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

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

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Number of pages1
JournalBreast cancer research : BCR
Volume21
Issue number1
DOIs
StatePublished - Jul 24 2019
Externally publishedYes

Keywords

  • Breast cancer
  • Chromatin association
  • Cyclin D1
  • Estrogen receptor
  • Glucocorticoid receptor
  • Mutant activated estrogen receptor
  • Nuclear receptor crosstalk

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association'. Together they form a unique fingerprint.

  • Cite this

    Tonsing-Carter, E., Hernandez, K. M., Kim, C. R., Harkless, R. V., Oh, A., Bowie, K. R., West-Szymanski, D. C., Betancourt-Ponce, M. A., Green, B. D., Lastra, R. R., Fleming, G. F., Chandarlapaty, S., & Conzen, S. D. (2019). Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association. Breast cancer research : BCR, 21(1). https://doi.org/10.1186/s13058-019-1164-6