Overexpression of FGF2 modulates hormone receptor expression and induces endocrine resistance and breast cancer progression

ALFREDO MOLINOLO; MARÍA MAY; VIRGINIA FIGUEROA; CLAUDIA LANARI; MARTÍN C. ABBA; CAROLINE A. LAMB; ANA SAHORES; BRITTAM. JACOBSEN; SILVIA VANZULLI

Capital Federal

Congreso; Sociedad argentina de investigación clinica; 2017

Endocrine therapy is the standard treatment for patients with luminal breast cancer. However, resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a secreted low molecular weight form (LMW-FGF2) and several nuclear high molecular weight forms (HMWFGF2). We previously demonstrated that endocrine resistant mammary carcinomas display levels of progesterone receptor (PR) isoform A (PRA) lower than those of isoform B (PRB) and high levels of HMW-FGF2 compared to responsive tumors. Also, LMW- or HMW-FGF2 overexpression in human hormone responsive T47D-YA cells, engineered to only express PRA, induced endocrine resistance. To further understand the mechanism of FGF2-induced endocrine resistance, we performed RNA-seq studies comparing both, LMW- and HMWFGF2-transfected cells compared to control cells. We identified deregulated pathways related to hormone resistance, tumor invasiveness and cellular adhesion in FGF2-overexpressing cells. PR and estrogen receptor α (ER) were downregulated while androgen receptor was upregulated in cells overexpressing FGF2. As observed in the T47D-YA model, T47D cells, which express endogenous levels of both PR isoforms and were transfected with LMW- or HMW-FGF2, also developed endocrine resistance both in vitro and in vivo. Moreover, these tumor xenografts showed high mitotic activity, vascular emboli, and lung metastasis that were absent in control xenografts. In concordance with RNA-seq assays, Western blot studies revealed a decrease in ER and PR expression in FGF2overexpressing cells compared to control cell lines, together with a more pronounced decrease of PRA than that of PRB, resulting in a low PRA/PRB ratio. In conclusion, our results suggest that an increase in intrinsic FGF2 associated with low PRA/PRB ratios provides a novel mechanism to explain endocrine resistance and metastatic dissemination.