Estrogen Receptor Variants and Breast Cancer

描述：(申请人提供)乳腺癌是影响女性的最具破坏性的疾病之一。北美女性面临的风险 自1940年以来，患乳腺癌的人数翻了一番，目前每八名女性中就有一名 有患上这种疾病的风险。雌激素在体内起着重要作用 乳腺癌的发展。雌激素的促有丝分裂作用被放大 激素依赖的转录因子雌激素受体(ER)，它 以配体依赖的方式组装转录辅助蛋白。这 多面化过程在很大程度上得益于配体诱导的构象 ER配体结合域(LBD)的调节。然而，这一贡献 在ER作用的这个关键阶段，相邻的F-结构域的情况不是很好 明白了。我们假设ERA的F-域对 配体诱导的LBD构象，决定了LBD的募集 共调器安装在ER上以实现其功能。在目标1中，我们将重点介绍 Era F结构域在配体依赖的共激活因子招募中的作用。我们有 设计了几种方法来解决此问题，其中包括协同激活剂 在没有染色质和存在染色质的情况下F结构域突变体的招募。目标2 将测量F域扰动对生物的影响 时代的属性。在目标3中，我们将使用核磁共振分析来解决大多数 F-结构域是否会影响LBD的整体拓扑的紧迫问题。 在缺乏E-F结构域的晶体结构的情况下，我们的结果是 AIM将首次阐明E-F领域的解决方案结构。 这将极大地帮助我们理解时代行动的机制。目标4 将决定F结构域是否影响ER的非遗传行为。我们 期望成功完成我们的目标不仅将提供 更多地了解雌激素受体的作用，但也将提供新的 开发新的药理化合物以对抗 雌激素的促分裂作用。

DESCRIPTION: (provided by the applicant) Breast cancer is among the most devastating diseases affecting women. The risk for a North American women getting breast cancer has doubled since 1940, and at present one woman in eight is at risk of developing the disease. Estrogens play a significant role in the development of breast cancer. The mitogenic action of estrogen is amplified by the hormone-dependent transcription factor, estrogen receptor (ER), which assembles transcription accessory proteins in a ligand dependent manner. This multifaceted process is largely aided by the ligand-induced conformational adjustments in the ligandbinding domain (LBD) of ER. However, the contribution of the neighboring F-domain in this critical stage of ER action is not well understood. We hypothesize that the F-domain of ERa contributes to the ligandinduced conformation of the LBD, which determines the recruitment of comodulators onto ER for its function. In Aim 1, we will focus on the role of ERa F-domain in the ligand-dependent recruitment of coactivators. We have designed several approaches to address this issue, which include coactivator recruitment by F-domain mutants in the absence and presence of chromatin. Aim 2 will measure the consequence of F-domain perturbation on the biological properties of ERa. In Aim 3, we will employ NMR analysis to address the most pressing question of whether F-domain affects the overall topology of the LBD. In the absence of a crystal structure of the E-F domain, our results from this Aim will, for the first time, shed light on E-F domain's solution structure. This will greatly aid us in understanding the mechanism of ERa actions. Aim 4 will determine if the F-domain influences the non-genotropic actions of ER. We expect that a successful completion of our objectives will not only provide a greater understanding of estrogen receptor actions, but will also provide new opportunities to develop novel pharmacological compounds to antagonize the mitogenic actions of estrogens.