Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, TX 77030, USA

Correspondence to: D Yu, Department of Surgical Oncology, Box 107, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, TX 77030, USA; E-mail: dyu@mdacc.org

^aJ Yao and S Xiong contributed equally to this paper

Matrix metalloproteinase-9 (MMP-9) plays important roles in tumor invasion and angiogenesis. Secretion of MMP-9 has been reported in various cancer types including lung cancer, colon cancer, and breast cancer. In our investigation of MMP-9 regulation by growth factors, MMP-9 was activated by heregulin-1 as shown by zymography in both SKBr3 and MCF-7 breast cancer cell lines. Increase in MMP-9 activity was due to increased MMP-9 protein and mRNA levels, which mainly results from transcriptional upregulation of MMP-9 by heregulin-1. Heregulin-1 activates multiple signaling pathways in breast cancer cells, including Erk, p38 kinase, PKC, and PI3-K pathways. We examined the pathways involved in heregulin-1-mediated MMP-9 activation using chemical inhibitors that specifically inhibit each of these heregulin-1-activated pathways. The PKC inhibitor RO318220 and p38 kinase inhibitor SB203580 completely blocked heregulin-1-mediated activation of MMP-9. MEK-1 inhibitor PD098059 partially blocked MMP-9 activation, whereas PI3-K inhibitor wortmannin had no effect on heregulin-1-mediated MMP-9 activation. Therefore, at least three signaling pathways are involved in the activation of MMP-9 by heregulin-1. Since MMP-9 is tightly associated with invasion/metastasis and angiogenesis, our studies suggest that blocking heregulin-1-mediated activation of MMP-9 by inhibiting the related signaling pathways may provide new strategies for inhibition of cancer metastasis and angiogenesis. Oncogene (2001) 20, 8066-8074.

MMP-9; heregulin-1; signaling; breast cancer; invasion

MMP-9, matrix metalloproteinase-9; Erk, extracellular response kinase; PKC, protein kinase C; PI3-K, phosphatidylinositol 3-kinase; PMA, phorbol 12-myristate 13-acetate; JNK, Jun amino-terminus kinase; TGF, transforming growth factor.