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.

p53 pathway determines the cellular response to alcohol-induced DNA damage in MCF-7 breast cancer cells

“…In their study, alcohol increased cancer stem cell populations with colocalized activation of ErbB2, and promoted colon and lung metastases. Their molecular analysis of signaling pathways affected by alcohol stimulation, revealed the activation of MAPK p38, which is supported by in vitro work in our lab [11]. Our cellular model emphasizes the consequences of alcohol exposure on potentially cancer-initiating DNA damage in another breast cancer subtype, ER + /ErbB2-.…”

“…Increasing evidence, including our previous findings, suggests that oxidative stress, resulting from alcohol metabolism, is a primary culprit for the increased risk and progression of alcohol-associated breast cancer [10, 11]. Alcohol is metabolized mostly via oxidation to acetaldehyde by alcohol dehydrogenase (ADH) and microsomal cytochrome P450 2E1 (CYP2E1) [12, 13].…”

Silencing of α-complex protein-2 reverses alcohol- and cytokine-induced fibrogenesis in hepatic stellate cells

“…In addition, PDGF promotes the migration of murine HSC line GRX [46]. Alcohol has also been reported to promote migration and invasion of triple-negative breast cancer cells through activation of p38 MAPK and c-Jun N-terminal kinase [47]. In this study, PDGF, TGF-β1, EGF, and alcohol were used to exert a migration effect on HSCs.…”

The Association between Alcohol Consumption and Breast Density: A Systematic Review and Meta-analysis

“…The association of alcohol use with breast cancer according to the molecular phenotype of the tumor was examined in a metaanalysis of 20 cohort studies, with more than a million subjects, 21 Zhao and colleagues (44) showed in cell culture of breast cancer cells without receptors for estrogen, progesterone, or EGF (triple negative) that a low concentration of alcohol increased cell proliferation, migration, and invasiveness that might increase radiologically dense breast tissue. These effects were associated with alcohol-induced reactive oxygen species production and increased p38 and JNK phosphorylation.…”