Intrinsic FGF2 induces endocrine resistance in breast cancer: Differential role between low and high molecular weight FGF2 isoforms in tumor progression

MAY, MARÍA; SEQUEIRA, GONZALO; LANARI, CLAUDIA; FIGUEROA, VIRGINIA; JACOBSEN, BRITTA; MOLINOLO, ALFREDO; SAHORES, ANA; ABBA, MARTIN; ÁLVAREZ, MICHELLE MARILYN; LAMB, CAROLINE A.

Sunday River

Congreso; Gordon Research Conference; 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. FGF2 consists of a secreted low molecular weight form (LMW-FGF2) and several nuclear high molecular weight forms (HMW-FGF2) but most attention has focused in signaling through LMW-FGF2. The role of the intracrine signaling related to HMW-FGF2 forms remains poorly understood. We previously demonstrated that endocrine resistant mammary carcinomas display levels of progesterone receptor (PR) isoform A (PRA) lower than those of isoform B (PRB). In this study, we show that this is associated with high levels of HMW-FGF2. HMW-FGF2 overexpression in human hormone responsive T47D-YA cells, engineered to only express PRA, induced an increase in tumor growth, spontaneous lung metastasis, and endocrine resistance with a concomitant decrease in estrogen receptor α (ERα) and PR expression. Similar results were obtained in T47D cells; the decrease in PRA expression proved more pronounced than that of PRB, resulting in a low PRA/PRB ratio. RNA-seq studies identified deregulated pathways related to hormone resistance and xenobiotic metabolism. In conclusion, the increase in intrinsic HMW-FGF2 associated with low PRA/PRB ratios provides a novel mechanism to explain endocrine resistance.