title: Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ.
abstract: Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12-48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the scattering of MCF7, BT20 and T47D cell colonies in a 3-dimension culture system. Chronic ethanol exposure also increased colony formation in an anchorage-independent condition and stimulated cell invasion/migration. Chronic ethanol exposure increased cancer stem-like cell (CSC) population by more than 20 folds. Breast cancer cells exposed to ethanol in vitro displayed a much higher growth rate and metastasis in mice. Ethanol selectively activated p38γ MAPK and RhoC but not p38α/β in a concentration-dependent manner. SP-MCF7 cells, a derivative of MCF7 cells which compose mainly CSC expressed high levels of phosphorylated p38γ MAPK. Knocking-down p38γ MAPK blocked ethanol-induced RhoC activation, cell scattering, invasion/migration and ethanol-increased CSC population. Furthermore, knocking-down p38γ MAPK mitigated ethanol-induced tumor growth and metastasis in mice. These results suggest that chronic ethanol exposure can enhance the aggressiveness of breast cancer by activating p38γ MAPK/RhoC pathway.
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 23002, China.
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.|Pathophysiological Department, School of Basic Medicine, Anhui Medical University, Hefei, Anhui 23002, 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: Jacqueline A
authors.initials: JA
authors.lastname: Frank
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Xiuwei H
authors.initials: XH
authors.lastname: Yang
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 Biochemistry, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Zun-Ji
authors.initials: ZJ
authors.lastname: Ke
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: Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000633:toxicity; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
chemical_list: D002492:Central Nervous System Depressants; D034741:RNA, Small Interfering; D000431:Ethanol; D048051:p38 Mitogen-Activated Protein Kinases; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein
keywords: alcohol abuse; cancer stem cells; mammary tumor; metastasis