Alcohol and Breast Cancer

项目总结/摘要 酒精中毒、酗酒和过量饮酒的并发症是主要的 全球性的健康问题。酒精是一种肿瘤促进剂。流行病学研究表明， 大量饮酒会增加患乳腺癌的风险，并与晚期乳腺癌有关， 侵袭性乳腺肿瘤然而，酒精诱导的肿瘤促进的病因是难以捉摸的。 酒精促进肿瘤发展的细胞/分子机制 进展仍然未知。ErbB 2，表皮生长因子受体成员 酪氨酸激酶家族，经常在人乳腺癌中过度表达。我们有 表明酒精显著促进乳腺上皮细胞的迁移/侵袭 和过表达ErbB 2的乳腺癌细胞。我们还发现，人类跨膜 粘蛋白（MUC 1）对酒精高度敏感。α-连环蛋白是一种原癌基因， 在肿瘤发生和癌症进展中起重要作用。E-钙粘蛋白/a-连环蛋白复合物，a 细胞-细胞粘附的关键组分，维持上皮细胞相互作用的完整性， 调节细胞迁移/侵袭。我们提出MUC 1作为一种衔接蛋白的新作用， 桥接ErbB 2和α-连环蛋白，促进ErbB 2/α-连环蛋白相互作用和E钙粘蛋白/ α-连环蛋白复合物。我们的中心假设是乙醇诱导的氧化应激上调 MUC 1作为衔接蛋白促进ErbB 2/α-连环蛋白相互作用， a-连环蛋白/E-钙粘蛋白复合物的解离，导致细胞转化和细胞凋亡。 移民/入侵。将利用体外和体内模型来检验这一新假设。 特异性目的1将确定MUC 1在乙醇促进的ErbB 2/α-连环蛋白中的关键作用 互动具体目标2将确定乙醇是否促进细胞转化， 癌细胞的迁移/侵袭是由E钙粘蛋白的MUC 1依赖性解离介导的。 α-连环蛋白复合物。具体目标3将研究乙醇的体内效应。我们将 探讨乙醇对MMTV-Neu乳腺肿瘤发生/转移的影响 转基因小鼠我们将进一步研究乙醇对 MUC 1、ErbB 2、a-catenin和E-cadherin以及ROS和MUC 1在乙醇介导的细胞凋亡中的作用 在转基因小鼠和裸鼠中的肿瘤发生/转移。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 酒精促进乳腺癌发生和恶性进展的机制 癌本研究将阐明ErbB 2和MUC 1在酒精诱导的肿瘤中的新功能 推广. ErbB 2和MUC 1的表达/活性在许多其他肿瘤中经常是异常的。 人类癌症和各种人类疾病;它们的水平也是发育的 监管.了解酒精，ErbB 2和MUC 1之间的相互作用也将提供一个 对一些与酗酒有关的人类疾病的发病机理的重要见解， 以及酒精？发育过程中的致畸作用

Project Summary/Abstract 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. a-catenin is a proto-oncogene and plays an important role in tumorigenesis and cancer progression. The E-cadherin/a-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 a-catenin and facilitate ErbB2/a-catenin interaction and the dissociation of Ecadherin/ a-catenin complex. Our central hypothesis is that ethanol-induced oxidative stress upregulates MUC1 as an adaptor protein to promote ErbB2/a-catenin interaction which induces dissociation of the a-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/a-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 Ecadherin/ a-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, a-catenin and E-cadherin as well as the role of ROS and MUC1 in ethanolmediated 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