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

项目2：概要 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BCa最常见的亚型（约占所有病例的70%）， 以雌激素受体为靶点的抗内分泌治疗。然而，复发经常发生，导致 内分泌治疗抗性（ETR）和晚期转移性疾病的发展。大量证据 表明转录可塑性是ETR的一个突出特征，它提供了癌症的亚群， 有能力适应治疗挑战的细胞。然而，控制这些细胞的分子调控网络 BCa细胞中的抗雌激素反应性仍然知之甚少。已经确定组蛋白赖氨酸 乙酰化模式建立细胞类型增强子程序以指导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“可药物靶点”，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， 关于BRD在BCa抗雌激素反应中的作用。我们之前已经描述了 在BCa和ETR的细胞模型中的表观基因组谱。我们发表的结果支持表观基因组范围内 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。 通过一套完整而系统的具体目标，我们将检验BRD介导的假设 BCa的内分泌反应性。本项目将特别关注可能会影响 改进靶向治疗的潜力：鉴定特定的含溴结构域蛋白， 在癌症治疗中靶向增强细胞对他莫昔芬的反应， 在ET的早期和晚期，含BRD的蛋白质对转录可塑性的影响， 复发性转移性ER+乳腺癌的表观遗传学特征，以将全球 BRD的组蛋白结合活性。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，并将有助于发现新的生物标志物的内分泌反应和 开发新的治疗干预模式。

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.