Differential expression of FGFR-1 and -2 in hormone responsive and resistant murine mammary carcinomas

ANA SAHORES, TOMÁS GUILLARDOY, VICTORIA WARGON, CLAUDIA LANARI, CAROLINE LAMB

Washington

Congreso; Annual Meeting of the American Association of Cancer Research; 2013

AACR

Fibroblast growth factor (FGF) receptors (FGFRs) are dysregulated in a number of developmental and neoplastic conditions. Inhuman breast cancer samples we have previously demonstrated a significant association between FGFR2 expression and estrogenreceptors as well as a positive correlation of FGFR1 and high histological grade. Most breast carcinomas that express hormonereceptors respond initially to an endocrine therapy, but over time, they develop resistance (acquired hormone resistance). Othersfail to respond from the beginning (constitutive resistance). Using a breast cancer mouse model, we have previously demonstratedthat 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 expressionlevel of PRB. Moreover, we have demonstrated, in an antiprogestin-responsive tumor that FGFR2 activated by FGF2 released bythe stromal compartment participate in tumor growth activating PR. The aim of this study is to investigate the expression of FGF2,FGFR1, FGFR2 in C4-HI, C4-HIR and C4-2-HI tumor variants. By immunohistochemistry and western blot we observed adecrease in FGFR2 expression for C4-2-HI (p<0.001) and C4-HIR (p<0.01) as compared to C4-HI. Moreover, we found anincreased expression of FGF2 and FGFR1 by western blot (p<0.05) and immunohistochemistry in the epithelium of the resistanttumor variants. Similar results were obtained with another family of antiprogestin responsive and unresponsive tumors (59-HI and59-2-HI). These data suggest that in this mammary tumor model hormone resistance may be characterized by a switch fromparacrine to autocrine FGF2 signaling together with a decrease in FGFR2 and an increase in FGFR1. These results contribute tounderstand the role of the FGFR pathway in hormone resistance and support the use of FGFR inhibitors combined with hormonaltherapy to delay the onset of hormone resistance.