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Breast Cancer Research
Published in: Breast Cancer Research 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association

Authors: Eva Tonsing-Carter, Kyle M. Hernandez, Caroline R. Kim, Ryan V. Harkless, Alyce Oh, Kathleen R. Bowie, Diana C. West-Szymanski, Mayra A. Betancourt-Ponce, Bradley D. Green, Ricardo R. Lastra, Gini F. Fleming, Sarat Chandarlapaty, Suzanne D. Conzen

Published in: Breast Cancer Research | Issue 1/2019

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Abstract

Background

Non-ER nuclear receptor activity can alter estrogen receptor (ER) chromatin association and resultant ER-mediated transcription. Consistent with GR modulation of ER activity, high tumor glucocorticoid receptor (GR) expression correlates with improved relapse-free survival in ER+ breast cancer (BC) patients.

Methods

In vitro cell proliferation assays were used to assess ER-mediated BC cell proliferation following GR modulation. ER chromatin association following ER/GR co-liganding was measured using global ChIP sequencing and directed ChIP analysis of proliferative gene enhancers.

Results

We found that GR liganding with either a pure agonist or a selective GR modulator (SGRM) slowed estradiol (E2)-mediated proliferation in ER+ BC models. SGRMs that antagonized transcription of GR-unique genes both promoted GR chromatin association and inhibited ER chromatin localization at common DNA enhancer sites. Gene expression analysis revealed that ER and GR co-activation decreased proliferative gene activation (compared to ER activation alone), specifically reducing CCND1, CDK2, and CDK6 gene expression. We also found that ligand-dependent GR occupancy of common ER-bound enhancer regions suppressed both wild-type and mutant ER chromatin association and decreased corresponding gene expression. In vivo, treatment with structurally diverse SGRMs also reduced MCF-7 Y537S ER-expressing BC xenograft growth.

Conclusion

These studies demonstrate that liganded GR can suppress ER chromatin occupancy at shared ER-regulated enhancers, including CCND1 (Cyclin D1), regardless of whether the ligand is a classic GR agonist or antagonist. Resulting GR-mediated suppression of ER+ BC proliferative gene expression and cell division suggests that SGRMs could decrease ER-driven gene expression.
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Metadata
Title
Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association
Authors
Eva Tonsing-Carter
Kyle M. Hernandez
Caroline R. Kim
Ryan V. Harkless
Alyce Oh
Kathleen R. Bowie
Diana C. West-Szymanski
Mayra A. Betancourt-Ponce
Bradley D. Green
Ricardo R. Lastra
Gini F. Fleming
Sarat Chandarlapaty
Suzanne D. Conzen
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-019-1164-6

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