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Overexpression of ErbB2 enhances ethanol-stimulated intracellular signaling and invasion of human mammary epithelial and breast cancer cells in vitro

Oncogene volume 22, pages 5281–5290 (2003)Cite this article

Abstract

Both epidemiological and experimental studies indicate that ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the molecular mechanisms underlying ethanol-mediated tumor promotion remain unknown. Overexpression of ErbB proteins in breast cancer patients is generally associated with poor prognosis. The ErbB proteins are a family of receptor kinases that include four closely related members: epidermal growth factor receptor (EGFR/ErbB1), ErbB2/neu, ErbB3, and ErbB4. Particularly, ErbB2 plays a pivotal role in ErbB-mediated activities. Here we demonstrated that amplification of ErbB2 expression sensitized a specific cellular response to ethanol. Human breast cancer cells or mammary epithelial cells with a high expression of ErbB2 exhibited an enhanced response to ethanol-stimulated cell invasion in vitro. Ethanol also stimulated cell proliferation; however, this stimulation was independent of ErbB2 levels. Ethanol triggered divergent intracellular signaling among cells expressing different ErbB2 levels. In the cells overexpressing ErbB2, ethanol was more effective in the activation of c-Jun NH2 terminal protein kinases (JNKs) and p38 mitogen-activated protein kinase (p38 MAPK) as well as the induction of reactive oxygen species (ROS) than the cells with normal ErbB2 expression. Blockage of either JNKs or p38 MAPK activation eliminated ethanol-mediated cell invasion. In contrast, the reduction of hydrogen peroxide concentration by catalase exposure had little effect on ethanol-induced cell invasion. These results indicated that ethanol-induced cell invasion was primarily mediated by JNKs and p38 MAPK, whereas the involvement of ROS formation might be minimal. Our study suggests that overexpression of ErbB2 may augment ethanol-elicited signaling and promote ethanol-stimulated tumor metastasis.

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Acknowledgements

We thank Kimberly A Bower for her reading of this manuscript. This research was supported by grants from the National Institutes of Health (AA12968 and CA90385) and a grant from Alcohol Beverage Medical Research Foundation.

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Authors and Affiliations

  1. Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Robert C Byrd Health Science Center, Morgantown, 26506, WV, USA

    Cuiling Ma, Hong Lin & Jia Luo

  2. Department of Dermatology, Xijing Hospital, Xian, 710032, People's Republic of China

    Cuiling Ma

  3. Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, 26505, WV, USA

    Stephen S Leonard & Xianglin Shi

  4. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, 70808, LA, USA

    Jianping Ye

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Correspondence to Jia Luo.

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Ma, C., Lin, H., Leonard, S. et al. Overexpression of ErbB2 enhances ethanol-stimulated intracellular signaling and invasion of human mammary epithelial and breast cancer cells in vitro. Oncogene 22, 5281–5290 (2003). https://doi.org/10.1038/sj.onc.1206675

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