STROMAL FGF-2 PARTICIPATES IN HORMONE INDEPENDENT TUMOR GROWTH

J.P. CERLIANI; S. GIULIANELLI; V.T. FABRIS; V. NOVARO; A. GÓNGORA; A. BALDI; A. MOLINOLO; C. LANARI; C.A. LAMB

Kos, Grecia

Conferencia; 8th International Conference of Anticancer Research; 2008

We have developed an experimental model of breast cancer in BALB/c female mice in which metastatic ductal mammary carcinomas transit through different stages of hormone dependence. Hormone-dependent (HD) tumors need the exogenous administration of progestins to grow while hormone-independent (HI) carcinomas grow in vivo without exogenous progestin supply, although they retain high levels of estrogen and progesterone receptors (PR). In vitro, however, there are no differences in hormone responsiveness between both tumor types, suggesting the involvement of host factors regulating in vivo tumor growth. The mechanisms by which mammary carcinomas acquire hormone independence are still unknown. The aim of this study was to evaluate the role of carcinoma-associated fibroblasts (CAF) in the acquisition of hormone independence. 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. 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. In vivo, an FGFR inhibitor decreased HI tumor growth and exogenous administration of FGF-2 to HD tumors promoted growth. 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.