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.

Estrogen Receptor Alpha Mediates Progestin-Induced Mammary Tumor Growth by Interacting with Progesterone Receptors at the Cyclin D1/MYC Promoters

“…The fact that progestins exerted growth inhibitory effects on MDA-MB-231 cells stably transfected with PR (37) but stimulated cell proliferation in models that coexpress ERa and PR (11,12,15,16,38), also suggests that both receptors cooperate to trigger cell proliferation. In this regard, it is known that the human MYC gene A, confocal images of immunofluorescence using PR (Ab7) and ERa (SP1) antibodies in cells treated as described in Fig.…”

“…Human T47D cells obtained from American Type Culture Collection were validated by Genetica DNA Laboratories Inc. by short tandem repeat profiling and maintained as described (15). Passages lower than 15 were used.…”

Receptor Tyrosine Kinases in the Nucleus

“…The interaction of FGFR1 and the transcription factor Nurr 1 in the nucleus of dopaminergic neurons has been described (Baron et al 2012). Morphologic studies have recognized FGFR2 in the nucleus of tissue samples (Lu et al 2004;Schmahl et al 2004;Giulianelli et al 2008;Martin et al 2011), but without analysis of the size it is not possible to distinguish whether this represents an intact receptor or a receptor fragment.…”

Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

“…[10][11][12][13][14] FGF is one of the growth factors secreted by CAFs, which execute diverse functions by binding to and activating members of the fibroblast growth factor receptor 4 (FGFR4) family, such as cell survival, proliferation, and migration in a variety of cell types. 15,16 To date, 22 FGF genes have been identified in human, which are differentially expressed in many tissues.…”