title: Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens.
abstract: 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 cellsin vitroandin 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, particularlyIGFBP3Conclusions: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.,IGFBP3expression) 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.
authors.affiliation: 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.
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Andersen
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.|Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sikora
authors.affiliation: 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.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Boisen
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Tianzhou
authors.initials: T
authors.lastname: Ma
authors.affiliation: Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Alec
authors.initials: A
authors.lastname: Christie
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: George
authors.initials: G
authors.lastname: Tseng
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Soumya
authors.initials: S
authors.lastname: Luthra
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Uma
authors.initials: U
authors.lastname: Chandran
authors.affiliation: Oncology, Merck Research Laboratories, Rahway, New Jersey.
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Mantia-Smaldone
authors.affiliation: Department of Gynecologic Oncology, Roswell Park Cancer Institute, New York, New York.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.affiliation: Division of Gynecologic Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Karen
authors.initials: K
authors.lastname: McLean
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.|Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.affiliation: Department of Pathology, Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Esther
authors.initials: E
authors.lastname: Elishaev
authors.affiliation: Department of Obstetrics, Gynecology, & Reproductive Sciences, Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. oesterreichs@upmc.edu.|Molecular Pharmacology Training Program, University of Pittsburgh, Pittsburgh, Pennsylvania.|Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics*; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D061986:MCF-7 Cells; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D000077267:Fulvestrant; D004958:Estradiol