RAC1 plays an essential role in estrogen receptor alpha function in breast cancer cells

Jun Sun,Gabriel Gaidosh,Stephen D Nimer,Adnan Mookhtiar,Ezra Blumenthal,Pradeep Reddy Cingaram,Erik T Goka,Ramin Shiekhattar,Na Man,Marc E Lippman,Ye Xu

doi:10.1038/s41388-021-01985-1

Abstract

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.

Highlights

Estrogens play important physiological roles in various organs and participate in cancer development [1], in the 80% of breast cancers that are estrogen receptor alpha (ER)-positive [2], where estrogen promotes tumor growth [3]
We found that protein levels of RAC1 and ER were reduced in MCF-7 cells after cells were transfected with siRNAs targeting RAC1, two different
While RAC1 plays an essential role in mouse embryogenesis [39], genome-wide screens have found that RAC1 could be knocked out in cells from several cancer types [40]

Summary

Introduction

Estrogens play important physiological roles in various organs and participate in cancer development [1], in the 80% of breast cancers that are estrogen receptor alpha (ER)-positive [2], where estrogen promotes tumor growth [3]. ER is activated by estrogen to regulate gene transcription [4]. Estrogen stimulates the assembly of a multi-protein complex, which contains coactivators such as steroid receptor coactivators, and chromatin remodelers such as CARM1 and p300/CBP that cooperatively regulate ER target gene expression [5,6,7,8]. RAC1 is ubiquitously expressed [10] and plays important roles in cell adhesion, migration, cell cycle progression, transcriptional regulation, and tumor formation. Small molecule Rac inhibitors have been developed as potential cancer therapeutic agents [20,21,22], such as the Rac inhibitor EHT 1864, which blocks Rac and GTP interaction and keeps Rac in an inactive state [23]

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