CELLULAR AND MOLECULAR TOXICITY IN HUMAN MAMMARY CELLS

Neu和ras原癌基因的鉴定，p53抑癌基因作用的阐明，以及BRCA1和BRCA2乳腺癌易感基因的测序，标志着对乳腺癌遗传学基础认识的重大突破。尽管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。在地下水和商业程序中常见的几种化学物质被认为是引发各种癌症的罪魁祸首，包括乳腺癌。这些化学物质包括砷、镉、铜、汞、镍和有机磷农药。与已知可引发和/或促进啮齿动物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只需一次注射就能引起啮齿动物的肿瘤。同样，据报道，乳腺癌或乳腺癌的易感性需要数十年的发展。因此，正如最近萨福克县(纽约州)的证据所表明的那样，由慢性、低剂量、非致癌但有毒的化学品引发的一系列突变事件可能是乳腺细胞转化的基础。因此，这项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。这些结果将提高我们对乳腺细胞和重金属之间的相互作用以及这些化学物质引发突变和促进肿瘤的机制的理解。

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.