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.
Highlights
Global gene profiling has uncovered previously unrecognized subtype of human breast cancer, including the so-called “triple-negative” or “basal-like” tumors characterized by estrogen/progesterone receptor negativity, lack of HER2 amplification and high frequency of p53 mutation [1,2,3,4,5,6]
Our results demonstrated the presence of an fibroblast growth factor receptor 4 (FGFR4)/fibroblast growth factor 19 (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
Through an unbiased lentiviral shRNA kinome library screen, we identified FGFR4 as a www.impactjournals.com/oncotarget receptor tyrosine kinase that is required for the survival of a subset of basal-like breast cancer cells
Summary
Global gene profiling has uncovered previously unrecognized subtype of human breast cancer, including the so-called “triple-negative” or “basal-like” tumors characterized by estrogen/progesterone receptor negativity, lack of HER2 amplification and high frequency of p53 mutation [1,2,3,4,5,6]. These refractory tumors are insensitive to effective hormonal therapy or herceptinbased therapy and have a poor prognosis compared to other subtypes [1, 7,8,9]. The importance of FGF/FGFR signaling in tumor pathogenesis has been highlighted in large-scale analyses of human cancer genomes, in which components of the FGF/FGFR signaling pathways were the most commonly amplified or mutated in human cancers [12, 17,18,19,20]
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