ANDROGEN AND FIBROBLAST GROWTH-FACTOR (FGF) REGULATION OF FGF RECEPTORS S115 MOUSE MAMMARY-TUMOR CELLS

We studied the androgen regulation of fibroblast growth factor (FGF) r eceptors (FGFRs) in the Shionogi 115(S115) mouse mammary tumor cell li ne and its genetic variant Clone 22. In S115 cells, androgen maintains a transformed morphology, rate of proliferation, and serum and anchor age independence. Similar effects were induced by treatment of the cel ls with FGF-2 or a heparin-binding growth factor (HBGF) fraction prepa red from the medium conditioned by the cells. The effects of androgen and FGF-2 could be partly reversed with a specific anti-FGF-2 immunogl obulin G or by suramin, which inhibits binding of FGFs to their high a ffinity receptors. Testosterone and FGF-2 increased the expression of FGFR-1 messenger RNA (mRNA) and, to a lesser extent, FGFR-3 mRNA, but down-regulated FGFR-2 mRNA in S115 cells. No FGFR-4 mRNA was detected. FGF-2 also down-regulated the expression of syndecan-1, a heparan sul fate proteoglycan that binds FGF with low affinity. The binding of rad iolabeled FGF-2 to FGFRs was lower in the cells cultured with testeste rone or in the presence of the HBGFs from androgen-treated cells, pres umably because of the autocrine production of FGF-Like factors. In Clo ne 22 cells, FGFRs and syndecan-1 responded to androgen as in S115 cel ls, but they were less sensitive to FGF-2. Androgen or FGF-2 could not induce morphological transformation, although both stimulated prolife ration. Androgen-increased proliferation was not, however, decreased b y anti-FGF-2 immunoglobulin G in Clone 22 cells. These data suggest th at of the HBGFs produced, FGF-2 is required in androgen induction of m orphological change, whereas the effect on proliferation involves othe r factors as well (perhaps mostly FGF-8). The results show that androg en differentially regulates the expression of the high and low affinit y FGF receptors, which could mediate androgen induction of the transfo rmed phenotype in S115 cells by an autocrine mechanism. The differenti al responses of the Clone 22 variant cells to androgen and FGF-2 sugge st that the pathways of steroid induction of different parameters of t he transformed phenotype, such as transition to fibroblastic morpholog y and stimulation of proliferation, are divergent.