Research Papers:

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 _

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Oncotarget. 2016; 7:3489-3505. https://doi.org/10.18632/oncotarget.6508

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Mei Xu1, Siying Wang1,2, Zhenhua Ren1,2, Jacqueline A. Frank1, Xiuwei H. Yang1, Zhuo Zhang3, Zun-ji Ke4, Xianglin Shi3, Jia Luo1

1Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA

2Pathophysiological Department, School of Basic Medicine, Anhui Medical University, Hefei, Anhui 23002, China

3Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40536, USA

4Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

Correspondence to:

Jia Luo, e-mail: [email protected]

Keywords: alcohol abuse, cancer stem cells, metastasis, mammary tumor

Received: July 27, 2015     Accepted: November 16, 2015     Published: December 07, 2015


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.

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