Cysteine, Related Gene Variants and Breast Cancer Risk

描述(申请人提供)：半胱氨酸是谷胱甘肽(GSH)生物合成中的限速氨基酸，谷胱甘肽是细胞内关键的抗氧化剂和解毒剂。有限的数据表明，循环中高水平的半胱氨酸可能会阻止乳腺癌的发展。半胱氨酸甘氨酸是谷氨酰转肽酶(GGT1)在细胞外分解GSH的产物，参与了活性氧的产生。然而，还没有研究评估半胱氨酸甘氨酸水平与乳腺癌风险的关系。尽管半胱氨酸和GSH分解代谢合成GSH的遗传差异可能会影响乳腺癌的风险，并可能改变半胱氨酸和半胱氨酸甘氨酸对乳腺癌风险的影响，但目前还没有公开的数据。因此，我们建议在护士健康研究(NHS)和护士健康研究II(NHSII)两个大型前瞻性队列中，对血浆半胱氨酸、半胱氨酸甘氨酸、参与半胱氨酸和GSH分解代谢合成GSH的基因变异及其对乳腺癌风险的交互作用进行前瞻性研究。应用最新的基因分型技术和统计方法，我们将评估常见的功能变异和确定四个相关候选基因的单倍型结构，包括谷氨酸-半胱氨酸连接酶(称为γ-谷氨酰半胱氨酸合成酶，一种限速酶，催化半胱氨酸生物合成的第一步[GCLC，催化亚基；GCLM，调节亚基j)，谷胱甘肽合成酶(GSS，催化第二步GSH生物合成的酶)和GGT1(参与GSH分解代谢生成半胱氨酸甘氨酸和半胱氨酸进入细胞的酶)。与这些候选基因的关联将为血浆半胱氨酸和半胱氨酸甘氨酸与乳腺癌风险之间的关联提供机械证据。在NHS和NHSII队列中，共有2279例乳腺癌病例及其匹配的对照将在获得血样并在基线水平上没有癌症的妇女中被确定。NHS和NHSII队列拥有大量的乳腺癌确诊病例，持续时间长，随访率高，协变量信息全面，因此提供了一个非同寻常的机会来研究半胱氨酸相关基因变异、血浆半胱氨酸和半胱氨酸甘氨酸的主要影响，以及它们与乳腺癌风险的相互作用。我们还将探索这些候选基因之间的相互作用。这项拟议研究的结果将有助于阐明半胱氨酸在乳腺癌发生中的作用，并可能建议未来乳腺癌化学预防的方法，因为/V-乙酰半胱氨酸和半胱氨酸膳食补充剂可以很容易地改善半胱氨酸状态。

DESCRIPTION (provided by applicant): Cysteine is the rate-limiting amino acid in biosynthesis of glutathione (GSH)-the key intracellular antioxidant and detoxifying agent. Limited data have suggested that high circulating levels of cysteine may prevent the development of breast cancer. Cysteinylglycine, a product of the extracellular GSH catabolism by y-glutamyltranspeptidase (GGT1), is involved in the generation of reactive oxygen species. However, no study has assessed the relation of Cysteinylglycine levels to breast cancer risk. Although genetic differences in GSH biosynthesis from cysteine and GSH catabolism could influence breast cancer risk and may modify the effect of cysteine and Cysteinylglycine on risk of breast cancer, no published data are available. We thus propose to conduct a prospective study of plasma cysteine, Cysteinylglycine, gene variants involved in GSH biosynthesis from cysteine and GSH catabolism, and their interactive effects on risk of breast cancer in two large prospective cohorts, the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII). Applying state-of-the-art genotyping technology and statistical methods, we will evaluate common functional variants and determine the structure of haplotypes in four relevant candidate genes, including glutamate-cysteine ligase (as known as y-glutamylcysteine synthetase, a rate-limiting enzyme catalyzing the first step of GSH biosynthesis from cysteine with two subunits [GCLC, catalytic subunit; GCLM, regulatory subunitj), glutathione synthetase (GSS, an enzyme catalyzing the second step of GSH biosynthesis) and GGT1 (an enzyme involved in the GSH catabolism to generate Cysteinylglycine and in the transport of cysteine into the cell). Associations with these candidate genes would provide mechanistic evidence for the association between plasma cysteine and Cysteinylglycine and breast cancer risk. A total of 2279 incident breast cancer cases and their matched controls will be identified in the NHS and NHSII cohorts among women with achieved blood samples and free of cancer at baseline. The NHS and NHSII cohorts have a large number of confirmed cases of breast cancer, long duration, high follow-up rates, and comprehensive covariate information, thus providing an extraordinary opportunity to examine the main effects of cysteine-related gene variants, plasma cysteine and Cysteinylglycine, and their interactions in relation to breast cancer risk. We will explore interactions among these candidate genes as well. Findings from this proposed study will help elucidate the role of cysteine in breast carcinogenesis, and may suggest future approaches for breast cancer chemoprevention, as /V-acetylcysteine and cysteine dietary supplements can readily improve cysteine status.