TUMOR SUPPRESSOR GENES IDENTIFIED FROM A MODEL SYSTEM

说明(申请人的说明已编辑)申请人建议 开始基础和临床之间的新协作努力 实验室使用从果蝇模型中获得的信息 一种识别人类肿瘤抑制基因(TSG)的系统，其中 遗传或体细胞基因改变都会导致乳房 癌症。这项工作涉及列出的两个优先领域 在申请申请中：即乳腺癌病因和 乳腺癌易感基因问题。此外，它还测试了 一种新的敏感度鉴定新技术 基因。这是一个试点项目，如果成功，将产生 关于乳腺癌的重要新信息，可以作为 为今后在乳房领域进行更全面的研究奠定基础 癌症。已鉴定出20个果蝇基因在其中丢失 功能突变导致想象中的细胞过度增殖 盘，这是幼虫中未分化的上皮囊 在变态过程中发育成成体结构。在某些情况下， 突变也会导致上皮结构的丧失和 差异化。其中六个基因已经被克隆和鉴定 在分子水平上，它们都与哺乳动物有明显的同源性 基因。因此，这些哺乳动物的同源物被认为是候选 上皮源性肿瘤的肿瘤抑制基因(TSG) 纸巾。乳腺肿瘤样本是在联合国儿童基金会的支持下积累起来的 奥兰治县癌症监测计划(CSPOC)，将 筛选哺乳动物同源基因表达的变化。 将对正常的乳房RNA进行探测，以确定哪些 同源基因在这个组织中表达，只有那些给予 积极的结果将进一步研究。组织切片将是 筛选候选TSG的改变或丢失的表达 共聚焦免疫荧光定位产品 显微镜。在此屏幕上显示表达发生变化的任何基因 将进一步检测紧密连锁的杂合性丢失 DNA标记，这一现象表明候选人 吉恩的表现就像一个经典的TSG。长期目标包括 检查这些基因是否有可能导致 乳腺肿瘤的发展。这项调查可能会导致 新型诊断和/或靶标试剂的开发 乳腺癌的治疗方法。

Description (Applicant's Description-edited) The applicant proposes to begin a new collaborative effort between basic and clinical laboratories to use information derived from the Drosophila model system to identify human tumor suppressor genes (TSGs) in which either inherited or somatic genetic alterations contribute to breast cancer. The work addresses two of the priority areas listed in the Request for Applications: namely, Breast Cancer Etiology and Breast Cancer Susceptibility Genes Issues. Furthermore, it tests an innovative new technique for the identification of susceptibility genes. It is a pilot project that, if successful, will yield important new information on breast cancer and could serve as the basis for more comprehensive future research in the area of breast cancer. Twenty drosophila genes have been identified in which loss of function mutations lead to excess cell proliferation in the imaginal discs, which are undifferentiated epithelial sacs in the larva that develop into adult structures during metamorphosis. In some cases the mutations also cause loss of epithelial structure and the ability to differentiate. Six of these genes have been cloned and characterized at the molecular level, and they all show clear homology to mammalian genes. These mammalian homologs, therefore, are considered candidate tumor suppressor genes (TSGs) for tumors derived from epithelial tissues. Breast tumor samples being accumulated under the auspices of the Cancer Surveillance Program of Orange County (CSPOC), will be screened for alterations in expression of the mammalian homologs. Normal breast RNA will be probed to determine which of the homologs are expressed in this tissue, and only those genes giving positive results will be studied further. Tissue sections will be screened for altered or lost expression of the candidate TSG products using immunofluorescence localization by confocal microscopy. Any genes showing changed expression in this screen will be further tested for loss of heterozygosity of closely linked DNA markers, a phenomenon which would suggest that the candidate gene is behaving as a classical TSG. Long-range goals include examination of these genes for mutations that might contribute to the development of breast tumors. This investigation may lead to the development of new reagents for diagnosis and/or targets for novel approaches to breast cancer treatment.