¨Role of FGF2 pathway in murine hormone resistant mammary carcinomas¨

ANA SAHORES, M.S.; VICTORIA WARGON, PHD; CLAUDIA LANARI, PHD; CAROLINE ANA LAMB, PHD

San Diego, CA

Congreso; AACR; 2013

AACR

Fibroblast growth factor (FGF) receptors (FGFRs) are dysregulated in a number of developmental and neoplastic conditions. In human breast cancer samples we have previously demonstrated a significant association between FGFR2 expression and estrogen receptors as well as a positive correlation of FGFR1 and high histological grade. Most breast carcinomas that express hormone receptors respond initially to an endocrine therapy, but over time, they develop resistance (acquired hormone resistance). Others fail to respond from the beginning (constitutive resistance). Using a breast cancer mouse model, we have previously demonstrated that antiprogestin-responsive tumors (C4-HI) show a higher expression level of progesterone receptor isoform A than PR isoform B (PRB), while tumors with constitutive (C4-2-HI) or acquired resistance (C4-HIR) to antiprogestins, display a higher expression level of PRB. Moreover, we have demonstrated, in an antiprogestin-responsive tumor that FGFR2 activated by FGF2 released by the stromal compartment participate in tumor growth activating PR. In recent experiments, we observed a decreased expression of FGFR2 in hormone resistant compared to hormone responsive variants. Conversely, we found an increased expression of FGF2 and FGFR1 in hormone resistant variants. The aim of this study is to evaluate the role of the FGF2-pathway in hormone resistant tumor variants. In primary cultures from hormone resistant C4-2-HI epithelial cells, we found that FGF2 (100 ng/ml) significantly increased cell proliferation (p<0,001) measured by 3H-thymidine uptake. Two different FGFR inhibitors, PD 173074 (0,1-1 µM) and BGJ398 (0,1-10 nM), significantly inhibited basal and FGF2-induced cell proliferation. In ongoing in vivo experiments, we are investigating the effect of blocking the PR and FGFR-pathways on hormone resistant compared to hormone responsive tumor growth. These data suggest that in this mammary tumor model FGF2 may be driving hormone resistant tumor growth mainly through FGFR1 autocrine signaling, in contrast to the paracrine signaling observed in hormone responsive carcinomas. These results contribute to understand the role of the FGFR pathway in hormone resistance and support the use of FGFR inhibitors combined with hormonal therapy to delay the onset of hormone resistance.