EPIGENETIC CHANGES AND VITAMIN STATUS IN BREAST CANCER

已知整体DNA低甲基化和区域DNA高甲基化伴随着乳腺癌的发生和发展。我们假设全球和基因特异性DNA甲基化与乳腺癌风险相关。我们进一步假设叶酸、维生素B12和维生素C状态可能通过影响DNA甲基化来影响乳腺癌风险。研究前两种维生素的基本原理是，它们在为组织中的DNA甲基化提供甲基方面发挥着关键的代谢作用。此外，最近的研究表明，饮食中叶酸摄入不足，特别是当与其他乳腺癌风险因素（如酒精）结合时，可能会增加患乳腺癌的风险。我们的研究设计建议从未接受雌激素替代治疗的妇女中收集100例原发性乳腺癌。将从每个乳腺癌标本中获得邻近未累及的乳腺组织样本。在特异性目标1中，将使用新鲜冷冻乳腺组织来评估乳腺癌与邻近正常乳腺组织在DNA甲基化（全局、抗5-甲基胞嘧啶、CpG岛和基因特异性）方面的差异。在Specific Aim 2中，重点将转移到这些乳腺癌患者和对照组中组织、循环和膳食叶酸、维生素B12和维生素C状态、DNA甲基化和MTHFR多态性之间的关系。我们的建议将对乳腺癌产生影响，因为它将提供有关控制特定基因甲基化或染色体区域的因素的基本信息，这些因素在乳腺癌的发展中很重要。癌症中的DNA低甲基化，以及可能由低甲基化引起的染色体改变，已经被发现有一段时间了。这些染色质结构的变化可能在乳腺癌的发展中起着非常重要的作用，但它们在很大程度上尚未得到研究。我们建议通过研究基因特异性和全局DNA甲基化模式与乳腺癌之间的关系来填补这一知识空白。

Global DNA hypomethylation and regional DNA hypermethylation are known to accompany the development and progression of breast cancer. We hypothesize that global and gene-specific DNA methylation are associated with breast cancer risk. We further hypothesize that folate, vitamin B12 and vitamin C status might influence breast cancer risk via effects on DNA methylation. The rationale for studying the first two vitamins is that they play a key metabolic role in supplying methyl groups for DNA methylation in tissues. In addition, recent studies suggest that poor dietary intake of folate, particularly when combined with other breast cancer risk factors such as alcohol, may increase the risk for breast cancer. Our study design proposes to collect 100 primary breast carcinomas from women who have not been on estrogen replacement therapy. A sample of adjacent uninvolved breast tissue will be obtained from each breast carcinoma specimen. In Specific Aim 1, fresh frozen breast tissues will be used to evaluate differences between breast carcinoma and adjacent normal breast tissue, with respect to DNA methylation (global, anti-5-methylcytosine, CpG island and gene specific). In Specific Aim 2, the focus will shift to the relationship between tissue, circulating and dietary folate, vitamin B12 and vitamin C status, DNA methylation and MTHFR polymorphism in these breast cancer patients and controls. Our proposal will have an impact on breast cancer because it will provide basic information relative to factors that control methylation of specific genes or regions of the chromosome that are important in the development of breast cancer. DNA hypomethylation in cancer, as well as chromosomal alterations that may result from hypomethylation, have been known for some time. These changes in chromatin structure could play a very important role in the development of breast cancer, but they have been largely uninvestigated. We propose to fill this gap in knowledge by investigating the association between gene-specific and global DNA methylation patterns and breast cancer.