Fetal alcohol, estrogen-regulated genes and prostate cancer

 描述(由申请人提供)：现在人们普遍认为，怀孕期间暴露在不利的环境条件和生活方式选择中会导致胎儿程序化，这是成年后疾病易感性的基础。一个研究不足的领域是母亲酗酒对子女患癌症的影响。迅速积累的大量证据表明，许多疾病必须从终生的角度来理解，就像从受孕开始到几十年后临床检测出来的轨迹。在怀孕期间改变性激素水平的因素可能会对后代的健康产生长期影响，包括前列腺癌风险的变化。现在有几项研究发现，怀孕期间酒精摄入量与血清雌激素水平呈正相关。尽管有这些信息，但很少有研究确定怀孕期间酒精促进雌激素水平与后代患前列腺癌或其他癌症风险的关系。我们最近对啮齿动物的研究提供了证据，证明出生前接触酒精的动物前列腺癌的发病率更高。此外，已有研究表明，暴露于酒精的胎鼠后代中，前列腺癌进展为恶性表型的频率更高。因此，研究酒精诱导的胎盘程序化促进前列腺癌的机制是一个需要研究的重要问题。我们现在有初步证据表明，酒精对前列腺的发育重新编程可能部分是通过ESR1激活的转录机制介导的。本申请的目的是详细描述早期酒精暴露引起的前列腺组织中转录变化的特征，并确定它们是否参与致癌的易感性。因此，我们建议确定雌激素受体1的激活是否会促进，而阻断雌激素受体活性是否会抑制胎儿酒精诱导的转录反应和肿瘤易感性。我们建议使用CHIP-SEQ来确定雌激素受体1的占位位置，并使用RNA-SEQ来确定胎儿酒精诱导的前列腺中基因表达的变化。此外，还将采用免疫细胞化学和组织病理学方法来测量前列腺癌的生长和进展。拟议的研究采用了一种综合的方法，包括调查在致癌过程中胎儿酒精暴露引起的受影响组织中雌激素受体1结合和基因表达的全基因组变化。这些研究解决了一个重要的问题，即早期酒精暴露导致的前列腺癌的表观遗传/基因组印记是否会增加前列腺癌的易感性。这些研究具有很高的创新性，因为它们将首次确定前列腺癌胎儿酒精编程过程中增加肿瘤发生敏感性的分子途径。

 DESCRIPTION (provided by applicant): It is now widely accepted that exposure to adverse environmental conditions and lifestyle choices during pregnancy can result in fetal programming that underlies disease susceptibility in adulthood. One area that is understudied is the impact of maternal alcohol abuse on the offspring's susceptibility to cancer. A rapidly accumulating body of evidence indicates that many diseases must be understood in a life-long perspective, as trajectories that start at conception and surface upon clinical detection decades later. Factors that change sex hormone levels during pregnancy may have long-term health consequences for the offspring, including changes in prostate cancer risk. Several studies now identified alcohol intake positively correlated with the serum estrogen levels during pregnancy. Despite this information, very few studies have conducted to determine the association of alcohol promotion of estrogen level during pregnancy with the subsequent risk of prostate or other cancer risk in offspring. Our recent studies in rodents have provided evidence for higher incidence of prostate cancers in prenatal alcohol exposed animals. In addition, it has been shown that prostate tumors progress more frequently to a malignant phenotype in fetal alcohol-exposed rat offspring. Therefore, the study of the mechanism by which alcohol-induced fetal programming promotes prostate cancer is an important issue that needs investigation. We now have preliminary evidence that developmental reprogramming of the prostate by alcohol may be mediated, in part, through ESR1 activated transcriptional machineries. The objectives of the present application are to characterize in detail the transcriptional alterations in the prostatic tissues that result from early-life alcohol exposures and to determine if they are involved in predisposition to carcinogenesis. Hence, we propose to determine if the estrogen receptor 1-activation will promote while blocking estrogen receptor activity will suppress fetal alcohol-induced transcriptional responses and tumor susceptibility. We propose to use ChIP-seq to identify sites of occupancy for estrogen receptor 1 and RNA-seq to determine changes in gene expression in the prostate induced by fetal alcohol. Additionally, immunocytochemical and histopathological approaches will be employed to measure the growth and progression of prostatic tumors. The proposed studies employ an integrated approach that include the investigation of genome-wide changes in estrogen receptor 1 binding and gene expression caused by fetal alcohol exposure in the effected tissue during carcinogenesis. These studies address an important issue if epigenetic/genomic imprinting of the prostate gland by early ethanol exposure augments the susceptibility to prostate cancer. These studies are highly innovative as they would be the first to identify the molecular pathway in the process of fetal alcohol programming of the prostate that increases the sensitivity to tumorigenesis.