EPIGENETIC CHANGES AND VITAMIN STATUS IN BREAST CANCER

众所周知，整体DNA低甲基化和局部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的DNA甲基化与乳腺癌风险有关。我们进一步假设，叶酸、维生素B12和维生素C状态可能通过对DNA甲基化的影响而影响乳腺癌风险。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起着关键的代谢作用。此外，最近的研究表明，叶酸的饮食摄入不足，特别是与酒精等其他乳腺癌风险因素结合在一起时，可能会增加乳腺癌的风险。我们的研究设计建议从没有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取相邻的未受影响的乳腺组织的样本。在具体目标1中，新鲜的冷冻乳腺组织将被用来评估乳腺癌和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。在具体目标2中，重点将转移到这些乳腺癌患者和对照组的组织、循环和饮食叶酸、维生素B12和维生素C状态、DNA甲基化和MTHFR多态之间的关系。我们的提案将对乳腺癌产生影响，因为它将提供与控制特定基因或染色体区域甲基化的因素相关的基本信息，这些基因或区域在乳腺癌的发展中非常重要。癌症中的DNA低甲基化，以及可能由低甲基化导致的染色体改变，已经被知道了一段时间。染色质结构的这些变化可能在乳腺癌的发展中起到非常重要的作用，但它们在很大程度上还没有得到研究。我们建议通过研究基因特异性和全球DNA甲基化模式与乳腺癌之间的联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.