Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ

Mei Xu; Siying Wang; Zhenhua Ren; Jacqueline A Frank; Xiuwei H Yang; Zhuo Zhang; Zun-Ji Ke; Xianglin Shi; Jia Luo

doi:10.18632/oncotarget.6508

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Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ

Journal article

Open access

Peer reviewed

Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ

Mei Xu, Siying Wang, Zhenhua Ren, Jacqueline A Frank, Xiuwei H Yang, Zhuo Zhang, Zun-Ji Ke, Xianglin Shi and Jia Luo

Oncotarget, Vol.7(3), pp.3489-3505

01/19/2016

DOI: 10.18632/oncotarget.6508

PMCID: PMC4823122

PMID: 26655092

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https://doi.org/10.18632/oncotarget.6508View

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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.

Animals

Apoptosis - drug effects

Blotting, Western

Breast Neoplasms - chemically induced

Breast Neoplasms - metabolism

Breast Neoplasms - pathology

Cell Movement - drug effects

Cell Proliferation - drug effects

Central Nervous System Depressants - toxicity

Ethanol - toxicity

Female

Fluorescent Antibody Technique

Gene Expression Regulation, Neoplastic - drug effects

Humans

Immunoenzyme Techniques

Immunoprecipitation

Mice

Mice, Nude

p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors

p38 Mitogen-Activated Protein Kinases - genetics

p38 Mitogen-Activated Protein Kinases - metabolism

rho GTP-Binding Proteins - genetics

rho GTP-Binding Proteins - metabolism

rhoC GTP-Binding Protein

RNA, Small Interfering - genetics

Tumor Cells, Cultured

Xenograft Model Antitumor Assays

Details

Title: Subtitle: Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ
Creators: Mei Xu - University of Kentucky
Siying Wang - Anhui Medical University
Zhenhua Ren - University of Kentucky
Jacqueline A Frank - University of Kentucky
Xiuwei H Yang - University of Kentucky
Zhuo Zhang - University of Kentucky
Zun-Ji Ke - Shanghai University of Traditional Chinese Medicine
Xianglin Shi - University of Kentucky
Jia Luo - University of Kentucky
Resource Type: Journal article
Publication Details: Oncotarget, Vol.7(3), pp.3489-3505
DOI: 10.18632/oncotarget.6508
PMID: 26655092
PMCID: PMC4823122
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Grant note: AA015407 / NIAAA NIH HHS P30 CA177558 / NCI NIH HHS AA017226 / NIAAA NIH HHS R01 AA015407 / NIAAA NIH HHS R01 AA017226 / NIAAA NIH HHS
Language: English
Date published: 01/19/2016
Academic Unit: Pathology
Record Identifier: 9984201114202771

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