Matrix metalloproteinases (MMPs) play an important role in cancer metastasis. Here. we investigated the effect of fibroblast growth factor-2 (FGF-2) and 12-O-tetradecanoylphorbol-13-acetate (TPA) on the secretion of type IV collagenases (MMP-2, MMP-9) in breast cancer MCF-7 cells. As shown by gelatin zymography, both FGF-2 and TPA stimulated the secretion of MMP-9 in MCF-7 cells while they did not change the level of MMP-2 secretion. Signaling cascade studies indicated that both FGF-2 and TPA induced Ras activation. c-Raf phosphorylation, mitogen-activated protein kinase/ERK kinase (MEK1,2) phosphorylation, and extracellular signal-regulated kinase (ERK1,2) phosphorylation. The FGF-2- and TPA-induced MMP-9 secretion was significantly inhibited by transient transfection of MCF-7 cells with dominant negative Ras (Ras-N17) and by treatment with MEK1/2 inhibitor PD98059 A pan-protein kinase C (PKC) inhibitor, GF109203X, was found to totally abolish the FGF-2- and TPA-induced MMP-9 secretion and ERK1,2 phosphorylation. Use of isoform-specific PKC inhibitors such as Rotllerin and Go6976 Suggested, moreover, that the PKC-delta isoform is a likely component of FGF-2 and TPA trophic signaling, These results demonstrated that FGF-2 and TPA induce MMP-9 secretion in MCF-7 cells mainly through PKC-dependent activation of the Ras/ERK1/2 signaling pathway. (C) 2002 Elsevier Science (USA). All rights reserved.