Background: Both epidemiological and experimental studies suggest that excessive alcohol exposure increases the risk for breast cancer and enhances metastasis/recurrence. We have previously demonstrated that alcohol enhanced the migration/invasion of breast cancer cells and cancer cells overexpressing ErbB2/HER2 were more sensitive to alcohol exposure. However, the underlying mechanisms remain unclear. This study was designed to investigate the mechanisms underlying alcohol-enhanced aggressiveness of breast cancer. Cancer stem cells (CSCs) play a critical role in cancer metastasis and recurrence.
Methods: We evaluated the effect of chronic alcohol exposure on mammary tumor development/metastasis in MMTV-neu transgenic mice and investigated the cell signaling in response to alcohol exposure in breast cancer cells overexpressing ErbB2/HER2.
Results and discussion: Chronic alcohol exposure increased breast cancer stem cell-like CSC population and enhanced the lung and colon metastasis in MMTV-neu transgenic mice. Alcohol exposure caused a drastic increase in CSC population and mammosphere formation in breast cancer cells overexpressing ErbB2/HER2. Alcohol exposure stimulated the phosphorylation of p38 gamma MAPK (p-p38 gamma) which was co-localized with phosphorylated ErbB2 and CSCs in the mammary tumor tissues. In vitro results confirmed that alcohol activated ErbB2/HER2 and selectively increased p-p38 gamma MAPK as well as the interaction between p38 gamma MAPK and its substrate, SAP97. However, alcohol did not affect the expression/phosphorylation of p38 alpha/beta MAPKs. In breast cancer cell lines, high expression of ErbB2 and p-p38 gamma MAPK was generally correlated with more CSC population. Blocking ErbB2 signaling abolished heregulin beta 1- and alcohol-stimulated p-p38 gamma MAPK and its association with SAP97. More importantly, p38 gamma MAPK siRNA significantly inhibited an alcohol-induced increase in CSC population, mammosphere formation and migration/invasion of breast cancer cells overexpressing ErbB2.
Conclusions: p38 gamma MAPK is downstream of ErbB2 and plays an important role in alcohol-enhanced aggressiveness of breast cancer. Therefore, in addition to ErbB2/HER2, p38 gamma MAPK may be a potential target for the treatment of alcohol-enhanced cancer aggressiveness.
[1]Anhui Med Univ, Sch Basic Med, Pathophysiol Dept, Hefei 230032, Anhui, Peoples R China.
[2]Univ Kentucky, Coll Med, Dept Pharmacol & Nutr Sci, Lexington, KY 40536 USA.
[3]Shanghai Univ Tradit Chinese Med, Dept Biochem, Shanghai 201203, Peoples R China.
[4]North Shore Long Isl Jewish Hlth System Hofstra U, Sch Med, Dept Surg, Manhasset, NY USA.
[5]Univ Kentucky, Coll Med, Dept Toxicol & Canc Biol, Lexington, KY 40536 USA.
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