诱导二元化的体质雌激素受体α突变促进受体活性和乳腺癌扩散
Seema Irani1, Wuwei Tan2, Qing Li1
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
The Journal of clinical investigation
|October 26, 2023
概括
新的乳腺癌突变通过促进受体二分化来激活雌激素受体α (ERα),而不是通过重新定位螺旋12. 这种独特的机制为ER-依赖性癌症提供了潜在的治疗点.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 结构生物学是结构生物学.
背景情况:
- 雌激素受体α (ERα) 的激活通常需要雌激醇 (E2) 结合,从而导致螺旋体12重新定位以招募联合激活剂.
- 乳腺癌中ERα的突变很常见,通常会通过螺旋体12重新定位引起E2独立激活.
- 在乳腺癌患者中发现的一组ERα突变通过未知的机制起作用.
研究的目的:
- 通过在乳腺癌中发现的新突变来研究E2独立ERα激活的机制.
- 为了确定这些突变是否与已知的H12重新定位突变体相比,代表了不同的激活途径.
- 探索针对这种新发现的ERα激活机制的治疗潜力.
主要方法:
- 扩展了乳腺癌患者的遗传测序.
- 机器学习和计算结构分析.
- 在体外和细胞内测定中使用全长ERα和孤立的带结合域.
- 局部定向的突变发生来破坏ERα二元化.
主要成果:
- 鉴定了远离螺旋12的ERα突变,促进了E2独立转录和癌细胞生长.
- 计算分析表明,这些突变在ERα二聚体接口上诱导了构造变化.
- 实验分析证实,这些突变物增强了ERα二分化,稳定性和核定位.
- 特别破坏二分化的突变取消了E2独立的转录活性.
结论:
- 通过一种新的机制激活ERα,该机制涉及强制受体二分化,独立于螺旋体12的重新定位.
- 这种由二分化驱动的激活促进了乳腺癌细胞的增殖.
- 破坏ERα二分化为ER-依赖性癌症提供了一个潜在的治疗策略.
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