GR and ER coactivation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome

Diana C. West, Deng Pan, Eva Y. Tonsing-Carter, Kyle M. Hernandez, Charles F. Pierce, Sarah C. Styke, Kathleen R. Bowie, Tzintzuni I. Garcia, Masha Kocherginsky, Suzanne D. Conzen*

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)707-719
Number of pages13
JournalMolecular Cancer Research
Volume14
Issue number8
DOIs
StatePublished - Aug 1 2016

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Glucocorticoid Receptors
Estrogen Receptors
Breast Neoplasms
Gene Expression
Response Elements
Chromatin
Neoplasms
Wnt Signaling Pathway
Chromatin Immunoprecipitation
MCF-7 Cells
Progesterone Receptors
Cytoplasmic and Nuclear Receptors
Natural History
Genetic Promoter Regions
Transcriptional Activation

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

West, D. C., Pan, D., Tonsing-Carter, E. Y., Hernandez, K. M., Pierce, C. F., Styke, S. C., ... Conzen, S. D. (2016). GR and ER coactivation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome. Molecular Cancer Research, 14(8), 707-719. https://doi.org/10.1158/1541-7786.MCR-15-0433
West, Diana C. ; Pan, Deng ; Tonsing-Carter, Eva Y. ; Hernandez, Kyle M. ; Pierce, Charles F. ; Styke, Sarah C. ; Bowie, Kathleen R. ; Garcia, Tzintzuni I. ; Kocherginsky, Masha ; Conzen, Suzanne D. / GR and ER coactivation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome. In: Molecular Cancer Research. 2016 ; Vol. 14, No. 8. pp. 707-719.
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abstract = "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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West, DC, Pan, D, Tonsing-Carter, EY, Hernandez, KM, Pierce, CF, Styke, SC, Bowie, KR, Garcia, TI, Kocherginsky, M & Conzen, SD 2016, 'GR and ER coactivation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome', Molecular Cancer Research, vol. 14, no. 8, pp. 707-719. https://doi.org/10.1158/1541-7786.MCR-15-0433

GR and ER coactivation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome. / West, Diana C.; Pan, Deng; Tonsing-Carter, Eva Y.; Hernandez, Kyle M.; Pierce, Charles F.; Styke, Sarah C.; Bowie, Kathleen R.; Garcia, Tzintzuni I.; Kocherginsky, Masha; Conzen, Suzanne D.

In: Molecular Cancer Research, Vol. 14, No. 8, 01.08.2016, p. 707-719.

Research output: Contribution to journalArticle

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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.

PY - 2016/8/1

Y1 - 2016/8/1

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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