FACTORS CONTROLLING SUSCEPTIBILITY TO MAMMARY CANCER

控制乳腺癌易感性的因素

• 批准号: 2414098
• 负责人: MICHAEL N GOULD
• 金额: $ 25.69万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414098
• 关键词: artificial chromosomes; autosomal dominant trait; breast neoplasms; cancer risk; carcinogenesis; cell differentiation; chemical carcinogenesis; embryo /fetus tissue /cell culture; gene expression; genetic mapping; genetic markers; genetically modified animals; laboratory rat; linkage mapping; mammary epithelium; molecular cloning; molecular genetics; molecular oncology; neoplasm /cancer genetics; nucleic acid probes; nucleic acid repetitive sequence; radiation carcinogenesis; tissue /cell culture; tumor suppressor genes

The continuing goal of this project is to characterize factors that control susceptibility to carcinogen, hormonal and spontaneous mammary carcinogenesis. The focus of this application is to functionally characterize, map and begin to clone a gene which prevents the development of mammary cancer following DMBA, NMU, and/or hormonal treatments. This gene, that is referred to as the mammary carcinoma suppressor (MCS) gene, is a dominant gene acting within the mammary parenchyma. Our aims are to: 1) Map the MCS gene to a specific chromosome region using a co-segregation analysis with minisatellite and microsatellite (SSR) probes. This will be followed by generation of a denser linkage map for the specific chromosome on which MCS resides using a MCS-chromosome specific SSR library; 2) Test the hypothesis that the loss of the MCS gene is required for the induction of mammary carcinomas by chemical carcinogens and ionizing radiation; 3) Test the hypothesis that the MCS gene is involved in mammary gland differentiation, and continue to characterize differential gene expression in mammary epithelial cells associated with the MCS gene; and 4) Initiate efforts to molecularly clone the MCS gene by screening a rat yeast artificial chromosome (YAC) library for clones with MCS-linked markers. Positive clones will be placed in a "contig" map and this contig will then be extended by the isolation of additional overlapping clones. Candidate MCS genes will then be identified using an integrated battery of screening procedures. cDNAs of candidate genes will then be cloned and characterized. Characterization will include an initial assay. Positive sequence will then be tested in vivo for MCS activity screen using a cell culture/in vitro using a transgenic model.

该项目的持续目标是表征 控制致癌，荷尔蒙和自发乳腺的敏感性 致癌作用。 该应用程序的重点是功能 表征，映射并开始克隆一个阻止该基因的基因 DMBA，NMU和/或激素后乳腺癌的发展 治疗。 该基因被称为乳腺癌 抑制剂（MCS）基因是作用在乳腺内的主要基因 实质。 我们的目的是：1）将MCS基因映射到特定 使用Minisatellite和 微卫星（SSR）探针。 随后会产生 MCS使用的特定染色体的密度链接图 MCS-chromosoms特定的SSR库； 2）检验以下假设 诱导乳腺瘤需要MCS基因的损失 通过化学致癌物和电离辐射； 3）检验假设 MCS基因参与乳腺分化，并且 继续表征乳腺中差异基因表达 与MCS基因相关的上皮细胞； 4）开始努力 通过筛选大鼠酵母人工来克隆MCS基因 具有MCS连接标记的克隆的染色体（YAC）库。 积极的 克隆将被放置在“重叠”地图中，然后将此重叠群为 通过隔离其他重叠的克隆来扩展。 候选人 然后，将使用集成电池来识别MCS基因 筛选程序。然后，将克隆候选基因的cDNA，然后 特征。 表征将包括初始测定。 积极的 然后，将使用单元格在体内测试MCS活动屏幕的序列 使用转基因模型培养/体外。