MMP-2 mediates ethanol-induced invasion of mammary epithelial cells over-expressing ErbB2.

Abstract

Ethanol is a tumor promoter and may enhance the metastasis of breast cancer. We have previously demonstrated that over-expression of ErbB2 promoted ethanol-mediated invasion of mammary epithelial cells and breast cancer cells. However, the underlying cellular/molecular mechanisms remain unknown. By gelatin zymography, we showed that over-expression of ErbB2 increased the production of matrix metalloproteinase-2 (MMP-2) and MMP-9 in human mammary epithelial cells (HB2). Transient or stable transfection of ErbB2 cDNA to HB2 cells upregulated the transcripts and the activity of the MMP-2/-9 gene promoter; the upregulation of MMP-2/-9 expression was mediated by p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinase (PI3K). Although ethanol, at physiologically relevant concentrations (100-400 mg/dl), did not affect the production of MMP-2/-9, it activated MMP-2 in HB2 cells over-expressing ErbB2 (HB2(ErbB2)), but not HB2 cells; it enhanced the cleavage of proform MMP-2 (72 kDa) to an active form (62 kDa). The activation was dependent on c-jun N-terminal kinases (JNKs) and reactive oxygen species (ROS). On the other hand, ethanol affected neither the expression nor the activation of MMP-9. Selective inhibitors of MMP-2 (SB-3CT and OA-Hy) and antioxidants significantly inhibited ethanol-stimulated invasion of HB2(ErbB2) cells. Furthermore, knocking down MMP-2 by small interference RNA also induced a partial blockage on ethanol-promoted invasion of HB2(ErbB2) cells. Thus, ethanol-stimulated invasion of cells over-expressing ErbB2 was mediated, at least partially, by MMP-2 activation.

• Authors: Zunji Ke, Hong Lin, Zhiqin Fan, Tian-Quan Cai, Rebecca A Kaplan, Cuiling Ma, Kimberly A Bower, Xianglin Shi, Jia Luo
• Journal: International journal of cancer (Int J Cancer) Vol. 119 Issue 1 Pg. 8-16 (Jul 01 2006) ISSN: 0020-7136 [Print] United States
• PMID: 16450376 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Blotting, Western
• Cell Culture Techniques
• Epithelial Cells (enzymology)
• Ethanol (pharmacology)
• Female
• Gene Expression Regulation
• Genes, erbB-2
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mammary Glands, Human (cytology, enzymology)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Polymerase Chain Reaction
• Reactive Oxygen Species (metabolism)
• Receptor, ErbB-2 (genetics)
• Transcription, Genetic
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)