ErbB2 and p38γ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis

Mei Xu, Zhenhua Ren, Xin Wang, Ashley Comer, Jacqueline A. Frank, Zun Ji Ke, Yi Huang, Zhuo Zhang, Xianglin Shi, Siying Wang, Jia Luo

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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 p38γ MAPK (p-p38γ) 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-p38γ MAPK as well as the interaction between p38γ MAPK and its substrate, SAP97. However, alcohol did not affect the expression/phosphorylation of p38α/β MAPKs. In breast cancer cell lines, high expression of ErbB2 and p-p38γ MAPK was generally correlated with more CSC population. Blocking ErbB2 signaling abolished heregulin β1- and alcohol-stimulated p-p38γ MAPK and its association with SAP97. More importantly, p38γ MAPK siRNA significantly inhibited an alcohol-induced increase in CSC population, mammosphere formation and migration/invasion of breast cancer cells overexpressing ErbB2. Conclusions: p38γ MAPK is downstream of ErbB2 and plays an important role in alcohol-enhanced aggressiveness of breast cancer. Therefore, in addition to ErbB2/HER2, p38γ MAPK may be a potential target for the treatment of alcohol-enhanced cancer aggressiveness.

Original languageEnglish
Article number52
JournalMolecular Cancer
Issue number1
StatePublished - Jul 14 2016

Bibliographical note

Funding Information:
This research is supported by grants from the National Institutes of Health (NIH) (AA017226 and AA015407).

Publisher Copyright:
© 2016 Luo et al.


  • Alcohol
  • Cancer stem cell
  • MCF7-ErbB2
  • Metastasis
  • P38 gamma
  • Tumor promotion

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research


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