Repressive Transcriptional Programs in Breast Cancer

摘要 我们提出了一项研究乳腺癌细胞中核受体之间的功能相互作用的项目。 在这项美国-NFSC倡议下，具有巨大的科学和智力利益，基于两个密切- 合作的调查人员有共同的研究兴趣，但具有不同的专业领域。迈克尔博士 罗森菲尔德和刘文有着广泛的有效合作历史，这在许多方面都是明证 过去十年的基本发现，包括九篇合著论文。这个项目，涉及一个 持续、密切的科学互动和协作是基于他们的互补专业知识、重点和 资源。我们建议建立一种未被认可但关键的分子策略，作为基础 对于大型增强子依赖的编码目标基因转录抑制的程序，在乳房中很重要 癌症。这一计划取决于这样一个事实，即ERα是以反式方式招募到基础活性增强子的 介导抑制转录程序，与反式结合的ERα受体招募去甲基酶， 基于其DNA结合域的可用性，这反过来又招募导致Pol被解雇的机制 II来自这些碱基高活性的增强剂，导致它们的抑制。因此，该机制代表了一种 一种以前不被认可的压抑策略，涉及到一组强大的基因 十年无转移生存期的预后指标。这将揭示一组基本上被忽视的 乳腺癌患者的预后生物标志物，可能最终提供潜在的治疗靶点 或预防侵袭性乳腺癌。提出了一种加强配基能力的策略。 糖皮质激素受体在乳腺癌细胞中抑制ERα激活的调节增强子，基于 核受体家族不同成员之间的竞争。

ABSTRACT We propose a study of functional interactions between nuclear receptors in breast cancer cells as a project under this USA-NFSC initiative, with great scientific and intellectual benefit, based on the efforts of two closely- collaborating investigators with shared research interests, but with disparate areas of expertise. Drs. Michael Rosenfeld and Wen Liu have an extensive history of effective collaborations, as evidenced in a number of fundamental discoveries over the past ten years, including nine co-authored papers. This project, involving a sustained, close scientific interaction and collaboration is based on their complementary expertise, focus and resources. We propose to establish an unappreciated, but critical, molecular strategy that serves as the basis for large enhancer-dependent programs of coding target gene transcriptional repression important in breast cancer. This program depends on the fact that ERα is recruited in trans to the basally active enhancers that mediate the repressive transcriptional program, with trans-bound ERα receptor recruiting a demethylase, based on the availability of its DNA binding domain, which in turn recruits machinery leading to dismissal of Pol II from these basally highly active enhancers, causing their repression. This mechanism therefore represents a previously unappreciated type of repressive strategy, and involves a gene set that serves as a powerful prognostic indicator of a ten-year metastasis-free survival. This would uncover a set of largely overlooked prognostic biomarkers for breast cancer patients, perhaps ultimately providing a potential target for treatment or prevention of aggressive breast cancers. A strategy is proposed to underlie the ability of liganded glucocorticoid receptor to inhibit the ERα-activated regulatory enhancers in breast cancer cells, based on competition between different members of the nuclear receptor family.