Alcohol and Breast Cancer

描述（由申请人提供）：酒精中毒，酒精滥用和过量饮酒的医学并发症是世界范围内主要的健康问题。酒精是肿瘤的促进剂。流行病学研究表明，大量饮酒会增加患乳腺癌的风险，并与晚期和浸润性乳腺肿瘤有关。然而，酒精诱导肿瘤促进的病因尚不清楚。酒精促进肿瘤发生和进展的细胞/分子机制尚不清楚。ErbB2是表皮生长因子受体酪氨酸激酶家族的一员，在人类乳腺癌中经常过度表达。我们已经证明，酒精显著促进过表达ErbB2的乳腺上皮细胞和乳腺癌细胞的迁移/侵袭。我们还发现人类跨膜粘蛋白（MUC1）对酒精高度敏感。？-catenin是一种原癌基因，在肿瘤发生和肿瘤进展中起重要作用。钙粘蛋白/ ?-catenin复合物是细胞-细胞粘附的关键成分，维持上皮细胞相互作用的完整性并调节细胞迁移/侵袭。我们提出MUC1作为连接ErbB2和？-catenin和促进ErbB2/？-catenin相互作用和E- cadherin/ ？连环蛋白复杂。我们的中心假设是乙醇诱导的氧化应激上调MUC1作为一种适应蛋白，以促进ErbB2/ ？-连环蛋白相互作用诱导？-catenin/E-cadherin复合物，导致细胞转化和细胞迁移/侵袭。体外和体内模型都将被用来检验这一新的假设。特异性Aim 1将确定MUC1在乙醇促进的ErbB2/ ？连环蛋白相互作用。特异性Aim 2将确定乙醇促进的细胞转化和癌细胞迁移/侵袭是否通过muc1依赖性E-cadherin/2-catenin复合物的解离介导。特异性目的3将研究乙醇在体内的作用。我们将研究乙醇对MMTV-Neu转基因小鼠乳腺肿瘤发生/转移的影响。我们将进一步研究乙醇对MUC1， ErbB2, ？-catenin和E-cadherin以及ROS和MUC1在乙醇介导的小鼠肿瘤发生/转移中的作用。作为一个有凝聚力的单位，使用体外和体内模型的多学科方法将系统地探索酒精促进肿瘤发生和乳腺癌恶性进展的机制。该研究将阐明ErbB2和MUC1在酒精诱导的肿瘤促进中的新功能。ErbB2和MUC1的表达/活性在许多其他人类癌症和多种人类疾病中经常异常；它们的水平也受发育调节。了解酒精、ErbB2和MUC1之间的相互作用也将为了解一些与酒精滥用有关的人类疾病的发病机制以及酒精在发育过程中的致畸作用提供重要的见解。

DESCRIPTION (provided by applicant): 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.