Estrogen Receptor Variants and Breast Cancer

雌激素受体变异与乳腺癌

• 批准号: 6870190
• 负责人: Sohaib A. Khan
• 金额: $ 27.54万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870190
• 关键词: breast neoplasms; cell line; estradiol; estrogen inhibitor; estrogen receptors; gene induction /repression; gene mutation; hormone regulation /control mechanism; hormone related neoplasm /cancer; mitogen activated protein kinase; neoplasm /cancer genetics; neoplasm /cancer pharmacology; nuclear magnetic resonance spectroscopy; phosphatidylinositol 3 kinase; protein isoforms; protein protein interaction; protein structure function; receptor binding; site directed mutagenesis; surface plasmon resonance; yeast two hybrid system

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.

描述：（由申请人提供）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，患乳腺癌的人数增加了一倍，目前八分之一的女性患乳腺癌 有患这种疾病的风险。雌激素在其中发挥着重要作用 乳腺癌的发展。雌激素的有丝分裂作用被放大 激素依赖性转录因子，雌激素受体（ER）， 以配体依赖性方式组装转录辅助蛋白。这 多方面的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) 的调整。然而，贡献 在 ER 作用的这个关键阶段，相邻 F 域的状态不佳 明白了。我们假设 ERa 的 F 域有助于 配体诱导的 LBD 构象，决定了招募 共调制器到 ER 上以发挥其功能。在目标 1 中，我们将重点关注 配体依赖性共激活剂募集中的 ERa F 结构域。我们有 设计了几种方法来解决这个问题，其中包括共激活剂 在染色质不存在和存在的情况下通过 F 结构域突变体进行募集。目标2 将测量 F 域扰动对生物的影响 ERa 的性质。在目标 3 中，我们将采用 NMR 分析来解决最常见的问题 F 域是否影响 LBD 的整体拓扑是一个紧迫的问题。 在缺乏 E-F 域晶体结构的情况下，我们的结果 Aim 将首次阐明 E-F 域的解决方案结构。 这将极大地帮助我们理解 ERa 的作用机制。目标 4 将确定 F 结构域是否影响 ER 的非遗传性作用。我们 期望成功完成我们的目标不仅会提供 更好地了解雌激素受体的作用，也将提供新的 开发新的药理化合物来拮抗的机会 雌激素的促有丝分裂作用。