Role Of Estrogen Receptor α-mediated Inhibition Of Type Ⅰ Interferon Response In Promoting Breast Cancer

Breast cancer has become the most common and biggest threat to women’s health in the world.The estrogen receptor α(ERα)is expressed in approximately 70% of breast cancers and is an important therapeutic target for ERα-positive breast cancer.Previous studies have suggested that ERα promotes breast carcinogenesis by up-regulating positive proliferation regulators,including survivin,growth factors and cell cycle-related genes.A recent study demonstrates that ERα acts as an RNA-binding protein to sustain tumor cell survival and drug resistance by regulating RNA metabolism,which ultimately promotes the occurrence and development of breast cancer.However,it is unclear whether ERα affects the development of breast cancer by modulating the interferon(IFN)response.IFNs are secreted by a large number of immune and non-immune cells.IFNs exert biological activity by activating the JAK-STAT signaling to induce transcription of hundreds of interferon-stimulated genes(ISGs).Numerous studies have shown that IFNs exhibit potent antiviral and antitumor activities.IFNs directly inhibit tumor growth by inhibiting cell proliferation and tumor angiogenesis or inducing tumor cell apoptosis.In addition,IFNs also enhance antitumor immunity by regulating the tumor immune microenvironment.ERα-positive breast cancer has been recognized as an immunologically ‘cold’ tumor,which is resistant to immune checkpoint blockade(ICB)therapy.This ‘cold’ tumor may be caused by defects in antigen presentation due to impaired interferon response.Thus,exploring whether and how IFN response in ERα-positive breast cancer cells is impaired will further reveal the basic laws of breast cancer occurrence and development,and provide a theoretical basis for the development of combination therapies for breast cancer.In this study,we show that ERα is a negative regulator of type I IFN response.By analyzing RNA-seq data from clinical breast cancer samples in TCGA database,we found that the average ISG scores of ERα-positive samples were significantly lower than that of ERα-negative samples.Our experiments indicated that overexpression of ERαinhibited type I IFN response,while the deficiency of ERα had the opposite effects.Propyl pyrazole triol(PPT),an agonist of ERα,inhibited type I IFN response,while fulvestrant(FUL),an antiestrogen and potent ERα antagonist,promoted type I IFN response.As expected,ERα-deficiency abolished the inhibitory effects of PPT or the promoting effects of FUL on type I IFN response.These results suggest that ERα inhibits type I IFN response.Mechanistically,ERα inhibits type I IFN response by two distinct mechanisms.ERα induces expression of the histone 2A variant H2 A.Z in dependence on the transcriptional activation of ERα,which restricts engagement of the ISGF3 complex at the ISG promoters.ERα also interacts with the N-terminus of STAT2 to disrupt the assembly of the ISGF3 complex.These two molecular events mutually lead to decreased transcription of ISGs induced by type I IFN.In a xenograft mouse tumor model,FUL suppressing ERα-positive breast tumor growth is partially dependent on type I IFN response,and the combination of IFN-β and FUL inhibits ERα-positive breast tumor growth more effectively than either one alone.Consistently,the clinical data suggests that the ERα-positive breast cancer patients with higher levels of ISGs exhibit an increased survival rate,and ISG levels including MHC(major histocompatibility complex)molecules were higher in breast cancer samples receiving hormone therapy than in samples not receiving hormone therapy.In summary,our findings suggest that ERα inhibits the occupancy of the ISGF3 complex on ISG promotors by inducing expression of H2 A.Z and interacting with STAT2 to negatively regulate type I IFN response.Additionally,the combination of FUL and IFN-β enhances type I IFN response of breast cancer cells and more effectively inhibits the growth of breast tumors.This study reveals a molecular mechanism,how ERαpromotes the occurrence and development of breast cancer from the perspective of interferon response,and provides a new clue for the combination therapy of this type of tumor.