Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Oncogene. 2021 Oct;40(40):5950-5962. doi: 10.1038/s41388-021-01985-1. Epub 2021 Aug 9.
The activity of Rho family GTPase protein, RAC1, which plays important normal physiological functions, is dysregulated in multiple cancers. RAC1 is expressed in both estrogen receptor alpha (ER)-positive and ER-negative breast cancer (BC) cells. However, ER-positive BC is more sensitive to RAC1 inhibition. We have determined that reducing RAC1 activity, using siRNA or EHT 1864 (a small molecule Rac inhibitor), leads to rapid ER protein degradation. RAC1 interacts with ER within the ER complex and RAC1 localizes to chromatin binding sites for ER upon estrogen treatment. RAC1 activity is important for RNA Pol II function at both promoters and enhancers of ER target genes and ER-regulated gene transcription is blocked by EHT 1864, in a dose-dependent manner. Having identified that RAC1 is an essential ER cofactor for ER protein stability and ER transcriptional activity, we report that RAC1 inhibition could be an effective therapeutic approach for ER-positive BC.
Rho 家族 GTP 酶蛋白 RAC1 的活性在多种癌症中失调，而 RAC1 发挥着重要的正常生理功能。RAC1 在雌激素受体 alpha（ER）阳性和 ER 阴性乳腺癌（BC）细胞中均有表达。然而，ER 阳性 BC 对 RAC1 抑制更为敏感。我们已经确定，使用 siRNA 或 EHT 1864（一种小分子 Rac 抑制剂）降低 RAC1 活性会导致 ER 蛋白迅速降解。RAC1 在 ER 复合物内与 ER 相互作用，并且在雌激素处理时，RAC1 定位于 ER 的染色质结合位点。RAC1 活性对于 ER 靶基因的启动子和增强子处的 RNA Pol II 功能很重要，并且 EHT 1864 以剂量依赖的方式阻断 ER 调节的基因转录。由于已经确定 RAC1 是 ER 蛋白稳定性和 ER 转录活性的必需 ER 共因子，我们报告称 RAC1 抑制可能是 ER 阳性 BC 的一种有效治疗方法。
