Sodium Phenylacetate (NaPq) has been shown to suppress tumor growth and promote differentiation in experimental models. Thus, we have previously shown an inhibition of MCF-7ras cell proliferation by NaPa both in vitro and in vivo on xenographed tumors. In order to study the action of NaPa on the synthesis of paracrine or autocrine growth factors, conditioned media were prepared from breast pretumoral HBL100 cells, tumoral MCF-7 and MCF-7ras cells in the presence of NaPa. Growth factor activities of these media were tested on Balb c/3T3 fibroblasts and on the above breast tumor cells. Conditioned media from the 3 cell types contained different mitogenic activities when tested on the same cell lines. NaPa treatment for 24 hours inhibited differentially and dose-dependently the mitogenic activity of conditioned media. Inhibitions of HBL100 and MCF-7 cell proliferation by MCF-7ras medium conditioned with 20 mM NaPa reached 75% and 48% respectively. In contrast, NaPa treated MCF-7 conditioned medium decreased HBL100 and MCF-7ras proliferation by 49% and 72%, respectively, at the same NaPa concentration. The efficiency of NaPa inhibition reached an optimum as soon as one day after treatment. Among growth factors secreted by MCF-7 and MCF-7ras, TGF beta synthesis is inhibited and stimulated in MCF-7 and MCF-7ras cells respectively after NaPa treatment. We showed that NaPa modifies the synthesis of growth factors secreted by MCF-7 and MCF-7ras tumor cells leading to cell proliferation inhibitions. The synthesis of these previously identified factors was more involved in MCF-7 cells than fibroblast cell proliferation. In vitro and in vivo NaPa inhibition of MCF-7ras cells which secreted higher levels of these growth factors could be explained by this mechanism of action.