Journal article
ErbB2 and p38[gamma] MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis
Molecular cancer, Vol.15(1), 52
07/14/2016
DOI: 10.1186/s12943-016-0532-4
PMCID: PMC4944437
PMID: 27416801
Abstract
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. Keywords: Alcohol, Cancer stem cell, p38 gamma, MCF7-ErbB2, Metastasis, Tumor promotion
Details
- Title: Subtitle
- ErbB2 and p38[gamma] MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis
- Creators
- Mei Xu - University of KentuckyZhenhua Ren - University of KentuckyXin Wang - University of KentuckyAshley Comer - University of KentuckyJacqueline A Frank - University of KentuckyZun-ji KeYi Huang - North Shore-LIJ Health SystemZhuo Zhang - University of KentuckyXianglin Shi - University of KentuckySiying Wang - Anhui Medical UniversityJia Luo - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- Molecular cancer, Vol.15(1), 52
- DOI
- 10.1186/s12943-016-0532-4
- PMID
- 27416801
- PMCID
- PMC4944437
- NLM abbreviation
- Mol Cancer
- ISSN
- 1476-4598
- eISSN
- 1476-4598
- Publisher
- BioMed Central Ltd
- Grant note
- DOI: 10.13039/100000027, name: National Institute on Alcohol Abuse and Alcoholism, award: AA017226, AA015407
- Language
- English
- Date published
- 07/14/2016
- Description audience
- Academic
- Academic Unit
- Pathology
- Record Identifier
- 9984201121902771
Metrics
11 Record Views