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

IF 5.3 2区 生物学 Q2 CELL BIOLOGY Journal of Molecular Cell Biology Pub Date : 2024-01-05 DOI:10.1093/jmcb/mjad047
Li-Bo Cao, Zi-Lun Ruan, Yu-Lin Yang, Nian-Chao Zhang, Chuan Gao, Cheguo Cai, Jing Zhang, Ming-Ming Hu, Hong-Bing Shu
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Abstract

Estrogen receptor α (ERα) is an important driver and therapeutic target in ∼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. Activation of ERα by its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes (ISGs), whereas ERα deficiency or the stimulation with its antagonist fulvestrant has opposite effects. Mechanistically, ERα induces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3 (ISGF3) complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex. These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs. In a xenograft mouse model, fulvestrant enhances the ability of IFN-β to suppress ERα+ breast tumor growth. Consistently, clinical data analysis reveals that ERα+ breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates. Taken together, our findings suggest that ERα inhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.

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雌激素受体α介导的信号传导抑制 I 型干扰素反应,从而促进乳腺癌的发生。
雌激素受体α(ERα)是70%乳腺癌的重要驱动因素和治疗靶点。ERα如何驱动乳腺癌的发生尚未完全明了。在这项研究中,我们发现ERα是I型干扰素(IFN)反应的负调控因子。ERα的天然配体雌二醇激活ERα会抑制IFN-β诱导的下游IFN刺激基因(ISGs)的转录,而ERα缺乏或用其拮抗剂氟维司群刺激则会产生相反的效果。从机理上讲,ERα会诱导组蛋白2A变体H2A.Z的表达,从而限制IFN刺激基因因子3(ISGF3)复合物与ISGs启动子的接触,同时ERα还会与STAT2相互作用,破坏ISGF3复合物的组装。这两个事件共同导致 I 型 IFN 诱导的 ISG 转录受到抑制。在异种移植小鼠模型中,氟维司群增强了 IFN-β 抑制 ERα+ 乳腺肿瘤生长的能力。同样,临床数据分析显示,ISGs水平较高的ERα+乳腺癌患者的长期生存率也较高。综上所述,我们的研究结果表明,ERα通过两种不同的机制抑制I型IFN反应,从而促进乳腺癌的发生。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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