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

项目总结/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。然而，癌细胞通常会产生治疗抗性。一个决定是否 肿瘤复发或对这些癌症疗法有反应的原因是干扰素（IFN）在促进或 分别阻止癌症进展。一组干扰素刺激基因（ISG），即所谓的“干扰素相关基因”， DNA损伤抗性标记”（IRDS），最近被牵连在抗辐射和 不同类型癌症的化疗，包括乳腺癌。放疗和一些化疗 药物导致癌细胞DNA损伤，IFN 1诱导介导DNA损伤的IRDS表达 对治疗的抵抗。因此，在理论上，抑制IFN 1通路可以恢复治疗敏感性。 然而，不加选择地抑制IFN 1信号传导也可能限制其抗肿瘤作用，这将不会影响其抗肿瘤作用。 为患者提供所需的临床疗效。抑制IRDS介导的促肿瘤活性，但保留 IFN 1诱导的抗肿瘤作用可能是为患者提供主要益处的有利策略。本 最后，了解IRDS是如何调节的，以及它如何保护癌细胞免受治疗是迫切的， 重要.富含AT的相互作用结构域4 B（ARID 4 B）属于ARID家族，是一种染色质重塑蛋白， 蛋白我们的初步数据表明，ARID 4 B在人乳腺癌中高表达，其高表达与乳腺癌的发生有关。 表达与乳腺癌患者的不良临床结果相关。乳腺中ARID 4 B的敲除 癌细胞系和小鼠模型损害了肿瘤发生。此外，ARID 4 B的消融减少了DNA 损伤修复和增加敏感性辐射和DNA损伤药物在乳腺癌细胞。 从机制上讲，ARID 4 B是IFN 1介导的STAT 1-IRDS轴激活所必需的，并调节 乳腺癌细胞中的PAR化/去PAR化。该提议的一个中心假设是： 作用由ARID 4 B决定，因为ARID 4 B对于IFN 1-STAT 1-IRDS信号传导的激活至关重要 调节PAR化/去PAR化依赖性DNA损伤反应促进乳腺癌的途径 进展和对辐射和DNA损伤药物的治疗抗性。假设将被检验 三个具体目标：目标1。确定ARID 4 B在调节PAR化/去PAR化中的作用- 依赖性DNA损伤应答以促进IFN 1-IRDS促肿瘤作用。目标2.确定机制 ARID 4 B通过其调节IFN-STAT 1-IRDS通路。目标3：ARID 4 B影响的临床前分析 乳腺癌对辐射和DNA损伤药物的抗性。这项研究是创新的，因为它揭示了 ARID 4 B作为IFN促肿瘤作用的特异性决定因素。这项研究意义重大，因为分析 ARID 4 B功能及其调控途径可能导致新的治疗方法，改善治疗 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.