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 乳腺癌是一种异质性极高的疾病，影响全球近 200 万女性 每年。在这些乳腺肿瘤中，大约 70% 表达孕酮受体 (PR)，这是一种核 受体和配体激活的转录因子，响应黄体酮而被激活。引人注目 临床试验数据表明，孕激素在乳腺癌的发展中发挥作用，与乳腺癌的发生无关。 广泛研究的雌激素受体。然而，这种现象发生的机制还没有得到充分研究。我们的 实验室利用微阵列数据与基因集富集分析相结合，确定了一个新的基因子集 PR 激活后表达发生改变。这些基因主要参与干扰素信号传导—— 通常用于应对病毒感染的途径。我们的数据显示，许多正常情况下的基因 当 PR 被抑制时，响应干扰素信号传导（干扰素刺激基因，ISG）而被激活的基因被抑制。 被其配体激活。我们的实验室还表明，当 PR 表达暂时被抑制时，ISG 转录抑制消失，表明这些基因的抑制是 PR 依赖性的。最后，我们有 进行染色质免疫沉淀实验并观察到 ​​ISG 募集减少 ISG 启动子区域的转录机制，证明 PR 在干扰经典干扰素中的作用 发信号。免疫系统的逃避最近已被添加到癌症和我们的标志列表中 初步数据表明肿瘤能够逃避免疫检测的潜在机制。 I 型干扰素信号传导的激活是标记肿瘤进行免疫清除的早期步骤，并且通过 抑制ISG蛋白表达，这些肿瘤有可能可以逃避免疫检测，导致肿瘤发生 的建立和进展。本文提出的实验旨在阐明其机制 PR 抑制经典干扰素信号传导和 ISG 表达，以及这种抑制如何影响乳腺肿瘤 体内的形成和免疫反应。我们将通过识别之间的直接相互作用来解决前者 PR 和干扰素信号成分以及使用称为快速的高通量技术 内源蛋白免疫沉淀质谱 (RIME) 鉴定 PR 与 转录辅助因子可能有助于抑制 ISG 转录。然后我们将通过利用 同基因小鼠模型，使我们能够在功能齐全的情况下观察肿瘤的形成 免疫系统。我们将评估存在和不存在时肿瘤潜伏期和免疫反应的变化 PR 和黄体酮。确定 PR 和孕激素在免疫逃避中的这种新作用提供了以下见解： 可以帮助改进现有的仅以雌激素为基础的预防和治疗激素疗法 依赖性乳腺癌。