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: Sebastián Giulianelli, Juan P Cerliani, Caroline A Lamb, Victoria T Fabris, María C Bottino, María A Gorostiaga, Virginia Novaro, Adrián Góngora, Alberto Baldi, Alfredo Molinolo, Claudia Lanari
• Journal: International journal of cancer (Int J Cancer) Vol. 123 Issue 11 Pg. 2518-31 (Dec 01 2008) ISSN: 1097-0215 [Electronic] United States
• PMID: 18767044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• Protein Kinase Inhibitors
• RNA, Small Interfering
• Receptors, Progesterone
• Fibroblast Growth Factor 2
• Progesterone
• Receptor, Fibroblast Growth Factor, Type 2

Topics

• Animals
• Breast Neoplasms (metabolism, pathology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Coculture Techniques
• Female
• Fibroblast Growth Factor 2 (pharmacology)
• Fibroblasts
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Inbred BALB C
• Progesterone (metabolism)
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• RNA, Small Interfering (genetics)
• Receptor, Fibroblast Growth Factor, Type 2 (antagonists & inhibitors, genetics, metabolism)
• Receptors, Progesterone (metabolism)
• Signal Transduction (drug effects)