Estrogen Receptor Variants and Breast Cancer

描述：（由申请人提供）乳腺癌是最常见的癌症之一。 影响妇女的毁灭性疾病。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，目前每八名妇女中就有一名 有患上这种疾病的风险雌激素在这一过程中起着重要的作用。 乳腺癌的发展。雌激素的促有丝分裂作用被放大， 雌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是由配体诱导的构象 ER的配体结合结构域（LBD）的调节。然而，贡献 在ER作用的这个关键阶段，邻近F-结构域的 明白我们假设ER α的F-结构域有助于 LBD的配体诱导构象，其决定了LBD的募集。 为它的功能添加了共调节剂。在目标1中，我们将重点关注 ER α F结构域在辅激活因子的配体依赖性募集中的作用。我们有 设计了几种方法来解决这个问题，其中包括辅活化剂， 在不存在和存在染色质的情况下通过F结构域突变体的募集。目的2 将测量F域扰动对生物学特性的影响。 ER a的特性。在目标3中，我们将使用NMR分析来解决最 F域是否影响LBD的整体拓扑结构的紧迫问题。 在缺乏E-F结构域的晶体结构的情况下，我们的结果从这个 Aim将首次揭示E-F域的解结构。 这将极大地帮助我们理解ERa作用的机制。目标4 将确定F-结构域是否影响ER的非遗传性作用。我们 我们期望，成功地完成我们的目标不仅将提供一个 更好地了解雌激素受体的作用，但也将提供新的 开发新的药理学化合物来拮抗 雌激素的促有丝分裂作用。

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.