TY - JOUR
T1 - GR and ER coactivation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome
AU - West, Diana C.
AU - Pan, Deng
AU - Tonsing-Carter, Eva Y.
AU - Hernandez, Kyle M.
AU - Pierce, Charles F.
AU - Styke, Sarah C.
AU - Bowie, Kathleen R.
AU - Garcia, Tzintzuni I.
AU - Kocherginsky, Masha
AU - Conzen, Suzanne D.
N1 - Funding Information:
The study was supported by NIH R01 CA089208, The University of Chicago Comprehensive Cancer Center NIH P30 CA014599, Susan G. Komen for the Cure IIR12223772, and the Prostate Cancer Foundation Movember Challenge Award. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/8
Y1 - 2016/8
N2 - In estrogen receptor (ER)-negative breast cancer, high tumor glucocorticoid receptor (GR) expression has been associated with a relatively poor outcome. In contrast, using a metaanalysis of several genomic datasets, here we find that tumor GR mRNA expression is associated with improved ER+ relapsefree survival (RFS; independently of progesterone receptor expression). To understand the mechanism by which GR expression is associated with a better ER+ breast cancer outcome, the global effect of GR-mediated transcriptional activation in ER+ breast cancer cells was studied. Analysis of GR chromatin immunoprecipitation followed by high-throughput sequencing in ER+/GR+ MCF-7 cells revealed that upon coactivation of GR and ER, GR chromatin association became enriched at proximal promoter regions. Furthermore, following ER activation, increased GR chromatin association was observed at ER, FOXO, and AP1 response elements. In addition, ER associated with GR response elements, suggesting that ER and GR interact in a complex. Coactivation of GR and ER resulted in increased expression (relative to ER activation alone) of transcripts that encode proteins promoting cellular differentiation (e.g., KDM4B, VDR) and inhibiting the Wnt signaling pathway (IGFBP4). Finally, expression of these individual prodifferentiation genes was associated with significantly improved RFS in ER+ breast cancer patients. Together, these data suggest that the coexpression and subsequent activity of tumor cell GR and ER contribute to the less aggressive natural history of early-stage breast cancer by coordinating the altered expression of genes favoring differentiation. Implications: The interaction between ER and GR activity highlights the importance of context-dependent nuclear receptor function in cancer.
AB - In estrogen receptor (ER)-negative breast cancer, high tumor glucocorticoid receptor (GR) expression has been associated with a relatively poor outcome. In contrast, using a metaanalysis of several genomic datasets, here we find that tumor GR mRNA expression is associated with improved ER+ relapsefree survival (RFS; independently of progesterone receptor expression). To understand the mechanism by which GR expression is associated with a better ER+ breast cancer outcome, the global effect of GR-mediated transcriptional activation in ER+ breast cancer cells was studied. Analysis of GR chromatin immunoprecipitation followed by high-throughput sequencing in ER+/GR+ MCF-7 cells revealed that upon coactivation of GR and ER, GR chromatin association became enriched at proximal promoter regions. Furthermore, following ER activation, increased GR chromatin association was observed at ER, FOXO, and AP1 response elements. In addition, ER associated with GR response elements, suggesting that ER and GR interact in a complex. Coactivation of GR and ER resulted in increased expression (relative to ER activation alone) of transcripts that encode proteins promoting cellular differentiation (e.g., KDM4B, VDR) and inhibiting the Wnt signaling pathway (IGFBP4). Finally, expression of these individual prodifferentiation genes was associated with significantly improved RFS in ER+ breast cancer patients. Together, these data suggest that the coexpression and subsequent activity of tumor cell GR and ER contribute to the less aggressive natural history of early-stage breast cancer by coordinating the altered expression of genes favoring differentiation. Implications: The interaction between ER and GR activity highlights the importance of context-dependent nuclear receptor function in cancer.
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U2 - 10.1158/1541-7786.MCR-15-0433
DO - 10.1158/1541-7786.MCR-15-0433
M3 - Article
C2 - 27141101
AN - SCOPUS:84982126663
SN - 1541-7786
VL - 14
SP - 707
EP - 719
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -