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

定义酒精诱导的乳腺癌全基因组转录变化

基本信息

批准号：
9761407
负责人：
Jennifer F. Kugel
金额：
$ 7.7万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761407
关键词：
Address Alcohol consumption Alcohols Binding Sites Biological Breast Breast Cancer Cell Breast Cancer Risk Factor Bromouridine sequencing Cancer Etiology Cancerous breast Cells ChIP-seq Chemicals Clinical Complex DNA Polymerase II Development Diet Disease Disease Progression Environmental Risk Factor Epidemiology Estrogen receptor negative Estrogen receptor positive Estrogens Ethanol Etiology Foundations Future Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genomics Human Life Malignant Neoplasms Medical Messenger RNA Molecular Mutation Pathway interactions Pattern Process RNA RNA Polymerase II Research Research Personnel Role Techniques United States Woman Work alcohol abuse therapy alcohol exposure alcohol response breast cancer progression cell type epidemiology study experimental study genome-wide insight malignant breast neoplasm mortality transcription factor tumor progression

项目摘要

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.

项目总结乳腺癌是一种复杂的疾病，尽管进行了多年的研究，但仍有许多有待了解它的启动和发展。除了遗传因素，乳腺癌还可能受到外部因素的影响饮食和化学物质等因素。数百项流行病学研究表明，两者之间存在正相关乳腺癌和适度饮酒之间的区别。此外，流行病学和试验性有证据表明，雌激素和酒精之间存在相互作用，尽管确切的关系并不是deﬁNed。尽管有这些证据，但酒精究竟如何导致乳腺癌并与雌激素协同作用仍然存在。人们对此知之甚少。总体而言，许多与癌症进展有关的分子因素最终导致了它们的通过引起基因表达的变化而产生的影响。调控基因表达的一个关键控制点是 MRNA转录水平。因此，对酒精诱导转录扰动的理解乳腺癌细胞中的基因水平将显著有助于理解ﬁ的分子基础由于饮酒导致的乳腺癌发病率的增加。这项拟议的研究将使用基因组技术来确定转录是如何变化的。酒精对三种类型的人细胞的作用：1)雌激素受体阳性的乳腺癌细胞，2)雌激素受体阴性的乳腺癌细胞和3)正常乳腺细胞。此外，雌激素对女性性激素的影响全球酒精诱导的转录变化将在所有三种细胞类型中确定。重要的是，将使用的技术-Bru-seq和POLII芯片-seq-将区分博纳ﬁ的转录变化影响细胞RNA水平的其他生物途径的变化。拟议的工作将对增进对适量饮酒与乳腺癌增加的关系。鉴定基因它们的转录水平因酒精而改变将揭示酒精通过有助于临床上ﬁ不能的乳腺癌的进展。因此，结果将建立一个很大的为未来研究酒精诱发乳腺癌的病因及其相关因素提供必要的平台进步。