title: Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer.
abstract: Progesterone, acting through its receptor, PR (progesterone receptor), is the natural inhibitor of uterine endometrial carcinogenesis by inducing differentiation. PR is downregulated in more advanced cases of endometrial cancer, thereby limiting the effectiveness of hormonal therapy. Our objective was to understand and reverse the mechanisms underlying loss of PR expression in order to improve therapeutic outcomes. Using endometrial cancer cell lines and data from The Cancer Genome Atlas, our findings demonstrate that PR expression is downregulated at four distinct levels. In well-differentiated cancers, ligand-induced receptor activation and downregulation are intact. miRNAs mediate fine tuning of PR levels. As differentiation is lost, PR silencing is primarily at the epigenetic level. Initially, recruitment of the polycomb repressor complex 2 to the PR promoter suppresses transcription. Subsequently, DNA methylation prevents PR expression. Appropriate epigenetic modulators reverse these mechanisms. These data provide a rationale for combining epigenetic modulators with progestins as a therapeutic strategy for endometrial cancer.
  
  
  CONCLUSIONS
  Traditional hormonal therapy for women with endometrial cancer can be molecularly enhanced by combining progestins with epigenetic modulators, thereby increasing progesterone receptor expression and significantly improving treatment efficacy.
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA. Carver College of Medicine and Holden Comprehensive Cancer Center, University of Iowa, IA, 52242, USA.
authors.forename: Shujie
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Winters
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Devor
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Adriann M
authors.initials: AM
authors.lastname: Hovey
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Henry D
authors.initials: HD
authors.lastname: Reyes
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Xiao
authors.affiliation: The Interdisciplinary Graduate Program in Informatics, University of Iowa, IA, 52242, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Donghai
authors.initials: D
authors.lastname: Dai
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA. Carver College of Medicine and Holden Comprehensive Cancer Center, University of Iowa, IA, 52242, USA.
authors.forename: Xiangbing
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA.
authors.forename: Kristina W
authors.initials: KW
authors.lastname: Thiel
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, IA, 52242, USA. Carver College of Medicine and Holden Comprehensive Cancer Center, University of Iowa, IA, 52242, USA.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Domann
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA. Carver College of Medicine and Holden Comprehensive Cancer Center, University of Iowa, IA, 52242, USA.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
mesh_terms: D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D000077767:Panobinostat; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D035683:MicroRNAs; D011980:Receptors, Progesterone; D000077767:Panobinostat; D063151:Polycomb Repressive Complex 2