CREBBP/EP300 Acetyltransferase Inhibition Disrupts FOXA1-bound Enhancers to Inhibit the Proliferation of ER+ Breast Cancer Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2022 Mar 30

PMID 35353838

Authors

Archana Bommi-Reddy

Sungmi Park-Chouinard

David N Mayhew

Esteban Terzo

Aparna Hingway

Michael J Steinbaugh

Jonathan E Wilson

Robert J Sims 3rd

Andrew R Conery

Affiliations

Soon will be listed here.

Abstract

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.

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