Abstract 1307: Enhancing hormone therapy in endometrial cancer by differentially targeting epigenetic repression of progesterone receptor expression.
Authors: Yang Shujie , Jia Yichen , Liu Xiaoyue , Xaio Xue , Zhang Yuping , Devor Eric J. , Meng Xiangbing , Leslie Kimberly K. 
Published: August 2014

Endometrial cancer, the most common gynecological cancer in women worldwide, has a worse relative five year survival rate today than in 1975, signifying the urgent need for innovative new treatment strategies. Endometrial cancer is a hormonally-regulated disease in which progesterone counters the proliferative effect of estrogen. Response to progestin-based therapy strongly correlates with expression of progesterone receptor (PR). However, many endometrial tumors have low levels or loss of PR, which limits the clinical application of progestin-based therapy. Using endometrial cancer cell lines with variable expression of endogenous PR, our objectives are to 1) understand the epigenetic mechanisms by which PR is suppressed in different endometrial tumor types, and 2) apply clinically-relevant strategies to restore functional PR expression and amplify efficacy of progestin therapy.

In well-differentiated type I endometrial cancer cells with modest baseline PR expression, we found that a component of the polycomb-repressor complex (PRC) mediated PR transcriptional suppression through binding to the PRB promoter. Treatment with histone deacetylase inhibitors (HDACi) effectively reversed this transcriptional repression as evidenced by a 10-fold increase in PR mRNA levels. On the contrary, PRC did not occupy the PRB promoter in poorly-differentiated type II endometrial cancer cells devoid of PR expression, and HDACi had no impact on PR expression in these cells. Rather, PR expression was permanently repressed by DNA methylation as demonstrated by direct methylation-specific DNA sequencing. In addition, histone H3 in the PRB promoter region was methylated in these PR-negative cell lines, providing further support for PR transcriptional suppression. This “permanent” suppression could be partially overcome with DNA methyltransferase inhibitors (DNMTi). Importantly, the restored PR in both well-differentiated and poorly-differentiated endometrial cancer cells was functional as a progesterone-activated transcription factor as demonstrated by nuclear localization of PR, increased transcription of multiple PR target genes, and cell cycle arrest.

Our findings reveal that, depending on the mechanism of PR transcriptional suppression, epigenetic modulation restores endogenous PR expression and progesterone-mediated activation in endometrial cancer cell lines. Ongoing studies are confirming that sensitivity to progestin therapy can be restored with epigenetic modulators in human-in-mouse xenograft models. This preclinical study provides the foundation for future clinical trials in which strategies to re-establish functional PR expression are anticipated to resensitize endometrial tumors to progestin therapy.

Citation Format: Shujie Yang, Yichen Jia, Xiaoyue Liu, Xue Xaio, Yuping Zhang, Eric J. Devor, Xiangbing Meng, Kimberly K. Leslie. Enhancing hormone therapy in endometrial cancer by differentially targeting epigenetic repression of progesterone receptor expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1307. doi:10.1158/1538-7445.AM2013-1307