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Clin Cancer Res. 2017 Jul 15;23(14):3802-3812. doi: 10.1158/1078-0432.CCR-16-1501. Epub 2017 Jan 10.

Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens.

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Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Molecular Pharmacology Training Program, University of Pittsburgh, Pittsburgh, Pennsylvania.
Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Department of Obstetrics, Gynecology, & Reproductive Sciences, Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania.
Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Oncology, Merck Research Laboratories, Rahway, New Jersey.
Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Department of Gynecologic Oncology, Roswell Park Cancer Institute, New York, New York.
Division of Gynecologic Oncology, University of Michigan, Ann Arbor, Michigan.
Department of Pathology, Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania.
Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.


Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ERα) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERα has been understudied as a target in this disease. We sought to identify hormone-responsive, ERα-dependent HGSOC.Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), 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 ERα target genes. Expression of this panel and ERα 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 ERα-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERα targets. The selective ERα downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERα action. ERα H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERα and endocrine responsiveness. Assessing ERα 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. Clin Cancer Res; 23(14); 3802-12. ©2017 AACR.

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