Department of Biochemistry and Molecular Biology, Department of Cancer Biology, University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
Departments of Medicine and Pathology, Microbiology, and Immunology, and Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA.
Oncoimmunology. 2020 Apr 30;9(1):1758547. doi: 10.1080/2162402X.2020.1758547. eCollection 2020.
Type I (IFNα/β) interferon signaling represents a critical transduction pathway involved in recognition and destruction of nascent tumor cells. Downregulation of this pathway to promote a more immunosuppressed microenvironment contributes to the ability of tumor cells to evade the immune system, a known Hallmark of Cancer. The present study investigates the progesterone receptor (PR), which is expressed in the vast majority of breast cancers, and its ability to inhibit efficient interferon signaling in tumor cells. We have shown that PR can block the interferon signaling cascade by promoting ubiquitination and degradation of STAT2. Targeting STAT2 is critical, as we show that it is an essential protein in inducing transcription of interferon-stimulated genes (ISG); shRNA-mediated knockdown of STAT2 severely abrogates the interferon response . Importantly, we were able to reverse this inhibition by treating with onapristone, an anti-progestin currently being investigated in breast cancer clinical trials. Additionally, we have found that an interferon-related gene signature (composed of ISGs) is inversely correlated with PR expression in human tumors. We speculate that PR inhibition of interferon signaling may contribute to creating an immunosuppressed microenvironment and reversal of this through anti-progestins may present a novel therapeutic target to promote immune activity within the tumor.
I 型（IFNα/β）干扰素信号转导代表了识别和破坏新生肿瘤细胞的关键转导途径。下调该途径以促进更具免疫抑制性的微环境有助于肿瘤细胞逃避免疫系统，这是癌症的一个已知特征。本研究调查了孕激素受体（PR），它在绝大多数乳腺癌中表达，及其抑制肿瘤细胞中有效干扰素信号转导的能力。我们已经表明，PR 可以通过促进 STAT2 的泛素化和降解来阻断干扰素信号级联反应。靶向 STAT2 至关重要，因为我们表明它是诱导干扰素刺激基因（ISG）转录的必需蛋白；STAT2 的 shRNA 介导敲低严重削弱了干扰素反应。重要的是，我们能够通过用正在乳腺癌临床试验中研究的抗孕激素(onapristone)治疗来逆转这种抑制。此外，我们发现干扰素相关基因特征（由 ISGs 组成）与人类肿瘤中的 PR 表达呈负相关。我们推测，PR 抑制干扰素信号可能有助于创造免疫抑制性微环境，通过抗孕激素逆转这种抑制可能为促进肿瘤内免疫活性提供新的治疗靶点。
