GST, ENVIRONMENT FACTORS AND BREAST CANCER RISK

最近的流行病学研究表明，GST基因多态性可能影响个体患乳腺癌的风险。所谓的GST效应在生物学上是合理的，因为GST基因产物催化谷胱甘肽与潜在的细胞和基因毒性反应性化学中间体结合，产生无活性产物，从而提供了一种防止癌症发展的保护机制。迄今为止，将GST多态性与乳腺癌风险联系起来的流行病学研究尚无定论。考虑到建议的高风险GST基因型通常发生在一般人群中，计算出的人群归因风险可能很高。在此背景下，我们拟在美国乳腺癌发病率最高的地区之一康涅狄格州开展GST遗传多态性、环境因素与乳腺癌风险的病例对照研究。本病例对照研究的主要目的是研究GSTM1、GSTT1和GSTP1三种主要GSTs的遗传变异与乳腺癌易感性之间的关系。该研究将(1)确定这些gst的缺乏或表达减少是否与乳腺癌风险增加有关；(2)确定乳腺癌的风险是否随着假定的高风险GST基因型数量的增加而增加；(3)确定这些GSTs是否改变了环境因素与乳腺癌风险之间的关系。用于拟议研究的血液样本将来自康涅狄格州正在进行的乳腺癌病例对照研究，该研究招募了349例乳腺癌病例和363例非癌症对照。关于环境暴露和其他潜在混杂因素的信息已经通过家长研究从病例和对照中收集到。拟议研究的结果将加强父母研究，以寻找可能解释康涅狄格州高乳腺癌发病率的风险因素。使用现有的血液样本和母体乳腺癌研究收集的环境暴露数据为研究提供了成本效益。由Ali-Osman博士领导的研究实验室，是谷胱甘肽S转移酶和癌症领域的世界领导者，也代表了该提案的独特优势。

Recent epidemiological studies have suggested that GST genetic polymorphisms may affect an individual's breast cancer risk. The alleged GST effects are biologically plausible because the GST gene products catalyze the conjugation with glutathione of potentially cyto- and genotoxic reactive chemical intermediates to yield inactive products, thereby, providing a protective mechanism against cancer development. Epidemiological studies linking GST polymorphism and breast cancer risk thus far produced inconclusive results. Considering that the suggested high risk GST genotypes commonly occur in the general population, the calculated population attributable risk can be high. Against this background, a case-control study of GST genetic polymorphisms, environmental factors and breast cancer risk is proposed in Connecticut, one of the areas with the highest incidence rates of breast cancer in the United States. The primary aim of the proposed case-control study is to examine the association between genetic variability in three major GSTs, namely, GSTM1, GSTT1, and GSTP1 and the susceptibility to breast cancer. The study will (1) determine if lack of or with reduced expression of these GSTs are associated with an increased risk of breast cancer; (2) determine if the risk of breast cancer increases as the number of putative high-risk GST genotypes increases; and (3) determine if these GSTs modify the association between environmental factors and the risk of breast cancer. The blood samples used for the proposed study will come from an on- going breast cancer case-control study in Connecticut, which has recruited 349 incident breast cancer cases and 363 noncancer controls. Information on environmental exposures and other potential confounding factors has already been collected from the cases and controls by the parent study. The results from the proposed study will strengthen the parent study in searching for the risk factors that might explain the high breast cancer rate in Connecticut. Use of existing blood samples and environmental exposure data collected by the parent breast cancer study provide cost efficiency to the study. The study laboratory led by Dr. Ali-Osman, a world leader in the field of glutathione S- transferase and cancer, also represents a unique strength of the proposal.