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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017226-05
Application #
8033266
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Jung, Kathy
Project Start
2008-03-05
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
5
Fiscal Year
2011
Total Cost
$313,667
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
Xu, Mei; Wang, Siying; Ren, Zhenhua et al. (2016) Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38?. Oncotarget 7:3489-505
Dai, Jin; Van Wie, Peter G; Fai, Leonard Yenwong et al. (2016) Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells. Toxicol Appl Pharmacol 311:106-112
Xu, Mei; Ren, Zhenhua; Wang, Xin et al. (2016) ErbB2 and p38? MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis. Mol Cancer 15:52
Xu, Mei; Wang, Siying; Qi, Yuanlin et al. (2016) Role of MCP-1 in alcohol-induced aggressiveness of colorectal cancer cells. Mol Carcinog 55:1002-11
Ren, Zhenhua; Wang, Xin; Xu, Mei et al. (2016) Binge ethanol exposure causes endoplasmic reticulum stress, oxidative stress and tissue injury in the pancreas. Oncotarget 7:54303-54316
Ren, Zhenhua; Yang, Fanmuyi; Wang, Xin et al. (2016) Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation. Toxicol Appl Pharmacol 308:11-19
Wang, Haiping; Wang, Xin; Ke, Zun-Ji et al. (2015) Tunicamycin-induced unfolded protein response in the developing mouse brain. Toxicol Appl Pharmacol 283:157-67

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