Clinically Observed Estrogen Receptor Alpha Mutations within the Ligand-Binding Domain Confer Distinguishable Phenotypes.
Clinically Observed Estrogen Receptor Alpha Mutations within the Ligand-Binding Domain Confer Distinguishable Phenotypes.
复制标题
临床观察到配体结合域内的雌激素受体α突变赋予可区分的表型。
作者：
Jia,Shanhang;Miedel,MarkT;Ngo,Marilyn;Hessenius,Ryan;Chen,Ning;Wang,Peilu;Bahreini,Amir;Li,Zheqi;Ding,Zhijie;Shun,TongYing;Zuckerman,DanielM;Taylor,DLansing;Puhalla,ShannonL;Lee,AdrianV;Oesterreich,Steffi;Stern,Andrew
20%至50%的雌激素受体阳性（ER+）转移性乳腺癌在ER配体结合结构域内表达突变。虽然大多数研究集中在雌激素剥夺治疗过程中选择这些突变通常产生的组成性ER信号传导活性，我们的研究旨在调查不同的突变赋予这类内独特的表型。MethodsWe研究了两个最普遍的突变，D538 G和Y 537 S，采用确证的基因组编辑和慢病毒转导的ER+ T47 D细胞模型。我们使用了一个基于腺苷酸酶的报告和内源性磷酸-ER免疫印迹分析，以表征雌激素反应的ER突变体，并确定其电阻已知的ER antagonists.ResultsConsistent与他们的选择在雌激素剥夺治疗，这些突变体赋予组成性ER活性。虽然Y 537 S突变体没有表现出雌激素依赖性，但D538 G突变体表现出增强的雌激素依赖性反应。这两种突变赋予抵抗ER拮抗剂，克服了在更高的剂量作用，特别是通过他们的ER target.ConclusionsThese观察提供了一个站得住脚的假设D538 G ESR 1表达克隆如何可以有助于更短的无进展生存期观察到的BOLERO-2研究的阿司坦手臂。因此，在那些具有显性D538 G表达克隆的患者中，对循环游离DNA中的这种突变的纵向分析可能证明有利于提供更优化的治疗方案。
ObjectiveTwenty to fifty percent of estrogen receptor-positive (ER+) metastatic breast cancers express mutations within the ER ligand-binding domain. While most studies focused on the constitutive ER signaling activity commonly engendered by these mutations selected during estrogen deprivation therapy, our study was aimed at investigating distinctive phenotypes conferred by different mutations within this class.MethodsWe examined the two most prevalent mutations, D538G and Y537S, employing corroborative genome-edited and lentiviral-transduced ER+ T47D cell models. We used a luciferase-based reporter and endogenous phospho-ER immunoblot analysis to characterize the estrogen response of ER mutants and determined their resistance to known ER antagonists.ResultsConsistent with their selection during estrogen deprivation therapy, these mutants conferred constitutive ER activity. While Y537S mutants showed no estrogen dependence, D538G mutants demonstrated an enhanced estrogen-dependent response. Both mutations conferred resistance to ER antagonists that was overcome at higher doses acting specifically through their ER target.ConclusionsThese observations provide a tenable hypothesis for how D538G ESR1-expressing clones can contribute to shorter progression-free survival observed in the exemestane arm of the BOLERO-2 study. Thus, in those patients with dominant D538G-expressing clones, longitudinal analysis for this mutation in circulating free DNA may prove beneficial for informing more optimal therapeutic regimens.