Role of matrix metalloproteinase-2 in ethanol-induced invasion by breast cancer cells

J Gastroenterol Hepatol. 2006 Oct;21 Suppl 3:S65-8. doi: 10.1111/j.1440-1746.2006.04578.x.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Epithelial Cells / enzymology
  • Ethanol / pharmacology*
  • Gene Expression Regulation
  • Genes, erbB-2*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / enzymology*
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor, ErbB-2 / genetics
  • Transcription, Genetic
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Reactive Oxygen Species
  • Ethanol
  • Phosphatidylinositol 3-Kinases
  • Receptor, ErbB-2
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9