Alcohol and Breast Cancer

描述(申请人提供)：酗酒、酗酒和过度饮酒引起的医疗并发症是世界性的主要健康问题。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，酒精促进肿瘤的病因尚不清楚。酒精促进肿瘤发生和发展的细胞/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成员之一，在人类乳腺癌中经常过表达。我们已经证明，酒精显著促进乳腺上皮细胞和过度表达ErbB2的乳腺癌细胞的迁移/侵袭。我们还发现人的跨膜粘蛋白(MUC1)对酒精高度敏感。？-连环蛋白是一种原癌基因，在肿瘤的发生、发展中起重要作用。E-钙粘蛋白/β-连环蛋白复合体是细胞-细胞黏附的重要组成部分，维持上皮细胞相互作用的完整性，调节细胞的迁移/侵袭。我们提出了一个新的作用，即MUC1作为连接ErbB2和β-catenin的接头蛋白，促进ErbB2/β-catenin相互作用和E-钙粘蛋白/β-catenin复合体的解离。我们的中心假设是，乙醇诱导的氧化应激上调MUC1作为一种适配蛋白，促进ErbB2/β-catenin相互作用，从而导致？-catenin/E-cadherin复合体的解离，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。具体目标1将确定MUC1在乙醇促进的ErbB2/β-连环蛋白相互作用中的关键作用。具体目标2将确定乙醇促进的细胞转化和癌细胞迁移/侵袭是否是通过依赖于MUC1的E-钙粘蛋白/2-连环蛋白复合体的解离来介导的。具体目标3将研究乙醇的体内效应。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、β-catenin和E-cadherin之间相互作用的影响，以及ROS和MUC1在乙醇介导的转基因和裸鼠肿瘤发生/转移中的作用。作为一个具有凝聚力的单元，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乳腺癌发生和恶性进展的机制。本研究将阐明ErbB2和MUC1在酒精促进肿瘤中的新功能。ErbB2和MUC1的表达/活性在许多其他人类癌症和各种人类疾病中经常异常；它们的水平也受到发育调节。了解酒精、ErbB2和MUC1之间的相互作用也将为了解与酒精滥用有关的一些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.