INTERACTION BETWEEN FIBROBLAST GROWTH FACTOR RECEPTORS (FGFR) AND PROGESTERONE RECEPTORS (PR) IN MAMMARY CARCINOMAS

CERLIANI JUAN PABLO; GIULIANELLI SEBASTIÁN; LAMB CAROLINE; GOROSTIAGA MARIA ALICIA; NOVARO VIRGINIA; MOLINOLO ALFREDO; LANARI CLAUDIA

Colby-Sawyer College New London, NH.

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

We have previously shown using the medroxyprogesterone acetate (MPA) mouse mammary cancer model, that a) carcinoma-associated fibroblasts from hormone-independent (HI) tumors expressed levels of FGF-2 and FGFR-1-4 higher than those of fibroblasts from hormone-dependent (HD) tumors, b) FGFR localized to the cell nucleus by immunohistochemistry, c) MPA increased the expression of FGFR-2 and FGFR-3, c) FGFR-2 or FGFR-3 siRNAs inhibited cell proliferation and e) the blockage of PR induced tumor regression. On these bases, we theorize that in HI tumors, stromal cells-derived FGFs could be activating FGFR in epithelial cells which would in turn activate PR, mimicking progesterone’s action. In this study we focused on the interaction between PR and FGFR. For this purpose we used primary cultures from the C4-HI tumor of our MPA mouse model and the T47D human breast cancer cells. Immunofluorescence studies were performed using the monoclonal Ab 7 PR antibody and the rabbit polyclonal FGFR-2 or FGFR-3 antibodies. Co-localization of PR with FGFR-2 but not FGFR-3 was observed in the nuclei of the epithelial tumor cells using a confocal microscope. Moreover, the incubation of the cells with FGF 2(50ng/ml) or with MPA (10 nM) induced an increase in co-localization. Co-immunoprecipitation assays using nuclear extracts of these cells and two different PR antibodies indicate that PR isoform A is involved in this interaction. The nuclear interaction of PR and FGFR-2 was also observed in T47D cells. Preliminary data showed that carcinoma associated fibroblasts from HI tumors also potentiated T47D cell proliferation. These results suggest novel interactions between progesterone receptors and fibroblast growth factor receptors at the cell nuclei which may be responsible of the HI phenotype; this interaction seems not to be exclusive of our murine cells. In addition, these results support our working hypothesis regarding the role of stromal cells in the onset of the HI phenotype.