CELLULAR AND MOLECULAR TOXICITY IN HUMAN MAMMARY CELLS

人类乳腺细胞的细胞和分子毒性

• 批准号: 6335946
• 负责人: FRANK A BARILE
• 金额: $ 3.15万
• 依托单位: YORK COLLEGE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6335946
• 关键词: SDS polyacrylamide gel electrophoresis; brca gene; breast neoplasms; cellular oncology; chemical carcinogenesis; chemical related neoplasm /cancer; cyclin dependent kinase; cytotoxicity; enzyme activity; fluorescent dye /probe; gene mutation; heavy metals; human tissue; mammary epithelium; metal poisoning; molecular oncology; polymerase chain reaction; radionuclides; scintillation counter; single strand conformation polymorphism; southern blotting; tissue /cell culture; tumor promoters; tumor suppressor genes; western blottings

The identification of the neu and ras protooncogenes, the elucidation of the role of p53 tumor suppressor genes, and the sequencing of BRCA1 and BRCA2 breast cancer susceptibility genes, marked a significant breakthrough for the understanding of the genetic basis of breast cancer. Although the causes of these genetic mutations are not well understood, several factors are currently accepted as increasing the risk of breast cancer, including genetic predisposition and environmental exposure. Several chemicals commonly found in ground water and commercial procedures have been implicated in initiating a variety of cancers, including breast cancer. These chemicals include arsenic, cadmium, copper, mercury, nickel, and organophosphate pesticides. Unlike the carcinogenic nitroso compounds known to initiate and/or promote tumor formation in rodents, heavy metals and ions have been shown to cause tumors in rodents with single injections. Similarly, breast cancer, or susceptibility to it, reportedly requires decades for development. Consequently, the initiation of a sequence of mutational events, triggered by chronic, low-dose, non-carcinogenic yet toxic chemicals, may be the basis for mammary cell transformation, as recent evidence in Suffolk County (NY State) suggests. This proposal, therefore, outlines a series of experiments directed at studying mammary epithelial cells and established breast cancer cell lines using cytotoxicity testing methods and molecular biology techniques. The results will improve our understanding of the interaction between mammary cells and heavy metals and the mechanism by which these chemicals initiate mutations and allow for tumor promotion.

新、ras原癌基因的鉴定，抑癌基因p53作用的阐明，乳腺癌易感基因BRCA1和BRCA2的测序，标志着对乳腺癌遗传基础认识的重大突破。虽然这些基因突变的原因尚不清楚，但目前有几个因素被认为是增加乳腺癌风险的因素，包括遗传易感性和环境暴露。地下水和商业程序中常见的几种化学物质与引发包括乳腺癌在内的多种癌症有关。这些化学物质包括砷、镉、铜、汞、镍和有机磷农药。与已知的致癌亚硝基化合物引发和/或促进啮齿动物肿瘤形成不同，重金属和离子已被证明单次注射就会导致啮齿动物肿瘤。同样，据报道，乳腺癌或对乳腺癌的易感性需要几十年的发展。因此，正如萨福克县（纽约州）最近的证据所表明的那样，由慢性、低剂量、非致癌但有毒的化学物质引发的一系列突变事件的启动可能是乳腺细胞转化的基础。因此，本提案概述了一系列旨在研究乳腺上皮细胞的实验，并利用细胞毒性测试方法和分子生物学技术建立了乳腺癌细胞系。该结果将提高我们对乳腺细胞与重金属之间相互作用的理解，以及这些化学物质引发突变和促进肿瘤的机制。