Introduction: As a tumor suppressor in the endometrium, progesterone and its synthesized analogue progestin have a long history as a treatment for endometrial cancer. Loss of progesterone receptor (PR) in endometrial cancer leads to therapeutic failure, and our group has identified several mechanisms underlying PR loss, most notably epigenetic silencing of PR transcription. Recently, a Finnish group demonstrated that progestin therapy in premenopausal women is associated with a lower incidence of not only endometrial cancer, but also ovarian, pancreatic and lung cancers. This unexpected protective function of progestin in organs outside of the reproductive system led us to hypothesize that tumor progression effects in endometrial, ovarian, pancreatic and lung cancer is occurs due to the loss of progesterone’s protective effects.

Methods and results: Supporting a potential protective role of progesterone, we discovered that PR is downregulated in multiple tumors, including breast, endometrial, ovarian, cervical, pancreatic and lung cancers, and loss of PR was consistently associated with a poor prognosis based on analysis of the Oncomine database. Similarly, PR expression was low in multiple ovarian, pancreatic and lung cancer cells. Mechanistic studies revealed that PR downregulation was mediated by the polycomb-repressor complex and DNA methylation, though the precise mechanism differed among cell lines and cancer types. Treatment with epigenetic modulators, which are FDA-approved for multiple myeloma, restored functional PR expression at both the mRNA and protein level and promoted marked cell death through induction of apoptosis. . Moreover, overexpression of PR or treatment with epigenetic modulators in combination with progesterone enhanced this effect, indicating a key protective role for progesterone signaling through PR.

Conclusion: These data suggest loss of PR may be a general theme for tumorigenesis or disease progression in multiple tumor types beyond the classically studied endometrial cancer. In addition, the epigenetic mechanisms contributing to PR downregulation in endometrial tumors were recapitulated in other tumor types, including ovarian, pancreatic and lung tumors. These studies collectively set the stage for use of progestin therapy in combination with epigenetic modulators, a concept we term “molecularly enhanced progestin therapy,” as a novel therapeutic approach for many cancers. This combinatorial strategy has the power to revitalize the use of epigenetic modulators, which have proved disappointing in solid tumors, as an approach to resensitize cancer cells to a tumor suppressor.

Citation Format: Yiyang Li, Tamar Kavlashvili, Cheng Huang, Yuping Zhang, Xiangbing Meng, Kristina Thiel, Kimberly Leslie, Shujie Yang. Loss of progesterone receptor through epigenetic regulation is associated with poor prognosis in multiple solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2556. doi:10.1158/1538-7445.AM2017-2556