Cysteine, Related Gene Variants and Breast Cancer Risk

描述（由申请人提供）：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，高循环水平的半胱氨酸可以预防乳腺癌的发展。半胱氨酸是y-谷氨酰转肽酶（GGT1）细胞外谷胱甘肽分解代谢的产物，参与活性氧的生成。然而，尚无研究评估半胱氨酸水平与乳腺癌风险的关系。虽然从半胱氨酸和谷胱甘肽分解代谢中合成谷胱甘肽的遗传差异可能影响乳腺癌的风险，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，但没有发表的数据。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、参与半胱氨酸和谷胱甘肽分解代谢的谷胱甘肽生物合成的基因变异及其对乳腺癌风险的相互作用进行前瞻性研究。应用最先进的基因分型技术和统计方法，我们将评估常见的功能变异，并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(也称为y-谷氨酰半胱氨酸合成酶，一种限速酶，催化半胱氨酸合成谷胱甘肽的第一步，具有两个亚基[GCLC，催化亚基；GCLM（调节亚基）、谷胱甘肽合成酶（GSS，一种催化谷胱甘肽生物合成第二步的酶）和GGT1（一种参与谷胱甘肽分解代谢生成半胱氨酸和将半胱氨酸转运到细胞中的酶）。与这些候选基因的关联将为血浆半胱氨酸和半胱氨酸与乳腺癌风险之间的关联提供机制证据。在NHS和NHSII的队列中，共有2279例乳腺癌病例及其匹配的对照病例将在获得血液样本且基线时无癌症的妇女中确定。NHS和NHSII队列有大量乳腺癌确诊病例，持续时间长，随访率高，协变量信息全面，因此提供了一个绝佳的机会来检查半胱氨酸相关基因变异、血浆半胱氨酸和半胱氨酸的主要影响，以及它们与乳腺癌风险的相互作用。我们也将探索这些候选基因之间的相互作用。这项研究的发现将有助于阐明半胱氨酸在乳腺癌发生中的作用，并可能为乳腺癌化学预防提供未来的方法，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.