Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer

Shujie Yang; Yichen Jia; Xiaoyue Liu; Christopher Winters; Xinjun Wang; Yuping Zhang; Eric J Devor; Adriann M Hovey; Henry D Reyes; Xue Xiao; Donghai Dai; Xiangbing Meng; Kristina W Thiel; Kimberly K Leslie; Yang Xu; Frederick E Domann

doi:10.18632/oncotarget.2392

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Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer

Journal article

Open access

Peer reviewed

Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer

Shujie Yang, Yichen Jia, Xiaoyue Liu, Christopher Winters, Xinjun Wang, Yuping Zhang, Eric J Devor, Adriann M Hovey, Henry D Reyes, Xue Xiao, …

Oncotarget, Vol.5(20), pp.9783-9797

2014

DOI: 10.18632/oncotarget.2392

PMID: 25229191

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Abstract

UNLABELLED: 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.SIGNIFICANCE: 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.

Details

Title: Subtitle: Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer
Creators: Shujie Yang
Yichen Jia
Xiaoyue Liu
Christopher Winters
Xinjun Wang
Yuping Zhang
Eric J Devor
Adriann M Hovey
Henry D Reyes
Xue Xiao
Donghai Dai
Xiangbing Meng
Kristina W Thiel
Kimberly K Leslie
Yang Xu
Frederick E Domann
Resource Type: Journal article
Publication Details: Oncotarget, Vol.5(20), pp.9783-9797
DOI: 10.18632/oncotarget.2392
PMID: 25229191
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Language: English
Date published: 2014
Academic Unit: Pathology; Surgery; Radiation Oncology; Obstetrics and Gynecology
Record Identifier: 9983931826402771

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