title: Carcinoma-associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: A role for the FGF-2/FGFR-2 axis.
abstract: 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.
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Giulianelli
authors.forename: Juan P
authors.initials: JP
authors.lastname: Cerliani
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lamb
authors.forename: Victoria T
authors.initials: VT
authors.lastname: Fabris
authors.forename: María C
authors.initials: MC
authors.lastname: Bottino
authors.forename: María A
authors.initials: MA
authors.lastname: Gorostiaga
authors.forename: Virginia
authors.initials: V
authors.lastname: Novaro
authors.forename: Adrián
authors.initials: A
authors.lastname: Góngora
authors.forename: Alberto
authors.initials: A
authors.lastname: Baldi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanari