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Clin Cancer Res. 2017 Jan 10. pii: clincanres.1501.2016. doi: 10.1158/1078-0432.CCR-16-1501. [Epub ahead of print]

Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens.

Author information

  • 1Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine.
  • 2Pharmacology and Chemical Biology, University of Pittsburgh.
  • 3Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital of UPMC.
  • 4Department of Statistics, University of Pittsburgh.
  • 5Women's Cancer Research Center, University of Pittsburgh Cancer Institute.
  • 6Pathology, University of Pittsburgh.
  • 7Biostatistics, University of Pittsburgh.
  • 8Biomedical Informatics, University of Pittsburgh.
  • 9Merck & Company, Merck & Company.
  • 10Department of Surgical Oncology, Fox Chase Cancer Center.
  • 11Immunology and Center for Immunotherapy, Roswell Park Cancer Institute.
  • 12Obstetrics and Gynecology, University of Michigan.
  • 13Pathology, Magee-Womens Hospital of UPMC.
  • 14Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine.
  • 15Department of Pharmacology and Chemical Biology, University of Pittsburgh oesterreichs@upmc.edu.

Abstract

PURPOSE:

High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha in ~80% of HGSOC and some small but promising clinical trials of endocrine therapy, estrogen receptor-alpha has been understudied as a target in this disease. We sought to identify hormone-responsive, estrogen receptor-alpha-dependent HGSOC.

EXPERIMENTAL DESIGN:

We characterized endocrine response in HGSOC cells across culture conditions (2-D, 3-D, forced suspension) and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of estrogen receptor-alpha target genes. Expression of this panel and estrogen receptor-alpha H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response.

RESULTS:

Proliferation is estrogen receptor-alpha-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3-D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as estrogen receptor-alpha targets. The selective estrogen receptor-alpha down-regulator (SERD) fulvestrant is more effective than tamoxifen in blocking estrogen receptor-alpha action. Estrogen receptor-alpha H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3.

CONCLUSIONS:

Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional estrogen receptor-alpha and endocrine responsiveness. Assessing estrogen receptor-alpha function (e.g. IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen.

PMID:
28073843
DOI:
10.1158/1078-0432.CCR-16-1501
[PubMed - as supplied by publisher]
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