Alcohol and Breast Cancer

酒精与乳腺癌

• 批准号: 7856018
• 负责人: JIA LUO
• 金额: $ 9.59万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7856018
• 关键词: Adaptor Signaling Protein; Adult; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; American; Animal Model; Animal Welfare; Bibliography; Breast Cancer Cell; Cell Communication; Cell-Cell Adhesion; Cells; Cellular Structures; Complex; Country; Development; Disease; Dissociation; E-Cadherin; ERBB2 gene; Environment; Environmental Impact; Epidemiologic Studies; Epidermal Growth Factor Receptor; Epithelial Cells; Equipment; Esophagus; Ethanol; Etiology; Family; Future; Genus Cola; Goals; Health; Heavy Drinking; Human; IACUC; In Vitro; International; Larynx; Literature; Liver; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Medical; Membrane; Molecular; Mucin-1 Staining Method; Mucins; Neoplasm Metastasis; Nude Mice; Oral cavity; Organ; Outcome; Ovary; Oxidative Stress; Pathogenesis; Patients; Pharyngeal structure; Phosphorylation; Play; Principal Investigator; Protein Tyrosine Kinase; Proto-Oncogenes; Reactive Oxygen Species; Rectum; Research; Research Ethics Committees; Research Personnel; Resources; Risk; Role; Stomach; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Tumor Promoters; Tumor Promotion; United States; Up-Regulation; Vertebrates; abstracting; alcohol effect; alcohol related problem; cancer cell; cancer risk; carcinogenesis; cell motility; cell transformation; cellular targeting; chronic alcohol ingestion; cost; expiration; human disease; human subject; in vivo; in vivo Model; insight; malignant breast neoplasm; medical complication; member; migration; novel; problem drinker; programs; tumor; tumor progression; tumorigenesis

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

项目摘要/摘要 酗酒、酗酒和过度饮酒引起的医疗并发症是主要原因 世界性的健康问题。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。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 进展情况尚不清楚。表皮生长因子受体成员ERBB2 酪氨酸激酶家族在人类乳腺癌中经常过度表达。我们有 显示酒精显著促进乳腺上皮细胞的迁移/侵袭 乳腺癌细胞过度表达ErbB2。我们还揭示了人类的跨膜 粘蛋白(MUC1)对酒精高度敏感。A-连环蛋白是一种原癌基因，在 在肿瘤发生和癌症进展中的重要作用。E-钙粘蛋白/a-连环蛋白复合体，a 细胞-细胞的关键组件附着，维持上皮细胞相互作用的完整性，并 调节细胞迁移/侵袭。我们提出了MUC1作为一种新的适配蛋白的作用 桥接ErbB2和a-catenin并促进ErbB2/a-catenin相互作用和Ecadherin/解离 A-连环蛋白复合体。我们的中心假设是乙醇诱导的氧化应激上调 MUC1作为接头蛋白促进ErbB2/a-catenin相互作用 α-连环蛋白/E-钙粘附素复合体的解离，导致细胞转化和细胞 迁徙/入侵。体外和体内模型都将被用来检验这一新的假设。 特定目标1将确定MUC1在乙醇促进的ErbB2/a-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和 癌细胞的迁移/侵袭是由MUC1依赖的Ecadherin/解离介导的 A-连环蛋白复合体。具体目标3将研究乙醇的体内效应。我们会 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相互作用的影响。 MUC1、ErbB2、α-连环蛋白和E-钙粘蛋白以及ROS和MUC1在乙醇介导中的作用 转基因和裸鼠体内肿瘤的发生和转移。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 酒精促进乳腺肿瘤发生和恶变的机制 癌症。这项研究将阐明ErbB2和MUC1在酒精诱导的肿瘤中的新功能 升职。ErbB2和MUC1在许多其他组织中表达/活性经常异常 人类癌症和各种人类疾病；它们的水平也在发育中 受监管的。了解酒精、ErbB2和MUC1之间的相互作用也将提供 对一些与酗酒有关的人类疾病的发病机制的重要洞察 那么酒精呢？S在发育过程中的致畸作用