Repressive Transcriptional Programs in Breast Cancer

摘要 我们提出了一个研究乳腺癌细胞核受体之间的功能相互作用作为一个项目 在美国-NFSC倡议下，具有巨大的科学和智力效益，基于两个密切的努力- 合作研究人员有共同的研究兴趣，但有不同的专业领域。迈克尔博士 罗森菲尔德和刘文在有效合作方面有着广泛的历史，这一点在许多 在过去的十年中，包括九个共同撰写的论文的基本发现。该项目涉及一个 持续、密切的科学互动和合作是基于他们互补的专业知识、重点和 资源我们建议建立一个不受重视的，但关键的，分子战略，作为基础， 对于乳腺癌中重要的编码靶基因转录抑制的大增强子依赖性程序 癌该程序依赖于ERα被反式募集到基础活性增强子的事实， 介导抑制性转录程序，反式结合ERα受体募集脱甲基酶， 基于其DNA结合域的可用性，其反过来招募导致Pol被解雇的机制， II从这些基础上高度活跃的增强子，导致他们的镇压。因此，该机制代表了 这是一种以前不受重视的压抑策略，涉及一组基因， 十年无转移生存的预后指标。这将揭示一系列基本上被忽视的 乳腺癌患者的预后生物标志物，也许最终提供了一个潜在的治疗目标， 或预防侵袭性乳腺癌。提出了一种策略来支持配体的能力， 糖皮质激素受体抑制乳腺癌细胞中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.