Progesterone Receptor Regulation of Interferon Signaling in Breast Cancer

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Abstract 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 and ligand-activated transcription factor that is activated in response to 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. 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. 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. Finally, we have performed chromatin immunoprecipitation experiments and observed diminished recruitment of ISG transcriptional machinery to ISG promoter regions, demonstrating PR's role in interrupting canonical interferon signaling. 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 tumors are able to escape immune detection. Activation of type I interferon signaling is an early step in marking tumors for immune clearance and, by repressing ISG protein expression, it is possible that these tumors can avoid immune detection leading to tumor establishment and progression. The experiments proposed herein aim to elucidate the mechanisms by which PR inhibits canonical interferon signaling and ISG expression, and how this inhibition affects mammary tumor formation and immune response in vivo. We will address the former by identifying direct interactions between PR and interferon signaling components as well as use a high throughput technique known as Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) to identify PR interactions with transcriptional cofactors that may aid in inhibiting ISG transcription. We will then address the latter by utilizing a syngeneic mouse model which allows us to observe tumor formation in the presence of a fully functioning immune system. We will evaluate changes in tumor latency and immune response in the presence and absence of PR and progesterone. Determining this novel role of PR and progestins in immune evasion offers insight that could aid in improving upon established estrogen only-based therapies for prevention and treatment of hormone dependent breast cancers.