title: ErbB2 and p38γ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.|Pathophysiological Department, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, 230032, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Comer
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Frank
authors.affiliation: Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
authors.forename: Zun-Ji
authors.initials: ZJ
authors.lastname: Ke
authors.affiliation: Department of Surgery, North Shore Long Island Jewish Health System-Hofstra University School of Medicine, Manhasset, NY, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Pathophysiological Department, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, 230032, China. sywang@ahmu.edu.cn.
authors.forename: Siying
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA. jialuo888@uky.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000438:Alcohols / Q000009:adverse effects*; D000818:Animals; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000074288:Discs Large Homolog 1 Protein; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D048291:Mitogen-Activated Protein Kinase 12 / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000438:Alcohols; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D048291:Mitogen-Activated Protein Kinase 12; D018719:Erb-b2 Receptor Tyrosine Kinases; C513314:DLG1 protein, human; C508053:ERBB2 protein, human
keywords: Alcohol; Cancer stem cell; MCF7-ErbB2; Metastasis; Tumor promotion; p38 gamma