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

1 Citation (Scopus)

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

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Glucocorticoid Receptors
Estrogen Receptors
Chromatin
Cell Proliferation
Breast Neoplasms
Gene Expression
Cyclin D1
Ligands
Neoplasm Genes
Cytoplasmic and Nuclear Receptors

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

Cite this

Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association. / Tonsing-Carter, Eva; Hernandez, Kyle M.; Kim, Caroline R.; Harkless, Ryan V.; Oh, Alyce; Bowie, Kathleen R.; West-Szymanski, Diana C.; Betancourt-Ponce, Mayra A.; Green, Bradley D.; Lastra, Ricardo R.; Fleming, Gini F.; Chandarlapaty, Sarat; Conzen, Suzanne D.

In: Breast cancer research : BCR, Vol. 21, No. 1, 24.07.2019.

Research output: Contribution to journalArticle

Tonsing-Carter, E, Hernandez, KM, Kim, CR, Harkless, RV, Oh, A, Bowie, KR, West-Szymanski, DC, Betancourt-Ponce, MA, Green, BD, Lastra, RR, Fleming, GF, Chandarlapaty, S & Conzen, SD 2019, 'Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association', Breast cancer research : BCR, vol. 21, no. 1. https://doi.org/10.1186/s13058-019-1164-6
Tonsing-Carter, Eva ; Hernandez, Kyle M. ; Kim, Caroline R. ; Harkless, Ryan V. ; Oh, Alyce ; Bowie, Kathleen R. ; West-Szymanski, Diana C. ; Betancourt-Ponce, Mayra A. ; Green, Bradley D. ; Lastra, Ricardo R. ; Fleming, Gini F. ; Chandarlapaty, Sarat ; Conzen, Suzanne D. / Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association. In: Breast cancer research : BCR. 2019 ; Vol. 21, No. 1.
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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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AU - Tonsing-Carter, Eva

AU - Hernandez, Kyle M.

AU - Kim, Caroline R.

AU - Harkless, Ryan V.

AU - Oh, Alyce

AU - Bowie, Kathleen R.

AU - West-Szymanski, Diana C.

AU - Betancourt-Ponce, Mayra A.

AU - Green, Bradley D.

AU - Lastra, Ricardo R.

AU - Fleming, Gini F.

AU - Chandarlapaty, Sarat

AU - Conzen, Suzanne D.

PY - 2019/7/24

Y1 - 2019/7/24

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Chromatin association

KW - Cyclin D1

KW - Estrogen receptor

KW - Glucocorticoid receptor

KW - Mutant activated estrogen receptor

KW - Nuclear receptor crosstalk

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