RAC1 Plays an Essential Role in Estrogen Receptor Alpha Function in Breast Cancer Cells

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2021 Aug 10

PMID 34373577

Citations 7

Authors

Jun Sun

Gabriel Gaidosh

Ye Xu

Adnan Mookhtiar

Na Man

Pradeep Reddy Cingaram

Ezra Blumenthal

Ramin Shiekhattar

Erik T Goka

Stephen D Nimer

Marc E Lippman

Affiliations

Soon will be listed here.

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.

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