Project 2: Bromodomains as Epigenetic Modulators of Endocrine Responsiveness in ER+ Breast Cancer

项目 2：溴结构域作为 ER 乳腺癌内分泌反应性的表观遗传调节剂

基本信息

批准号：
10380072
负责人：
Seth E Frietze
金额：
$ 37.26万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380072
关键词：
Acetylation Address Binding Biological Markers Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Cancer therapy Bromodomain Calorimetry Cancer Etiology Cell model Cells Cessation of life ChIP-seq Chromatin Data Development Disease Drug Targeting Effectiveness Elements Endocrine Enhancers Epigenetic Process Estrogen Antagonists Estrogen Receptor alpha Estrogen receptor positive Estrogens Exhibits Genes Genetic Transcription Genome Genomics Growth Histones Individual Ligand Binding Ligands Link Lysine Malignant Neoplasms Mammary Neoplasms Mediating Metastatic/Recurrent Modality Molecular Organoids Outcome Pathway interactions Patients Pattern Peptides Phase Phenotype Post-Translational Protein Processing Prognosis Proteins Publishing RUNX1 gene Reader Recurrence Refractory Regulator Genes Relapse Resistance Response Elements Role Signal Transduction System Tamoxifen Techniques Technology Testing Therapeutic Therapeutic Intervention Treatment Failure Variant Woman Work adjuvant endocrine therapy cancer cell cancer therapy cell type clinical application clinically relevant druggable target epigenetic regulation epigenome epigenomics gene regulatory network hormone therapy improved inhibitor insight malignant breast neoplasm novel precision medicine preference programs resistance mechanism response targeted treatment treatment response treatment risk tumor

项目摘要

PROJECT 2: SUMMARY Breast cancer (BCa) ranks among the leading causes of cancer death in women worldwide. Estrogen Receptor alpha positive tumors (ER+) are the most common subtype of BCa (~70% of all cases), and are effectively treated with anti-endocrine therapies that target ER. However, relapse frequently occurs resulting in the development of endocrine therapy resistance (ETR) and late stage metastatic disease. Substantial evidence indicates that transcriptional plasticity is a prominent feature of ETR, which provides subpopulations of cancer cells with the ability to adapt to therapeutic challenges. However, the molecular regulatory networks that govern anti-estrogen responsiveness in BCa cells remain poorly understood. It is well established that histone lysine acetylation patterns establish cell type enhancer programs to direct BCa phenotypes. Bromodomain (BRD) chromatin reader proteins are the primary readers of histone lysine acetylation. Despite being recognized as key epigenetic mechanisms in cancer and emerging `druggable targets', there are large gaps in our understanding of the functional relationships that exist between histone acetyllysine and BRDs. In addition, little is known regarding the role of BRDs in BCa anti-estrogen responses. We have previously characterized the altered epigenomic profiles in cell models of BCa and ETR. Our published results provide support that epigenome-wide reprogramming of estrogen-responsive elements is linked to endocrine sensitivity and the acquisition of ETR. Through an integrated and systematic set of specific aims, we will test the hypothesis that BRDs mediate endocrine responsiveness in BCa. This project will specifically focus on three main aspects that might have the potential for improved targeted therapies: The identification of specific bromodomain-containing proteins that can be targeted to enhance cellular responses to tamoxifen in cancer treatment, determination of the contributions of BRD-containing proteins to transcriptional plasticity during the early and late phases of ET, and characterization of the epigenetic landscape of recurrent metastatic ER+ breast cancer to link the global acetylome with histone binding activity of BRDs. Overall, this work will contribute to our understanding of BCa epigenetic mechanisms and will facilitate the discovery of new biomarkers for endocrine responsiveness and the development of new modalities for therapeutic intervention.

项目 2：总结乳腺癌 (BCa) 是全球女性癌症死亡的主要原因之一。雌激素受体 α 阳性肿瘤 (ER+) 是最常见的 BCa 亚型（约占所有病例的 70%），并且可有效治疗采用针对 ER 的抗内分泌疗法进行治疗。但经常会出现复发的情况内分泌治疗耐药（ETR）和晚期转移性疾病的发展。实质性证据表明转录可塑性是 ETR 的一个显着特征，它提供了癌症亚群细胞具有适应治疗挑战的能力。然而，控制的分子调控网络 BCa 细胞的抗雌激素反应仍知之甚少。众所周知，组蛋白赖氨酸乙酰化模式建立细胞类型增强子程序来指导 BCa 表型。溴结构域 (BRD) 染色质阅读器蛋白是组蛋白赖氨酸乙酰化的主要阅读器。尽管被认为是关键癌症的表观遗传机制和新兴的“药物靶点”，我们的理解存在很大差距组蛋白乙酰赖氨酸和 BRD 之间存在的功能关系。此外，鲜为人知的是关于 BRD 在 BCa 抗雌激素反应中的作用。我们之前已经描述了改变后的特征 BCa 和 ETR 细胞模型中的表观基因组图谱。我们发表的结果提供了表观基因组范围内的支持雌激素反应元件的重编程与内分泌敏感性和 ETR 的获得有关。通过一套综合且系统的具体目标，我们将检验 BRD 介导的假设 BCa 的内分泌反应性。该项目将特别关注三个主要方面改进靶向治疗的潜力：识别特定的含溴结构域蛋白旨在增强细胞对癌症治疗中他莫昔芬的反应，确定贡献在 ET 的早期和晚期阶段，含有 BRD 的蛋白质对转录可塑性的影响，以及复发性转移性 ER+ 乳腺癌的表观遗传学特征，将全球联系起来具有组蛋白结合活性的 BRD 乙酰化组。总的来说，这项工作将有助于我们对 BCa 的理解表观遗传机制，将有助于发现内分泌反应的新生物标志物和开发新的治疗干预方式。