Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival

// Kai Hung Tiong 1, 2, 3 , Boon Shing Tan 1, 4 , Heng Lungh Choo 1, 5 , Felicia Fei-Lei Chung 5 , Ling-Wei Hii 1, 5 , Si Hoey Tan 1, 5 , Nelson Tze Woei Khor 6 , Shew Fung Wong 7 , Sze-Jia See 5 , Yuen-Fen Tan 1, 5 , Rozita Rosli 8 , Soon-Keng Cheong 9 , Chee-Onn Leong 5, 10 1 School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia 2 Oral Cancer Research and Co-ordinating Center (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia 3 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia 4 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 5 Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia 6 School of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand 7 School of Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia 8 UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang, Selangor, Malaysia 9 Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Bandar Sungai Long, Selangor, Malaysia 10 School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia Correspondence to: Chee-Onn Leong, email: cheeonn_leong@imu.edu.my Keywords: fibroblast growth factor, breast cancer, RNAi screen, FGFR4, FGF19 Received: February 08, 2016      Accepted: April 26, 2016      Published: May 12, 2016 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.