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.
|Liu, Dexiang; Ke, Zunji; Luo, Jia (2016) Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy. Mol Neurobiol :|
|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|
|Xu, Mei; Ren, Zhenhua; Wang, Xin et al. (2016) ErbB2 and p38Î³ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis. Mol Cancer 15:52|
|Xu, Mei; Wang, Siying; Ren, Zhenhua et al. (2016) Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38Î³. Oncotarget 7:3489-505|
|Ren, Zhenhua; Yang, Fanmuyi; Wang, Xin et al. (2016) Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation. Toxicol Appl Pharmacol 308:11-9|
|Yang, Fanmuyi; Luo, Jia (2015) Endoplasmic Reticulum Stress and Ethanol Neurotoxicity. Biomolecules 5:2538-53|
|Wang, Fei; Yang, Jin-Lian; Yu, Ke-ke et al. (2015) Activation of the NF-ÎºB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma. Mol Cancer 14:10|
|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|
|Baldwin, Lauren A; Hoff, John T; Lefringhouse, Jason et al. (2014) CD151-Î±3Î²1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling. Oncotarget 5:12203-17|
|Lu, Yanmin; Ni, Fang; Xu, Mei et al. (2014) Alcohol promotes mammary tumor growth through activation of VEGF-dependent tumor angiogenesis. Oncol Lett 8:673-678|
Showing the most recent 10 out of 27 publications