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

• 批准号: 10608056
• 负责人: Seth E Frietze
• 金额: $ 37.21万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 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/10608056
• 关键词: Acceleration; Acetylation; Binding; Biological Markers; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer therapy; Bromodomain; Calorimetry; Cancer Cell Growth; 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; Estrogens; Exhibits; Genes; Genetic Transcription; Genome; Genomics; Histone Acetylation; 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

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 Alpha阳性肿瘤(ER+)是BCA最常见的亚型(约占所有病例的70%)，且有效 以ER为靶点的抗内分泌治疗。然而，复发经常发生，导致 内分泌治疗耐药与晚期转移性疾病的发展。确凿的证据 表明转录可塑性是ETR的一个显著特征，它提供了癌症的亚群 有能力适应治疗挑战的细胞。然而，管理的分子调控网络 BCA细胞中的抗雌激素反应仍然知之甚少。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 关于癌症的表观遗传机制和新出现的“可用药靶点”，我们的理解存在很大差距 组蛋白乙酰赖氨酸和BRDS之间存在的功能关系。此外，人们对此知之甚少 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 BCA和ETR细胞模型中的表观基因组图谱。我们公布的结果支持表观基因组范围内的 雌激素反应元件的重新编程与内分泌敏感性和ETR的获得有关。 通过一套完整和系统的具体目标，我们将检验金砖四国发挥中介作用的假设 BCA的内分泌反应性。这个项目将特别关注三个主要方面，它们可能具有 改进靶向治疗的可能性：鉴定特定的含有溴域的蛋白质，这些蛋白质可以 靶向增强细胞对他莫昔芬的反应在癌症治疗中的贡献，测定 在ET早期和晚期，含有BRD的蛋白质对转录可塑性的影响，以及 复发转移性ER+乳腺癌的表观遗传学特征与全球 具有BRD组蛋白结合活性的乙酰酶。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，并将促进发现新的内分泌反应和 开发治疗干预的新模式。