Abstract 515: Progesterone receptor inhibition of efficient type I interferon signaling in breast cancer

Abstract

Abstract A vast majority (65-70%) of breast cancers express the progesterone receptor (PR), a nuclear receptor that is activated in response to its ligand progesterone. Compelling clinical trial data have suggested that progestins have a role in breast cancer development, independent of the widely studied estrogen receptor. The mechanism by which this occurs, however, is vastly understudied. Traditionally, PR exerts its effects following ligand activation by translocating to the nucleus and binding to DNA where it affects the transcription of a variety of genes involved in growth, survival, and proliferation. Our lab has identified a novel subset of genes that have altered expression following PR activation. Interferon Stimulated Genes (ISGs)–primarily activated in response to interferon signaling (viral response pathway) –are repressed when PR is activated by its ligand. In attempting to elucidate a mechanism by which PR exerts this effect, we have investigated crosstalk of PR with canonical interferon signaling proteins and have found that PR interacts with these proteins and significantly reduces their ability to become activated. STAT1, a crucial protein involved in the interferon signaling cascade, is unable to efficiently be phosphorylated when PR is activated with ligand. ChIP experiments have also shown that PR inhibits the machinery necessary for ISG transcription from efficiently binding ISG promoters, possibly explaining the reduction in ISG expression observed following PR activation. Because of the importance of this particular signaling cascade in normal cell biology, multiple mechanisms most likely exist to fully inhibit interferon signaling and experiments are currently underway to identify other possibilities to better define PR’s functionality in this context. Evasion of the immune system is considered a Hallmark of Cancer and our preliminary data suggest a potential mechanism by which breast cancer is able to accomplish this. Activation of type I interferon signaling is an early step in marking tumors for immune clearance. By repressing ISG protein expression, it is possible that these tumors are able to avoid detection by host immune cells leading to tumor establishment and subsequent progression. This novel role of PR and progestins offers insight that could aid in improving upon established estrogen only-based therapies for prevention and treatment of hormone dependent breast cancers. Citation Format: Katherine Rose Walter, Merit Goodman, Christy Hagan. Progesterone receptor inhibition of efficient type I interferon signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 515.