Abstract 1536A: Progesterone receptor regulation of interferon signaling in breast cancer
Authors: Walter Katherine , Goodman Merit , Trinca Gloria , Hall Jade , Hagan Christy 
Published: July 2017

Breast cancer is an extremely heterogeneous disease that affects close to two million women across the globe each year. Of these breast tumors, approximately 70% express the progesterone receptor (PR), a nuclear receptor that is activated in response to its ligand progesterone. Compelling clinical trial data has 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, using microarray data combined with Gene Set Enrichment Analysis, has identified a novel subset of genes that have altered expression following PR activation. These genes are primarily involved in interferon signaling—a pathway normally utilized in response to viral infection. Our data show that many genes that are normally activated in response to interferon signaling (interferon stimulated genes, ISGs) are repressed when PR is activated by its ligand. Interestingly, this repression occurs even in the presence of interferon alpha—the activating ligand of the interferon signaling cascade. Our lab has also shown that when PR expression is transiently knocked down, ISG transcriptional repression is lost, indicating that the repression of these genes is PR dependent.

In attempting to elucidate a mechanism by which PR exerts this effect, we have performed chromatin immunoprecipitation experiments following PR activation and observed PR recruitment to ISG enhancer regions. This suggests PR is potentially interfering with normal transcription of these genes. We hypothesize that PR is functioning by either blocking normal transcriptional machinery and co-activators or through the recruitment of transcriptional co-repressors to these regions. Experiments to address these models are currently underway.

Evasion of the immune system has recently been added to the list of Hallmarks 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. Our preliminary data suggest that PR may be capable of aiding early breast malignancies in evading immune recognition. 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 Walter, Merit Goodman, Gloria Trinca, Jade Hall, Christy Hagan. Progesterone receptor regulation of interferon signaling in breast cancer [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 1536A. doi:10.1158/1538-7445.AM2017-1536A