Progesterone Receptor Regulation of Interferon Signaling in Breast Cancer

乳腺癌中干扰素信号传导的孕酮受体调节

• 批准号: 9753704
• 负责人: Katherine Rose Walter
• 金额: $ 3.41万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753704
• 关键词: Address; Affect; Biological Assay; Cancer Etiology; Cessation of life; Chromatin; Clinical Trials; Co-Immunoprecipitations; DNA; DNA Binding; Data; Detection; Development; Diagnosis; Disease; Down-Regulation; Estrogen Receptors; Estrogens; Family member; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Genomics; Histocompatibility; Histones; Hormones; Image; Immune; Immune Evasion; Immune response; Immune system; Immunofluorescence Immunologic; Immunoprecipitation; Incidence; Injections; Interferon Type I; Interferons; Interruption; Lesion; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mass Spectrum Analysis; Mediating; Methods; Modification; Mus; Nuclear Receptors; Pathway interactions; Patients; Post-Translational Protein Processing; Prevention therapy; Process; Production; Progesterone; Progesterone Receptors; Progestins; Promoter Regions; Proteins; Public Health; Receptor Activation; Regulation; Role; STAT protein; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Techniques; Testing; Therapeutic; Time; Transcription Coactivator; Transcription Repressor/Corepressor; Tumor-Associated Process; United States; Virus Diseases; Woman; attenuation; base; breast cancer progression; breast lesion; cell transformation; chromatin immunoprecipitation; clinically relevant; cofactor; cytokine; experimental study; gene repression; immune clearance; immune system function; immunological intervention; improved; in vivo; insight; interest; knock-down; malignant breast neoplasm; mouse model; novel; progesterone receptor A; progesterone receptor positive; promoter; protein expression; protein protein interaction; receptor; receptor expression; receptor function; recruit; response; transcription factor; tumor; tumor progression; tumorigenic

Abstract Breast cancer is an extremely heterogeneous disease that affects close to two million women across the globe each year. Of these breast tumors, approximately 70% express the progesterone receptor (PR), a nuclear receptor and ligand-activated transcription factor that is activated in response to progesterone. Compelling clinical trial data have suggested that progestins have a role in breast cancer development, independent of the widely-studied estrogen receptor. The mechanism by which this occurs, however, is vastly understudied. Our lab, using microarray data combined with Gene Set Enrichment Analysis, has identified a novel subset of genes that have altered expression following PR activation. These genes are primarily involved in interferon signaling— a pathway normally utilized in response to viral infection. Our data show that many genes that are normally activated in response to interferon signaling (interferon stimulated genes, ISGs) are repressed when PR is activated by its ligand. Our lab has also shown that when PR expression is transiently knocked down, ISG transcriptional repression is lost, indicating that the repression of these genes is PR dependent. Finally, we have performed chromatin immunoprecipitation experiments and observed diminished recruitment of ISG transcriptional machinery to ISG promoter regions, demonstrating PR's role in interrupting canonical interferon signaling. Evasion of the immune system has recently been added to the list of Hallmarks of Cancer and our preliminary data suggest a potential mechanism by which tumors are able to escape immune detection. Activation of type I interferon signaling is an early step in marking tumors for immune clearance and, by repressing ISG protein expression, it is possible that these tumors can avoid immune detection leading to tumor establishment and progression. The experiments proposed herein aim to elucidate the mechanisms by which PR inhibits canonical interferon signaling and ISG expression, and how this inhibition affects mammary tumor formation and immune response in vivo. We will address the former by identifying direct interactions between PR and interferon signaling components as well as use a high throughput technique known as Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) to identify PR interactions with transcriptional cofactors that may aid in inhibiting ISG transcription. We will then address the latter by utilizing a syngeneic mouse model which allows us to observe tumor formation in the presence of a fully functioning immune system. We will evaluate changes in tumor latency and immune response in the presence and absence of PR and progesterone. Determining this novel role of PR and progestins in immune evasion offers insight that could aid in improving upon established estrogen only-based therapies for prevention and treatment of hormone dependent breast cancers.

抽象的 乳腺癌是一种极其异质性疾病，全球影响近200万妇女 每年。在这些乳腺肿瘤中，大约70％表达孕酮受体（PR），核受体 响应孕酮激活的接收器和配体激活的转录因子。引人注目 临床试验数据表明，孕激素在乳腺癌发育中起作用，与 广泛研究的雌激素受体。然而，众所周知，发生这种情况的机制。我们的 实验室使用微阵列数据与基因集富集分析相结合，已确定了一个新的基因子集 PR激活后的表达改变。这些基因主要参与干扰素信号传导 - 通常用于病毒感染的途径。我们的数据表明，许多基因通常是 当PR为PR IS时，反映了干扰素信号传导（干扰素刺激的基因，ISG）激活的激活 被其配体激活。我们的实验室还表明，当PR表达瞬时敲低时，ISG 转录表达丢失，表明这些基因的表达取决于PR。最后，我们有 进行了染色质免疫沉淀实验，观察到ISG的募集减少 转录机械到ISG启动子区域，证明PR在中断规范干扰中的作用 信号。逃避免疫系统最近已添加到癌症的标志和我们的标志清单中 初步数据提出了一种潜在的机制，肿瘤能够逃脱免疫检测。 I型干扰素信号的激活是标记免疫清除肿瘤的早期步骤，并通过 抑制ISG蛋白表达，这些肿瘤可能避免免疫检测导致肿瘤 建立和进步。本文提出的实验旨在阐明该机制 PR抑制规范干扰信号传导和ISG表达，以及这种抑制作用如何影响乳腺肿瘤 体内形成和免疫反应。我们将通过识别直接互动来解决前者之间的直接互动 PR和干扰素信号传导组件以及使用高吞吐量技术称为快速 内源性蛋白质（RIME）的免疫沉淀质谱法，以鉴定与PR相互作用 转录辅助因子可能有助于抑制ISG转录。然后，我们将使用一个 合成小鼠模型，该模型使我们能够在功能齐全的情况下观察到肿瘤的形成 免疫系统。我们将在存在和不存在的情况下评估肿瘤潜伏期和免疫反应的变化 公关和孕激素。确定PR和孕激素在免疫进化中的新作用，提供了见解 可以帮助改善仅基于雌激素的疗法，以预防和治疗赛马 依赖的乳腺癌。