title: Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival.
abstract: Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.|Oral Cancer Research and Coordinating Center (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.|Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.
authors.forename: Kai Hung
authors.initials: KH
authors.lastname: Tiong
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.|Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Boon Shing
authors.initials: BS
authors.lastname: Tan
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.|Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Heng Lungh
authors.initials: HL
authors.lastname: Choo
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Felicia Fei-Lei
authors.initials: FF
authors.lastname: Chung
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.|Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Hii
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.|Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Si Hoey
authors.initials: SH
authors.lastname: Tan
authors.affiliation: School of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand.
authors.forename: Nelson Tze Woei
authors.initials: NT
authors.lastname: Khor
authors.affiliation: School of Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Shew Fung
authors.initials: SF
authors.lastname: Wong
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Sze-Jia
authors.initials: SJ
authors.lastname: See
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.|Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Yuen-Fen
authors.initials: YF
authors.lastname: Tan
authors.affiliation: UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang, Selangor, Malaysia.
authors.forename: Rozita
authors.initials: R
authors.lastname: Rosli
authors.affiliation: Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Bandar Sungai Long, Selangor, Malaysia.
authors.forename: Soon-Keng
authors.initials: SK
authors.lastname: Cheong
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.|School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004317:Doxorubicin / Q000737:chemistry; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C117476:FGF19 protein, human; D034741:RNA, Small Interfering; D005346:Fibroblast Growth Factors; D004317:Doxorubicin; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: FGF19; FGFR4; RNAi screen; breast cancer; fibroblast growth factor