title: Alcohol promotes migration and invasion of triple-negative breast cancer cells through activation of p38 MAPK and JNK.
abstract: Although alcohol is an established breast cancer risk factor, the underlying mechanisms remain unclear. Previous studies examined the general association between alcohol consumption and breast cancer risk; however, the risk for different breast cancer subtypes has been rarely reported. Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking hormone receptors and HER2 expression, and having poor prognosis. Understanding the molecular mechanisms of TNBC etiology remains a significant challenge. In this study, we investigated cellular responses to alcohol in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. Our results showed that alcohol at low concentrations (0.025-0.1% v/v) induced cell proliferation, migration, and invasion in 1% FBS-containing medium. Molecular analysis indicated that these phenotypic changes were associated with alcohol-induced reactive oxygen species production and increased p38 and JNK phosphorylation. Likewise, p38 or JNK inhibition attenuated alcohol-induced cell migration and invasion. We revealed that alcohol treatment activated/phosphorylated NF-κB regulators and increased transcription of NF-κB-targeted genes. While examining the role of acetaldehyde, the major alcohol metabolite, in alcohol-associated responses in TNBC cells, we saw that acetaldehyde induced cell migration, invasion, and increased phospho-p38, phospho-JNK, and phospho-IκBα in a pattern similar to alcohol treatment. Taken together, we established that alcohol promotes TNBC cell proliferation, migration, and invasion in vitro. The underlying mechanisms involve the induction of oxidative stress and the activation of NF-κB signaling. In particular, the activation of p38 and JNK plays a pivotal role in alcohol-induced cellular responses. These results will advance our understanding of alcohol-mediated development and promotion of TNBC. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina.
authors.forename: Erin W
authors.initials: EW
authors.lastname: Howard
authors.affiliation: Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Parris
authors.affiliation: Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Biology, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, North Carolina.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Yang
mesh_terms: D000438:Alcohols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000438:Alcohols; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: acetaldehyde; alcohol; cell migration/invasion; oxidative stress; triple-negative breast cancer