Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer
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Shujie Yang1,4, Yichen Jia1, Xiaoyue Liu1, Christopher Winters1, Xinjun Wang1, Yuping Zhang1, Eric J. Devor1, Adriann M. Hovey1, Henry D. Reyes1, Xue Xiao1, Yang Xu2, Donghai Dai1, Xiangbing Meng1,4, Kristina W. Thiel1, Frederick E. Domann3,4, Kimberly K. Leslie1,4
1Department of Obstetrics and Gynecology, University of Iowa, IA, 52242, USA
2The Interdisciplinary Graduate Program in Informatics, University of Iowa, IA, 52242, USA
3Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, IA, 52242, USA
4Carver College of Medicine and Holden Comprehensive Cancer Center, University of Iowa, IA, 52242, USA
Dr. Shujie Yang, e-mail: firstname.lastname@example.org
Dr. Kimberly K. Leslie, e-mail: Kimberlyemail@example.com
Keywords: Progesterone receptor, progestin, epigenetic regulation, DNA methylation, histone deacetylase inhibitor
Received: July 23, 2014 Accepted: August 23, 2014 Published: September 22, 2014
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.
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