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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



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.


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.


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.


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.

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