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: 6452775
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6452775
• 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.

neu和ras原癌基因的鉴定，p53抑癌基因作用的阐明，以及BRCA 1和BRCA 2乳腺癌易感基因的测序，标志着对乳腺癌遗传基础理解的重大突破。虽然这些基因突变的原因还不清楚，但目前有几个因素被认为会增加乳腺癌的风险，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各种癌症有关，包括乳腺癌。这些化学品包括砷、镉、铜、汞、镍和有机磷农药。与已知在啮齿动物中引发和/或促进肿瘤形成的致癌亚硝基化合物不同，重金属和离子已被证明在啮齿动物中通过单次注射引起肿瘤。同样，据报道，乳腺癌或其易感性需要数十年的发展。因此，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开始可能是乳腺细胞转化的基础，正如萨福克县（纽约州）最近的证据所表明的那样。因此，该提案概述了一系列旨在使用细胞毒性测试方法和分子生物学技术研究乳腺上皮细胞和已建立的乳腺癌细胞系的实验。这些结果将提高我们对乳腺细胞和重金属之间相互作用的理解，以及这些化学物质引发突变并促进肿瘤的机制。