Fibroblast growth factor receptors (FGFR) as potential therapeutic targets in breast cancer.

CERLIANI JP; NOVARO V; BOLADO J; LANARI C

San Diego, EEUU

Congreso; Advances in Breast Cancer Research, AACR; 2007

American Association of Cancer Research

Fibroblast growth factor receptors (FGFR) as potential therapeutic targets in breast cancer. Cerliani J. P., Novaro V., Bolado J., Lanari C. 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 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 blockage of FGFR-2 or 3 using siRNA FGFR, or the use of an antiprogestin, RU 486, inhibited the stimulation induced by carcinoma associated fibroblasts (CAF) on epithelial cell growth  d) nuclear co-localization between FGFR-2 and PR. These data led us to postulate that the stroma from HI tumors participates regulating HI tumor growth and we propose 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 therapeutic approach in vivo using a pharmacological inhibitor of the FGFRs, PD 173074 (PD; kindly provided by Pfizer) using the C4-HI tumor. First, we tested different concentrations of PD in vitro, evaluating the effect of PD on MPA, FGF-2 or CAF-induced cell proliferation. We have observed that 0,1 µM PD inhibited tumor cell proliferation induced by a) 10 nM MPA b) 50 ng/ml of FGF-2 c) co-culture with CAF (p<0,001) without affecting the control epithelial tumor cells (3H-thymidine uptake or calculating the % of  BrdU and cytokeratin positive cells in co-cultures). Similar observations were found in tridimensional cultures in matrigel. Next, we inoculated C4-HI cells sc into female BALB/c mice. When tumors reached a size of 20-40 mm2 mice were treated daily with PD (25mg/Kg, ip.), or RU 486 (10 mg/Kg s.c.), or with vehicle for ten days (n= 6/group). After 48 h, 3 mice per group were injected with BrdU (4 mg/mouse, ip) for 2 hours and then sacrificed. A decrease in tumor growth was observed in PD treated mice and tumor regression was observed in RU 486-treated mice. The inhibitory effect of PD on tumor growth was confirmed by immunohistochemistry evaluating the % of  BrdU positive cells (p<0.05) in each group.  In summary, these results are in agreement with our hypothesis regarding paracrine FGF-2 activating FGFR-2 which in turn activates PR inducing cell proliferation and they suggest that the FGFR are potential targets in the treatment of hormone related breast cancer.