Estrogen receptor α-mediated signaling inhibits type I interferon response to promote breast cancer.

Estrogen receptor α (ERα) is an important driver and therapeutic target in approximately 70% of breast cancers. How ERα drives breast carcinogenesis is not fully understood. In this study, we show that ERα is a negative regulator of type I interferon (IFN) response, which is critical for breast carcinogenesis. Activation of ERα by its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes (ISGs), whereas deficiency of ERα or stimulation with its antagonist fulvestrant has opposite effects. Mechanistically, ERα inhibits type I IFN response by two distinct mechanisms. ERα induces expression of the histone 2A variant H2A.Z, which restricts engagement of the IFN-stimulated gene factor 3 (ISGF3) complex at the ISG promoters. ERα also interacts with STAT2, which leads to disruption of the ISGF3 complex. These two events mutually lead to transcriptional inhibition of ISGs induced by type I IFNs. In a xenograft mouse tumor model, fulvestrant enhances the ability of IFN-β to suppress ERα+ breast tumor growth. Consistently, clinical data suggests that ERα+ breast cancer patients with higher levels of ISGs exhibit an increased survival rate. Our findings suggest that ERα inhibits type I IFN response via two distinct mechanisms to promote breast cancer.