Progesterone Receptor-Mediated Inhibition of Type I Interferon Signaling in Breast Cancer

Abstract

Breast Cancer is an extremely heterogenous disease that is the second leading cause of cancer-related death among women in the United States. Of those diagnosed, the majority of breast cancers are hormone receptor positive, characterized by the dual expression of the estrogen (ER) and progesterone (PR) receptors. Much of what is currently known regarding hormonal regulation of breast cancer development focuses on estrogen-dependent signaling and, as such, many of the current standard of care therapies target this signaling axis. Despite being relatively effective, many will relapse on these first- and second-line therapies. The progesterone receptor and its role in breast cancer development is less established. A ligand-activated, nuclear receptor, PR signals through binding of progesterone and regulating the transcription of a variety of genes involved in mammary gland development and pregnancy. The role of PR as a transcriptional activator is well-characterized. Its role as a transcriptional repressor, however, is less understood. Herein, we discover a novel role for PR as a potent repressor of type I interferon signaling in breast cancer. We establish that PR activation leads to the decreased activity of STAT1, a key player in the interferon signaling axis. We also demonstrate that compensatory mechanisms exist in the absence of a functional STAT1 complex, as interferon signaling remains active in STAT1 knock down cells. STAT2 is able to circumvent PR-mediated inhibition of STAT1 to propagate the interferon response. PR, however, promotes STAT2 ubiquitination and degradation, thereby abrogating interferon signaling with a “one, two punch” approach. These interactions between PR and interferon signaling components serve to decrease transcription of interferon stimulated genes (ISGs) and stifle this immune response. It is significant that the interferon response is hindered in breast cancer as this particular immune pathway is integral in clearing early transformed cells in the body. PR dampening this pathway may offer an explanation as to why hormone receptor positive tumors are immune “cold” and present a mechanism by which early tumor cells are able to escape immune-mediated destruction and progress to clinically relevant, PR-positive tumors.