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MMP‐2 mediates ethanol‐induced invasion of mammary epithelial cells over‐expressing ErbB2
Author(s) -
Ke Zunji,
Lin Hong,
Fan Zhiqin,
Cai TianQuan,
Kaplan Rebecca A.,
Ma Cuiling,
Bower Kimberly A.,
Shi Xianglin,
Luo Jia
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21769
Subject(s) - biology , matrix metalloproteinase , transfection , kinase , downregulation and upregulation , microbiology and biotechnology , p38 mitogen activated protein kinases , mapk/erk pathway , cancer research , cell culture , biochemistry , gene , genetics
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. © 2006 Wiley‐Liss, Inc.