authors.forename: Felipe
authors.initials: F
authors.lastname: Geyer
authors.forename: Maria A
authors.initials: MA
authors.lastname: Lopez-Garcia
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchio
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Iorns
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Cheryl
authors.initials: C
authors.lastname: Gillett
authors.forename: Anita
authors.initials: A
authors.lastname: Grigoriadis
authors.forename: Andrew
authors.initials: A
authors.lastname: Tutt
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D000077267:Fulvestrant; D005784:Gene Amplification; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis / Q000235:genetics*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D013629:Tamoxifen; D016222:Fibroblast Growth Factor 2; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3