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 Key words: alcohol; ErbB; metastasis; proteinases; signal transduction; oxidative stress Breast cancer is a leading cause of morbidity and mortality in women.1 The endogenous and environmental factors that contribute to its etiology remain elusive. Alcohol is a tumor promoter; there is a positive correlation between heavy alcohol intake and the risk of breast cancer.2-4 Epidemiological studies reveal that alcohol consumption is associated with advanced and invasive breast tumors, [5][6][7] suggesting that alcohol may enhance tumor development and metastasis. These epidemiological results are supported by experimental studies using animal models and cell culture systems, which consistently show that ethanol promotes mammary tumorigenesis and stimulates proliferation, as well as the invasion of breast cancer cells. [8][9][10][11][12][13][14][15][16] The molecular mechanisms underlying ethanol action, however, remain to be determined.The ErbB family of receptor kinases includes 4 closely related members: epidermal growth factor receptor (EGFR or ErbB1), ErbB2, ErbB3 and ErbB4. Among the family, ErbB2 is most directly related to breast cancer. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis.17 Over-expression of ErbB2 is positively correlated with lymph node metastasis in breast cancer patients. 18,19 Although no known ligand has been identified, ErbB2 is the preferred heterodimerization partner for all ErbB family members, and it plays a pivotal role in intracellular signaling mediated by other ErbB receptors. 20 The status of ErbB2 expression in a given cell is critical in determining the cellular response to growth factors or environmental stimuli. [21][22][23] We have previously shown that over-expression of ErbB2 dramatically promoted ethanol-induced invasion of mammary epithelial cells and breast tumor cells.12 The present study was designed to determine the underlying molecular mechanisms.The metastasis of cancer cells involves multiple steps. Tumor cells must first detach from the tumor mass and invade the surrounding extracellular m...

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