Affiliations 

  • 1 School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
  • 2 Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
  • 3 School of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand
  • 4 School of Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
  • 5 UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang, Selangor, Malaysia
  • 6 Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Bandar Sungai Long, Selangor, Malaysia
Oncotarget, 2016 Sep 06;7(36):57633-57650.
PMID: 27192118 DOI: 10.18632/oncotarget.9328

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.