Regulation of Type I Interferon Pro-tumor Effects in Breast Cancer

项目摘要/摘要 辅助放疗或化疗是乳腺癌患者手术切除后的标准治疗方法。 癌症的威胁。然而，癌细胞通常会产生治疗耐药性。一个关键因素决定了 肿瘤复发或对这些癌症治疗有反应是干扰素(干扰素)在促进或 分别抑制癌症的进展。一组干扰素刺激基因(ISGs)，即所谓的“干扰素相关基因” DNA损伤抗性信号“(IRDS)，最近被认为与抗辐射和 化疗适用于不同类型的癌症，包括乳腺癌。同时放射治疗和部分化疗 药物导致癌细胞DNA损伤，IFN1诱导介导DNA损伤的IRD表达 对治疗的抵抗力。因此，从理论上讲，抑制IFN1途径可以恢复治疗敏感性。 然而，不加区别地抑制IFN1信号也可能限制其抗肿瘤作用，而这不会 为患者提供理想的临床疗效。抑制IRDS介导的促肿瘤活性但保留 IFN1诱导的抗肿瘤作用可能是一种有利的策略，为患者提供重大好处。对这件事 最后，了解IRDS是如何受到调控的，以及它如何保护癌细胞免受治疗的影响是紧迫的，而且 很重要。富含AT的相互作用结构域4B(ARID4B)属于干旱家族，是一种染色质重塑 蛋白。我们的初步数据表明，ARID4B在人类乳腺癌及其高表达 在乳腺癌患者中，表达与不良的临床结果有关。ARID4B基因在乳腺中的敲除 癌细胞系和小鼠模型影响了肿瘤的发生。此外，ARID4B的消融减少了DNA 乳腺癌细胞的损伤修复和对辐射和DNA损伤药物的敏感性增加。 从机制上讲，ARID4B是IFN1介导的STAT1-IRDS轴激活所必需的，并调节 乳腺癌细胞的PAR化/去PAR化。这一提议的一个中心假设是：IFN1亲肿瘤 影响由ARID4B决定，因为ARID4B对于激活IFN1-STAT1-IRDS信号至关重要 调控依赖PAR化/DAR化的DNA损伤反应促进乳腺癌的途径 辐射和DNA损伤药物的进展和治疗耐药性。这一假设将得到检验。 目的1.确定ARID4B在PAR化/去PAR化调节中的作用-- 依赖DNA损伤反应促进IFN1-IRDS的亲肿瘤效应。目标2.确定机制 ARID4B通过其调控干扰素-STAT1-IRDS途径。目的3.ARID4B的临床前分析 乳腺癌对辐射和破坏DNA的药物的抗药性。这项研究具有创新性，因为它揭示了 ARID4B作为干扰素促肿瘤效应的特异性决定因素。这项研究具有重要意义，因为分析了 ARID4B功能及其调控通路可能导致改进治疗的新治疗方法 乳腺癌患者的疗效和生存率。

Project Summary/Abstract Adjuvant radiotherapy or chemotherapy is a standard treatment for breast cancer patients after surgical resection of cancer. However, cancer cells commonly develop therapeutic resistance. A crucial factor that decides whether a tumor relapses or responds to these cancer therapies is the dual role of interferon (IFN) in promoting or counteracting cancer progression, respectively. A set of IFN-stimulated genes (ISGs), the so-called “IFN-related DNA damage resistance signature” (IRDS), was recently implicated in resistance to irradiation and chemotherapy in different types of cancers, including breast cancer. While irradiation and some of chemotherapy drugs cause DNA damage in cancer cells, IFN1 induces expression of IRDS that mediates DNA damage resistance to treatments. Therefore, in theory, inhibiting the IFN1 pathway could restore therapeutic sensitivity. However, indiscriminate suppression of IFN1 signaling could also constrain its anti-tumor effects, which will not provide the desired clinical efficacy to patients. Inhibiting the IRDS-mediated pro-tumor activities but reserving the IFN1-induced anti-tumor effects could be a favorable strategy to provide major benefit to patients. To this end, understanding how the IRDS is regulated and how it protects cancer cells against therapies is urgent and important. AT-rich interaction domain 4B (ARID4B) belongs to the ARID family and is a chromatin remodeling protein. Our preliminary data demonstrate that ARID4B is highly expressed in human breast cancer and its high expression is associated with poor clinical outcomes in breast cancer patients. Knockout of ARID4B in breast cancer cell lines and mouse models compromised tumorigenesis. In addition, ablation of ARID4B reduced DNA damage repair and increased sensitivity to irradiation and DNA-damaging drugs in breast cancer cells. Mechanistically, ARID4B is required for IFN1-mediated activation of the STAT1-IRDS axis and regulates PARylation/dePARylation in breast cancer cells. A central hypothesis for this proposal is: The IFN1 pro-tumor effects are determined by ARID4B, because ARID4B is crucial for activation of the IFN1-STAT1-IRDS signaling pathway that regulates PARylation/dePARylation-dependent DNA damage response to promote breast cancer progression and therapeutic resistance to irradiation and DNA-damaging drugs. The hypothesis will be tested by three specific aims: Aim 1. Determine the role of ARID4B on regulation of PARylation/dePARylation- dependent DNA damage response to promote the IFN1-IRDS pro-tumor effects. Aim 2. Identify the mechanism by which ARID4B regulates the IFN-STAT1-IRDS pathway. Aim 3. Preclinical analyses of ARID4B impact on breast cancer resistance to irradiation and DNA-damaging drugs. This study is innovative because it uncovers ARID4B as the specific determinant of IFN pro-tumor effects. This study is significant because analyses of ARID4B function and its regulatory pathway could lead to new therapeutic approaches that improve treatment efficacy and survival for breast cancer patients.