Estrogen-independent Molecular Actions of Mutant Estrogen Receptor 1 in Endometrial Cancer

Overview

Journal Genome Res

Specialty Genetics

Date 2019 Aug 1

PMID 31362937

Citations 20

Authors

Zannel Blanchard

Jeffery M Vahrenkamp

Kristofer C Berrett

Spencer Arnesen

Jason Gertz

Affiliations

Soon will be listed here.

Abstract

Estrogen receptor 1 () mutations have been identified in hormone therapy-resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggest that mutant ESR1 exhibits estrogen-independent activity. In endometrial cancer, mutations are associated with worse outcomes and less obesity, however, experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wild-type ESR1. The D538G mutation impacted expression, including a large set of nonestrogen-regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is distinct from constitutive ESR1 activity because mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, the D538G mutant confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.

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