Alcoholism, alcohol abuse, and the medical complications of excessive drinking are major world-wide health problems. Alcohol is a tumor promoter. Epidemiological studies indicate that heavy alcohol consumption increases risk of breast cancer and is associated with advanced and invasive breast tumors. However, the etiology of alcohol-induced tumor promotion is elusive. Cellular/molecular mechanisms underlying alcohol-promoted tumor development and progression remain unknown. ErbB2, a member of the epidermal growth factor receptor tyrosine kinase family, is frequently over-expressed in human breast cancers. We have demonstrated that alcohol dramatically promotes migration/invasion of mammary epithelial cells and breast cancer cells over-expressing ErbB2. We also reveal that the human transmembrane mucin (MUC1) is highly sensitive to alcohol. ?-catenin is a proto-oncogene and plays an important role in tumorigenesis and cancer progression. The E-cadherin/?-catenin complex, a critical component of cell-cell adherens, maintains the integrity of epithelial cell interactions and regulates cell migration/invasion. We propose a novel role of MUC1 as an adaptor protein that bridges ErbB2 and ?-catenin and facilitate ErbB2/?-catenin interaction and the dissociation of E- cadherin/ ?-catenin complex. Our central hypothesis is that ethanol-induced oxidative stress up- regulates MUC1 as an adaptor protein to promote ErbB2/ ?-catenin interaction which induces dissociation of the ?-catenin/E-cadherin complex, leading to cell transformation and cell migration/invasion. Both in vitro and in vivo models will be utilized to test this novel hypothesis.
Specific Aim 1 will establish the pivotal role of MUC1 in ethanol-promoted ErbB2/ ?-catenin interaction.
Specific Aim 2 will determine whether ethanol-promoted cell transformation and cancer cell migration/invasion is mediated by MUC1-dependent dissociation of the E-cadherin/2-catenin complex.
Specific Aim 3 will investigate in vivo effects of ethanol. We will investigate the effect of ethanol on mammary tumorigenesis/metastasis in MMTV-Neu transgenic mice. We will further investigate the effect of ethanol on the interactions among MUC1, ErbB2, ?-catenin and E-cadherin as well as the role of ROS and MUC1 in ethanol- mediated tumorigenesis/metastasis in the transgenic and nude mice. As a cohesive unit, the multi-disciplinary approaches using in vitro and in vivo models will systematically explore the mechanisms underlying alcohol-promoted tumorigenesis and malignant progression of breast cancer. The study will elucidate a novel function of ErbB2 and MUC1 in alcohol-induced tumor promotion. The expression/activity of ErbB2 and MUC1 is frequently aberrant in many other human cancers and in a variety of human diseases;their levels are also developmentally regulated. Understanding the interactions among alcohol, ErbB2 and MUC1 will also provide an important insight into the pathogenesis of some human diseases related to alcohol abuse as well as alcohol's teratogenic effect during development.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Jung, Kathy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Ji, Zhe; Yuan, Lin; Lu, Xiong et al. (2018) Binge Alcohol Exposure Causes Neurobehavioral Deficits and GSK3? Activation in the Hippocampus of Adolescent Rats. Sci Rep 8:3088
Ren, Zhenhua; Wang, Xin; Xu, Mei et al. (2018) Minocycline Attenuates Ethanol-induced Cell Death and Microglial Activation in the Developing Spinal Cord. Alcohol :
Wang, Yongchao; Wang, Xin; Li, Hui et al. (2018) Binge ethanol exposure induces endoplasmic reticulum stress in the brain of adult mice. Toxicol Appl Pharmacol 356:172-181
Zhang, Kai; Wang, Haiping; Xu, Mei et al. (2018) Role of MCP-1 and CCR2 in ethanol-induced neuroinflammation and neurodegeneration in the developing brain. J Neuroinflammation 15:197
Zhang, Kai; Luo, Jia (2018) Role of MCP-1 and CCR2 in alcohol neurotoxicity. Pharmacol Res 139:360-366
Wang, Xin; Zhang, Kai; Yang, Fanmuyi et al. (2018) Minocycline protects developing brain against ethanol-induced damage. Neuropharmacology 129:84-99
Xu, Mei; Luo, Jia (2017) Alcohol and Cancer Stem Cells. Cancers (Basel) 9:
Wang, Xin; Xu, Mei; Frank, Jacqueline A et al. (2017) Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells. Toxicol Appl Pharmacol 320:26-31
Wang, Yongchao; Xu, Mei; Ke, Zun-Ji et al. (2017) Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer. Pharmacol Res 115:299-308
Liu, Dexiang; Ke, Zunji; Luo, Jia (2017) Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy. Mol Neurobiol 54:5440-5448

Showing the most recent 10 out of 36 publications