Testosterone-induced growth of S115 mouse mammary tumor cells is dependenton heparan sulfate

The androgen-induced proliferation of S115 mouse mammary tumor cells has be en suggested to involve autocrinic fibroblast growth factor signaling. Hepa ran sulfate proteoglycans are required for fibroblast growth factor signali ng, presumably due to their ability to alter binding of fibroblast growth f actors to their receptors. We have investigated the role of heparan sulfate proteoglycans in the testosterone-induced proliferation of S115 cells. We demonstrate that when the cells are treated with sodium chlorate, which inh ibits the sulfation of endogenous heparan sulfate proteoglycans, cell growt h becomes dependent on exogenous heparin. The shortest heparin oligosacchar ides supporting cell growth were octasaccharides, whereas dodecasaccharides were almost as effective as native heparin, The N-, 2-O-, and 6-O-sulfate groups of heparin were all required for full testosterone response. Treatme nt of S115 cells with chlorate or testosterone did not alter the expression of fibroblast growth factor receptors 1 or 3, whereas the expression of fi broblast growth factor receptor 2 was down-regulated. We have previously sh own that overexpression of syndecan-1 heparan sulfate proteoglycan renders S115 cells insensitive to testosterone and now demonstrate that this effect can be overcome by sodium chlorate treatment in combination with exogenous heparin. Our results suggest that heparin-like molecules are intimately in volved in the androgen-mediated proliferation of S115 cells. (C) 2001 Acade mic Press.