OVEREXPRESSION OF FGF2 MODULATES HOR- MONE RECEPTOR EXPRESSION AND INDUCES ENDO- CRINE RESISTANCE AND BREAST CANCER PROGRES- SION

FIGUEROA V; SAHORES A; VANZULLI S; MAY M; ABBA MC; JACOBSEN BM; MOLINOLO A; LANARI C; LAMB CA

Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

Endocrine therapy is the standard treatment for patients with lu-minal breast cancer. However, resistance may develop as a con-sequence of enhanced growth factor signaling. Fibroblast growthfactor 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 endocrine resistantmammary carcinomas display levels of progesterone receptor (PR)isoform A (PRA) lower than those of isoform B (PRB) and high lev-els of HMW-FGF2 compared to responsive tumors. Also, LMW- orHMW-FGF2 overexpression in human hormone responsive T47D-YA cells, engineered to only express PRA, induced endocrine resis-tance. To further understand the mechanism of FGF2-induced en-docrine resistance, we performed RNA-seq studies comparing both,LMW- and HMW-FGF2-transfected cells compared to control cells.We identified deregulated pathways related to hormone resistance,tumor invasiveness and cellular adhesion in FGF2-overexpressingcells. PR and estrogen receptor α (ER) were downregulated whileandrogen receptor was upregulated in cells overexpressing FGF2.As observed in the T47D-YA model, T47D cells, which expressendogenous levels of both PR isoforms and were transfected withLMW- or HMW-FGF2, also developed endocrine resistance both invitro and in vivo. Moreover, these tumor xenografts showed high mi-totic activity, vascular emboli, and lung metastasis that were absentin control xenografts. In concordance with RNA-seq assays, West-ern blot studies revealed a decrease in ER and PR expression inFGF2-overexpressing cells compared to control cell lines, togetherwith a more pronounced decrease of PRA than that of PRB, result-ing in a low PRA/PRB ratio. In conclusion, our results suggest thatan increase in intrinsic FGF2 associated with low PRA/PRB ratiosprovides a novel mechanism to explain endocrine resistance and metastatic dissemination.Keywords: Breast cancer; FGF2; hormone resistance, progester-one receptor, estrogen receptor.