Discovery of a glucocorticoid receptor (gr) activity signature using selective gr antagonis in er-negative breast cancer

Diana C. West, Masha Kocherginsky, Eva Y. Tonsing-Carter, D. Nesli Dolcen, David J. Hosfield, Ricardo R. Lastra, Jason P. Sinnwell, Kevin J. Thompson, Kathleen R. Bowie, Ryan V. Harkless, Maxwell N. Skor, Charles F. Pierce, Sarah C. Styke, Caroline R. Kim, Larischa De Wet, Geoffrey L. Greene, Judy C Boughey, Matthew Philip Goetz, Krishna R Kalari, Liewei M WangGini F. Fleming, Balazs Gyorffy, Suzanne D. Conzen

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Abstract

Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n ¼ 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR ¼ 1.9; P ¼ 0.012). Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients.

Original languageEnglish (US)
Pages (from-to)3433-3446
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number14
DOIs
StatePublished - Jul 15 2018

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Glucocorticoid Receptors
Breast Neoplasms
Estrogen Receptors
Genes
Gene Expression
Adjuvant Chemotherapy
Recurrence
Mifepristone

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

West, D. C., Kocherginsky, M., Tonsing-Carter, E. Y., Dolcen, D. N., Hosfield, D. J., Lastra, R. R., ... Conzen, S. D. (2018). Discovery of a glucocorticoid receptor (gr) activity signature using selective gr antagonis in er-negative breast cancer. Clinical Cancer Research, 24(14), 3433-3446. https://doi.org/10.1158/1078-0432.CCR-17-2793

Discovery of a glucocorticoid receptor (gr) activity signature using selective gr antagonis in er-negative breast cancer. / West, Diana C.; Kocherginsky, Masha; Tonsing-Carter, Eva Y.; Dolcen, D. Nesli; Hosfield, David J.; Lastra, Ricardo R.; Sinnwell, Jason P.; Thompson, Kevin J.; Bowie, Kathleen R.; Harkless, Ryan V.; Skor, Maxwell N.; Pierce, Charles F.; Styke, Sarah C.; Kim, Caroline R.; De Wet, Larischa; Greene, Geoffrey L.; Boughey, Judy C; Goetz, Matthew Philip; Kalari, Krishna R; Wang, Liewei M; Fleming, Gini F.; Gyorffy, Balazs; Conzen, Suzanne D.

In: Clinical Cancer Research, Vol. 24, No. 14, 15.07.2018, p. 3433-3446.

Research output: Contribution to journalArticle

West, DC, Kocherginsky, M, Tonsing-Carter, EY, Dolcen, DN, Hosfield, DJ, Lastra, RR, Sinnwell, JP, Thompson, KJ, Bowie, KR, Harkless, RV, Skor, MN, Pierce, CF, Styke, SC, Kim, CR, De Wet, L, Greene, GL, Boughey, JC, Goetz, MP, Kalari, KR, Wang, LM, Fleming, GF, Gyorffy, B & Conzen, SD 2018, 'Discovery of a glucocorticoid receptor (gr) activity signature using selective gr antagonis in er-negative breast cancer', Clinical Cancer Research, vol. 24, no. 14, pp. 3433-3446. https://doi.org/10.1158/1078-0432.CCR-17-2793
West, Diana C. ; Kocherginsky, Masha ; Tonsing-Carter, Eva Y. ; Dolcen, D. Nesli ; Hosfield, David J. ; Lastra, Ricardo R. ; Sinnwell, Jason P. ; Thompson, Kevin J. ; Bowie, Kathleen R. ; Harkless, Ryan V. ; Skor, Maxwell N. ; Pierce, Charles F. ; Styke, Sarah C. ; Kim, Caroline R. ; De Wet, Larischa ; Greene, Geoffrey L. ; Boughey, Judy C ; Goetz, Matthew Philip ; Kalari, Krishna R ; Wang, Liewei M ; Fleming, Gini F. ; Gyorffy, Balazs ; Conzen, Suzanne D. / Discovery of a glucocorticoid receptor (gr) activity signature using selective gr antagonis in er-negative breast cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 14. pp. 3433-3446.
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abstract = "Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n ¼ 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR ¼ 1.9; P ¼ 0.012). Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients.",
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T1 - Discovery of a glucocorticoid receptor (gr) activity signature using selective gr antagonis in er-negative breast cancer

AU - West, Diana C.

AU - Kocherginsky, Masha

AU - Tonsing-Carter, Eva Y.

AU - Dolcen, D. Nesli

AU - Hosfield, David J.

AU - Lastra, Ricardo R.

AU - Sinnwell, Jason P.

AU - Thompson, Kevin J.

AU - Bowie, Kathleen R.

AU - Harkless, Ryan V.

AU - Skor, Maxwell N.

AU - Pierce, Charles F.

AU - Styke, Sarah C.

AU - Kim, Caroline R.

AU - De Wet, Larischa

AU - Greene, Geoffrey L.

AU - Boughey, Judy C

AU - Goetz, Matthew Philip

AU - Kalari, Krishna R

AU - Wang, Liewei M

AU - Fleming, Gini F.

AU - Gyorffy, Balazs

AU - Conzen, Suzanne D.

PY - 2018/7/15

Y1 - 2018/7/15

N2 - Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n ¼ 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR ¼ 1.9; P ¼ 0.012). Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients.

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