Role of matrix metalloproteinase-2 in ethanol-induced invasion by breast cancer cells.
Ethanol is a tumor promoter and may enhance the metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Amplification of ErbB2, a receptor tyrosine kinase, is found in 20-30% of breast cancer patients. Ethanol preferably stimulates invasion by breast cancer cells over-expressing ErbB2 in vitro. Over-expression of ErbB2 is positively associated with elevated levels of matrix metalloproteinase-2 (MMP-2) and MMP-9. Ethanol at physiologically relevant concentrations activates MMP-2 without altering its expression level in mammary epithelial cells over-expressing ErbB2, but not in cells expressing low levels of ErbB2. The activation is dependent on c-jun N-terminal kinases (JNK) and reactive oxygen species. Selective inhibitors of MMP-2 and anti-oxidants significantly inhibit ethanol-stimulated cell invasion. Similarly, knocking down MMP-2 by small interference RNA induces a partial blockage on ethanol-promoted cell invasion. Matrix metalloproteinase-2 is predominantly expressed in stromal fibroblasts; ethanol also activates fibroblastic MMP-2. The conditioned medium collected from ethanol-exposed fibroblasts dramatically stimulates the invasion of breast cancer cells. The role of MMP-2 in ethanol-induced tumor promotion is discussed.
Luo
Jia
J
Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C Byrd Health Sciences Center, Morgantown, West Virginia 26506, USA. jluo@hsc.wvu.edu
D004847:Epithelial Cells / Q000201:enzymology; D000431:Ethanol / Q000494:pharmacology*; D005786:Gene Expression Regulation; D018734:Genes, erbB-2; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000431:Ethanol; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases