Defining the Genome-wide Alcohol-induced Transcriptional Changes in Breast Cancer

项目摘要 乳腺癌是一种复杂的疾病，尽管经过多年的研究，仍有许多有待了解 它的开始和发展。除了遗传因素外，乳腺癌还可能受到外部因素的影响。 如饮食和化学品。数百项流行病学研究表明， 乳腺癌和适度饮酒之间的联系此外，流行病学和实验 有证据表明雌激素和酒精之间存在相互作用，尽管确切的关系尚未确定。 尽管有这些证据，酒精到底是如何导致乳腺癌的，以及酒精与雌激素的协同作用仍然存在。 不太了解。 一般来说，许多参与癌症进展的分子因素最终会引起他们的免疫反应。 通过引起基因表达的变化而产生影响。调节基因表达的关键控制点是在 mRNA转录水平。因此，理解酒精诱导的转录扰动， 乳腺癌细胞中的基因水平将大大有助于理解乳腺癌的分子基础。 乳腺癌发病率的增加可归因于饮酒。 这项拟议中的研究将使用基因组技术来确定转录如何响应 在三种人类细胞类型中的酒精处理：1）雌激素受体阳性乳腺癌细胞，2）雌激素 受体阴性乳腺癌细胞和3）正常乳腺细胞。此外，雌激素对 将在所有三种细胞类型中确定整体酒精诱导的转录变化。重要的是 将使用的技术-BrU-seq和Pol II ChIP-seq-将区分真正的转录变化 其他生物学途径的变化影响细胞RNA水平。 拟议中的工作将对促进对 适度饮酒与乳腺癌增加之间的关系。识别基因 其转录水平因酒精而改变，将揭示酒精 有助于进展为临床上显著的乳腺癌。因此，结果将建立一个很大的 这是未来研究酒精诱发乳腺癌的病因学及其治疗所需要的平台。 进展

PROJECT SUMMARY Breast cancer is a complex disease, and despite years of research, much remains to be learned about its initiation and progression. In addition to genetic factors, breast cancer can also be impacted by external factors such as diet and chemicals. Hundreds of epidemiology studies have shown a positive correlation between breast cancer and moderate alcohol consumption. Moreover, epidemiological and experimental evidence suggest an interplay between estrogen and alcohol, although the precise relationship is not defined. Despite this evidence, how exactly alcohol contributes to breast cancer and synergizes with estrogen remain poorly understood. In general, many of the molecular factors that are involved in cancer progression ultimately elicit their effects by causing changes in gene expression. A critical control point for regulating gene expression is at the level of mRNA transcription. Therefore, an understanding of alcohol-induced perturbations in the transcription levels of genes in cancerous breast cells would significantly contribute to understanding the molecular basis for the increase in breast cancer development attributable to alcohol consumption. The proposed study will use genomic techniques to determine how transcription changes in response to alcohol treatment in three human cell types: 1) estrogen receptor positive breast cancer cells, 2) estrogen receptor negative breast cancer cells, and 3) normal breast cells. In addition, the impact of estrogen on the global alcohol-induced transcriptional changes will be determined in all three cell types. Importantly, the techniques that will be used – BrU-seq and Pol II ChIP-seq – will distinguish bona fide transcriptional changes from changes in other biological pathways that impact cellular RNA levels. The proposed work will constitute an important contribution toward advancing understanding of the relationship between moderate alcohol consumption and increased breast cancer. Identifying the genes whose transcription levels change due to alcohol will reveal new potential mechanisms by which alcohol contributes to the progression to clinically significant breast cancer. Hence, the results will build a much needed platform for future research to investigate the etiology of alcohol-induced breast cancer and its progression.