title: Androgen and fibroblast growth factor (FGF) regulation of FGF receptors in S115 mouse mammary tumor cells.
abstract: We studied the androgen regulation of fibroblast growth factor (FGF) receptors (FGFRs) in the Shionogi 115 (S115) mouse mammary tumor cell line and its genetic variant Clone 22. In S115 cells, androgen maintains a transformed morphology, rate of proliferation, and serum and anchorage independence. Similar effects were induced by treatment of the cells with FGF-2 or a heparin-binding growth factor (HBGF) fraction prepared from the medium conditioned by the cells. The effects of androgen and FGF-2 could be partly reversed with a specific anti-FGF-2 immunoglobulin G or by suramin, which inhibits binding of FGFs to their high affinity 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 sulfate proteoglycan that binds FGF with low affinity. The binding of radiolabeled FGF-2 to FGFRs was lower in the cells cultured with testosterone or in the presence of the HBGFs from androgen-treated cells, presumably because of the autocrine production of FGF-like factors. In Clone 22 cells, FGFRs and syndecan-1 responded to androgen as in S115 cells, but they were less sensitive to FGF-2. Androgen or FGF-2 could not induce morphological transformation, although both stimulated proliferation. Androgen-increased proliferation was not, however, decreased by anti-FGF-2 immunoglobulin G in Clone 22 cells. These data suggest that of the HBGFs produced, FGF-2 is required in androgen induction of morphological change, whereas the effect on proliferation involves other factors as well (perhaps mostly FGF-8). The results show that androgen differentially regulates the expression of the high and low affinity FGF receptors, which could mediate androgen induction of the transformed phenotype in S115 cells by an autocrine mechanism. The differential responses of the Clone 22 variant cells to androgen and FGF-2 suggest that the pathways of steroid induction of different parameters of the transformed phenotype, such as transition to fibroblastic morphology and stimulation of proliferation, are divergent.
authors.affiliation: Department of Anatomy, and MediCity Research Laboratory, University of Turku, Finland.
authors.forename: J K
authors.initials: JK
authors.lastname: Ruohola
authors.forename: E M
authors.initials: EM
authors.lastname: Valve
authors.forename: S
authors.initials: S
authors.lastname: Vainikka
authors.forename: K
authors.initials: K
authors.lastname: Alitalo
authors.forename: P L
authors.initials: PL
authors.lastname: Härkönen
mesh_terms: D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D003001:Cloning, Molecular; D017931:DNA Primers; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006133:Growth Substances / Q000096:biosynthesis*; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D053668:Syndecan-1; D053667:Syndecans; D013739:Testosterone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; C496457:Fgf8 protein, mouse; D006133:Growth Substances; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D051524:Fibroblast Growth Factor 8; D013739:Testosterone; D005346:Fibroblast Growth Factors