Multifaceted integration for estrogen receptor

摘要 人雌激素受体α（ER α）是乳腺癌细胞增殖的分子驱动因子 癌获得性ER α突变-Y537S和D538G是最常见的两种-代表了一种 新认识的耐药机制，由于其组成型转录活性。我们的初步 数据和最近发表的报告表明，这些耐药突变体是非传统的治疗药物， 靶向小分子结合以调节其活性并抑制细胞增殖。但 耐药突变作用于受体以调节激素信号的机制， 小分子抑制剂结合受体进行干预的程度尚不清楚。 ER α具有两个主要的功能实体，即，DNA结合结构域（DBD）和配体结合结构域 结构域（LBD）。我们最近报道了多结构域组装，并揭示了之间的相互作用模式 这两个域，通过以前未表征的域桥接接口。具体而言，突变 结构域界面阻止了两个结构域的通信并抑制了ER α活性，突出了 作为具有受体功能的损失/获得的"变构"通道的结构域界面的调节。该功能 重要性提出了以下问题：（a）耐药突变是否改变了结构域-结构域组装 以及DBD-LBD交互的模式，以及（B）域桥接接口是否/如何能够被 小分子来破坏受体活性。我们的初步研究表明一个被重新利用的小分子 通过结构域界面结合受体并抑制ER α介导的细胞功能。基于这些 研究结果和其他初步数据，我们假设ER α结构域如何相互作用， 受这些耐药突变的影响，这种结构域-结构域相互作用对于小分子 结合以改变受体功能。为了验证这一假设，我们将描述 抗病突变体（Y537S/D538G），并检查抑制剂的分子和功能相关性， 受体结合与目前所有药物都结合的酶结合口袋相反，这项研究将提供 ER α结构域界面作为小分子结合的新靶位点的新见解，并最终 为ER阳性乳腺癌治疗耐药性提供了急需的分子理解。

Abstract Human estrogen receptor alpha (ERα) is a molecular driver of hormone-responsive cell proliferation in breast cancer. Acquired ERα mutations—Y537S and D538G being the two most commonly found—represent a newly recognized mechanism of drug resistance due to their constitutive transcription activity. Our preliminary data and recently published reports indicate that these drug-resistant mutants are non-conventional therapeutic targets for small molecule binding to modulate their activity and inhibit cell proliferation. However, the mechanisms by which drug- resistant mutations act on the receptor to regulate hormonal signaling and the extent to which small molecule inhibitors bind the receptor for intervention are not yet known. The ERα harbors two major functional entities, i.e., the DNA-binding domain (DBD) and the ligand-binding domain (LBD). We recently reported the multi-domain assembly and revealed the mode of interactions between these two domains, through a previously uncharacterized domain-bridging interface. Specifically, mutations at the domain-interface prevent the two domains from communicating and inhibit ERα activity, highlighting the modulation of the domain- interface as an “allosteric” channel with loss/gain of receptor function. This functional significance raises the questions of (a) whether the drug-resistant mutations alter the domain-domain assembly and the mode of DBD-LBD interactions, and (b) whether/how the domain-bridging interface can be targeted by small molecules to disrupt receptor activity. Our preliminary studies show that a repurposed small molecule binds the receptor via the domain-interface and inhibits ERα-mediated cellular function. Based on these findings and other preliminary data, we hypothesize that how the ERα domains interact with one another is influenced by these drug- resistant mutations and this domain-domain interaction is critical for small molecule binding to alter receptor function. To test this hypothesis, we will characterize the multi-domain assemblies of disease-resistant mutants (Y537S/D538G) and examine the molecular and functional correlation of inhibitor- receptor binding. In contrast to the hormone-binding pocket where all current drugs bind, this study will provide novel insights into the ERα domain-interface as a new target site for small molecule binding, and ultimately offer a much-needed molecular understanding of ER-positive breast cancer therapy resistance.