FGFR Signaling Promotes the Growth of Triple-Negative and Basal-Like Breast Cancer Cell Lines Both In Vitro and In Vivo

Abstract

Purpose: The oncogenic drivers of triple-negative (TN) and basal-like breast cancers are largely unknown. Substantial evidence now links aberrant signaling by the fibroblast growth factor receptors (FGFR) to the development of multiple cancer types. Here, we examined the role of FGFR signaling in TN breast cancer.Experimental Design: We examined the sensitivity of a panel of 31 breast cancer cell lines to the selective FGFR inhibitor PD173074 and investigated the potential mechanisms underlying sensitivity.Results: TN breast cancer cell lines were more sensitive to PD173074 than comparator cell lines (P ¼ 0.011), with 47% (7/15) of TN cell lines showing significantly reduced growth. The majority of TN cell lines showed only modest sensitivity to FGFR inhibition in two-dimensional growth but were highly sensitive in anchorage-independent conditions. PD173074 inhibited downstream mitogen-activated protein kinase and PI3K-AKT signaling and induced cell-cycle arrest and apoptosis. Basal-like breast cancer cell lines were found to express FGF2 ligand (11/21 positive) and, similarly, 62% of basal-like breast cancers expressed FGF2, as assessed by immunohistochemistry compared with 5% of nonbasal breast cancers (P < 0.0001). RNA interference targeting of FGF2 in basal-like cell lines significantly reduced growth in vitro and reduced down stream signaling, suggesting an autocrine FGF2 signaling loop. Treatment with PD173074 significantly reduced the growth of CAL51 basal-like breast cancer cell line xenografts in vivo.Conclusions: Basal-like breast cancer cell lines, and breast cancers, express autocrine FGF2 and show sensitivity to FGFR inhibitors, identifying a potential novel therapeutic approach for these cancers.

Tackling the Diversity of Triple-Negative Breast Cancer

“…The mesenchymal stem-like subtype, in particular, describes a similar group of cancers previously described as claudin-low (24), that have lower proliferation relative to those of basal-like TNBCs, and are enriched for the expression of genes associated with a cancer stem cell-like (or tumor-initiating cell-like) phenotype (24). Multiple growth factor pathways are expressed at high levels in mesenchymal-like TNBCs, with the expression of the FGF2 ligand being an important autocrine growth factor in these cancers (37). Metaplastic breast cancers, especially those composed of spindle cells, may frequently fall in this subtype (25).…”

Amplification of FRS2 and Activation of FGFR/FRS2 Signaling Pathway in High-Grade Liposarcoma

“…We also found that FGFR inhibitors suppressed the activation of ERK and PI3K signaling pathways. Similarly, studies on breast cancer cells showed that PD173074 selectively inhibits FGFR tyrosine kinase activity, mitogen-activated protein kinase (MAPK), and PI3K signaling pathways (41,42). FRS2 itself is also a potentially attractive target for disruption of the mitogenic and tumorigenic effects of multiple FGFs.…”

Targeting FGFR Signaling in Cancer

“…Aberrant loops result from increased release of FGFs by tumor or stromal cells, promoting proliferation, survival, and angiogenesis. Interestingly, several studies have associated these aberrant loops with antitumor activity of either tyrosine kinase inhibitors (TKI) or antibodies directed against FGFR ligands (54)(55)(56). However, available data emerge mainly from preclinical work on cell line models, and further clinical confirmation is required.…”