Carcinoma‐associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: A role for the FGF‐2/FGFR‐2 axis

The mechanisms by which mammary carcinomas acquire hormone independence are still unknown. To study the role of cancer‐associated fibroblasts (CAF) in the acquisition of hormone‐independence we used a hormone‐dependent (HD) mouse mammary tumor and its hormone‐independent (HI) variant, which grows in vivo without hormone supply. HI tumors express higher levels of FGFR‐2 than HD tumors. In spite of their in vivo differences, both tumors have the same hormone requirement in primary cultures. We demonstrated that CAF from HI tumors (CAF‐HI) growing in vitro, express higher levels of FGF‐2 than HD counterparts (CAF‐HD). FGF‐2 activated the progesterone receptors (PR) in the tumor cells, thus increasing cell proliferation in both HI and HD tumors. CAF‐HI induced a higher proliferative rate on the tumor cells and in PR activation than CAF‐HD. The blockage of FGF‐2 in the co‐cultures or the genetic or pharmacological inhibition of FGFR‐2 inhibited PR activation and tumor cell proliferation. Moreover, in vivo, the FGFR inhibitor decreased C4‐HI tumor growth, whereas FGF‐2 was able to stimulate C4‐HD tumor growth as MPA. T47D human breast cancer cells were also stimulated by progestins, FGF‐2 or CAF‐HI, and this stimulation was abrogated by antiprogestins, suggesting that the murine C4‐HI cells respond as the human T47D cells. In summary, this is the first study reporting differences between CAF from HD and HI tumors suggesting that CAF‐HI actively participate in driving HI tumor growth. © 2008 Wiley‐Liss, Inc.