Interaction between fibroblast growth factor receptors (FGFR) and progesterone receptors (PR) in mammary carcinomas.

JUAN PABLO CERLIANI, SEBASTIAN GIULIANELLI, CAROLINE A. LAMB, MARIA ALICIA GOROSTIAGA, VIRGINIA NOVARO, ALFREDO MOLINOLO, CLAUDIA LANARI

Colby Sawyer, New London, NH.

Congreso; Gordon Conference on Hormone action in development and cancer; 2007

Gordon

We have developed a murine model of breast cancer progression in which ductal, hormone-dependent (HD) carcinomas transit through different stages of hormone responsiveness retaining the expression of high levels of estrogen (ER) and progesterone receptors (PR). Unlike HD carcinomas, hormone-independent (HI) tumors do not need the exogenous administration of medroxyprogesterone acetate (MPA) to grow. In vitro, however, there are no differences in hormone responsiveness between both types, suggesting the involvement of host factors regulating in vivo tumor growth. We have previously observed a) an increase in FGFR (1-4) expression, mainly FGFR-2 and -3, in HI tumors and in HD tumors growing with MPA as compared with untreated HD tumors; b) higher levels of FGF-2 in stroma from HI tumors; c) that the pharmacological or genetic blockage of FGFR-2 on one hand and antiprogestins on the other hand, inhibited the stimulation induced by carcinoma associated fibroblasts (CAF) on epithelial cell growth. These data led us to postulate that the stroma from HI tumors participates regulating HI tumor growth and we proposed that FGF-2 is a paracrine growth factor which activates FGFR in the epithelial cells, which in turn activate PR. The aim of this study was to evaluate a direct interaction between PR and FGFR using our tumor model and T47D cells. Purified epithelial cells of C4-HI and T47D cells were seeded in chamber slides and after few days of culture, they were starved in 1% charcoalized fetal calf serum (chFCS) and treated with FGF-2 (50 ng/ml), MPA (10-8M) or vehicle for 16 Hs. Confocal imaging shows an intimate interaction between FGFR-2 and PR when the cells (C4-HI or T47D cells) were treated with FGF-2 or MPA. Under these experimental conditions there was almost no interaction between PR and FGR1, FGFR-3 or FGFR-4 (p<0.05). In a time course experiment we showed that the peak of co-localization was observed after 20 min of incubation (p<0.05). Inmunoprecipitation data using C4-HI cells confirmed confocal observations. These results show for the first time nuclear interactions between FGFR-2 and PR in breast cancer models. In addition, they are in agreement with our hypothesis regarding FGF-2 activating FGFR-2 in epithelial cells as a mechanism of PR ligand independent activation, and they suggest that the FGFR are potential targets in the treatment of hormone related breast cancer.