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

Autor: Tonsing-Carter E; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA., Hernandez KM; Center for Research Informatics, The University of Chicago, Chicago, IL, 60637, USA.; Department of Pediatrics, The University of Chicago, Chicago, IL, 60637, USA., Kim CR; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA., Harkless RV; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA., Oh A; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA., Bowie KR; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA., West-Szymanski DC; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA., Betancourt-Ponce MA; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA., Green BD; Ben May Department for Cancer Research, The University of Chicago, 900 E 57th St, Chicago, IL, 60637, USA., Lastra RR; Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA., Fleming GF; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA., Chandarlapaty S; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Conzen SD; Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA. sdconzen@uchicago.edu.; Ben May Department for Cancer Research, The University of Chicago, 900 E 57th St, Chicago, IL, 60637, USA. sdconzen@uchicago.edu.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2019 Jul 24; Vol. 21 (1), pp. 82. Date of Electronic Publication: 2019 Jul 24.
DOI: 10.1186/s13058-019-1164-6
Abstrakt: 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.
Databáze: MEDLINE
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