RAC1 plays an essential role in estrogen receptor alpha function in breast cancer cells
Open Access
- 9 August 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (40), 5950-5962
- https://doi.org/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.Funding Information
- Lampert gift
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (5R01CA166835, 1P30CA240139)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
This publication has 61 references indexed in Scilit:
- Exome sequencing identifies recurrent somatic RAC1 mutations in melanomaNature Genetics, 2012
- A Landscape of Driver Mutations in MelanomaCell, 2012
- Fast gapped-read alignment with Bowtie 2Nature Methods, 2012
- Steroid receptor coactivators 1, 2, and 3: Critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapyMolecular and Cellular Endocrinology, 2012
- RAC3 is a pro-migratory co-activator of ERαOncogene, 2011
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Cofactor Dynamics and Sufficiency in Estrogen Receptor–Regulated TranscriptionCell, 2000
- Oestrogen-responsive human breast cancer in long term tissue cultureNature, 1975