Nuclear receptor ESRRA promotes ERa-positive breast cancer through dual action on super enhancers and promoters to regulate gene transcriptional programs

ESRRA (Estrogen-Related Receptor Alpha) is an orphan nuclear receptor that plays a pivotal role in regulating cellular metabolism, mitochondrial biogenesis, and energy homeostasis through gene transcriptional control. It has been implicated in various physiological processes and diseases, including cancer. However, the transcriptional programs it regulates and the underlying molecular mechanisms are yet to be comprehensively understood. Here, we demonstrated that ESRRA serves as a central regulator in orchestrating the transcriptional activation of ERa-occupied super enhancers (ERSEs) and cognate ERa-target genes. Meanwhile, it downregulates the expression of cytosolic RNA sensors RIG1 and MDA5 to inhibit type I interferon (IFN) and type I IFN-stimulated genes (ISGs). In terms of mechanism, ESRRA is recruited to ERSEs together with ERain response to estrogen, and their binding with ESREs are regulated in a mutual-dependent manner. However, ESRRA directly binds to the promoter regions of RIG1 and MDA5 to suppress their expression. Consistent with these findings, pharmacological inhibition of ESRRA with its inverse agonist XCT790 inhibits estrogen/ERa-induced gene transcription, and enhances the type I IFN pathway and antitumor immunity to suppress breast cancer cell growth both in vitro and in vivo. Co-treatment with XCT790 and endocrine therapy drugs including ERa antagonist Tamoxifen or degrader Fulvestrant exhibited synergistic effects. Furthermore, combination treatment with XCT790 and tamoxifen re-sensitized Tamoxifen-resistant (TamR) ERa-positive breast cancer cells to Tamoxifen treatment. In summary, our findings unveiled that ESRRA is a pivotal regulator of ERSEs and estrogen/ERa-target gene activation, as well as the type I IFN signaling pathway, offering a promising therapeutic avenue for treating ERa-positive breast cancer in the clinic.