NuclearReceptors2018 Poster Presentations (1) (7 abstracts)
Glucocorticoid receptor inhibits ER-mediated pro-proliferative gene expression
E Tonsing-Carter 1 , CR Kim 1 , KM Hernandez 2 , KR Bowie 1 , DC West 1 , S Chandarlapaty 3 , GL Greene 4 & SD Conzen 1,
1Department of Medicine, The University of Chicago, Chicago, Illinois, USA; 2The Center for Research Informatics, The University of Chicago, Chicago, Illinois, USA; 3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA; 4The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA.
Early-stage ER+ breast cancer (BC) with high tumor glucocorticoid receptor (GR) expression is associated with improved long term relapse-free survival compared to tumors with low GR expression. In addition, GR activity inhibits ER-mediated BC cell proliferation. We therefore hypothesized that GR and ER engage in nuclear receptor crosstalk to influence pro-proliferative gene expression, thus contributing to a better outcome in ER+/GR+ breast cancer. To understand the mechanisms by which ER/GR co-activation contribute to a more indolent ER+ BC phenotype, we performed ChIP-sequencing and gene expression analyses in ER+/GR+ BC cell lines. We found that activation of GR with the synthetic agonist, dexamethasone (dex), led to decreased ER+ BC cell proliferation. Furthermore, ER/GR co-activation dampened cell cycle gene expression (e.g. CDK6, CDK2, and CCND1) compared to ER-activation alone. GR and ER ChIP-sequencing revealed co-localization of ER and GR at a known downstream enhancer for ER-mediated CCND1 transcription suggesting direct GR-mediated antagonism of ER. The highly selective GR modulators (SGRMs), CORT125134 and CORT118335 also reduced ER-driven cell proliferation and E2-mediated pro-proliferative gene expression. Moreover, MCF-7 cells engineered to express ER ligand-binding domain mutations (Y537S and D538G) similarly demonstrated decreased proliferation with either dex or SGRM treatment. Taken together, these studies suggest that GR modulation deserves further investigation as an approach for inhibiting ER-driven BC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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