FGF2 overexpression promotes resistance to endocrine therapy in breast cancer by modulating hormone receptor expression and WNT signaling

MARTÍN C. ABBA; FIGUEROA, VIRGINIA; CLAUDIA LANARI; ANA SAHORES; CAROLINE A. LAMB

San Carlos de Bariloche

Simposio; South American Symposium in Signal Transduction and Molecular Medicine; 2018

SISTAM

Approximately two-thirds of breast cancers express hormone receptors and thus, endocrine therapy is the standard treatment. However, some patients are refractory or develop resistance after therapy, by mechanisms that may include deregulation of growth factor signaling pathways. Fibroblast growth factor 2 (FGF2) consists of a secreted low molecular weight form (LMW-FGF2) and several nuclear high molecular weight forms (HMW-FGF2). We previously demonstrated that FGF2-overexpression in endocrine responsive T47D-YA or T47D cell lines, induced endocrine resistance. The aim of this study was to explore the mechanism underlying endocrine resistance. We performed RNA-seq studies and found that the WNT signaling pathway was deregulated in LMW- and HMW-FGF2-transfected T47D-YA cells compared to control cells. Moreover, androgen receptors (AR) were upregulated in HMW-FGF2-overexpressing cells while progesterone (PR) and estrogen receptors were downregulated in both cell lines. These data were confirmed by Western blot studies and revealed that the decrease in PR isoform A (PRA) was more conspicuous than that of isoform B (PRB), resulting in a low PRA/PRB ratio, which is consistent with an endocrine resistant phenotype according to results previously published by our group. Moreover, preliminary results indicate that targeting AR and WNT pathways with the specific inhibitors, enzalutamide and LGK974, respectively, decrease cell proliferation of HMW-FGF2-overexpressing T47D cells. Our results suggest that targeting AR and/or WNT pathways may be an alternative therapy for endocrine-resistant breast carcinomas with low PR and high AR levels.