Targeting BET proteins in Triple Negative Breast Cancer

靶向三阴性乳腺癌中的 BET 蛋白

• 批准号: 9127467
• 负责人: RUTH A. KERI
• 金额: $ 37.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-14 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127467
• 关键词: Affect; Apoptosis; Apoptotic; BCL1 Oncogene; BRD2 gene; Binding; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Bromodomain; Cell Cycle; Cell Cycle Progression; Cell Death; Cell Fate Control; Cell Line; Cells; Cessation of life; ChIP-seq; Collection; Cytokinesis; Cytotoxic Chemotherapy; DNA; Data; Defect; Detection; Development; Disease; Down-Regulation; ERBB2 gene; Enhancers; Ensure; Estrogens; FOXM1 gene; Failure; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Genome; Genome Stability; Goals; Growth; Histone Code; Histones; In Vitro; Kinesin; Lead; Lysine; Malignant Neoplasms; Mitosis; Mitotic spindle; Modeling; Molecular Profiling; Neoplasm Metastasis; Normal Cell; Outcome; Paclitaxel; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Ploidies; Polyploid Cells; Polyploidy; Progesterone; Proteins; Reader; Recurrence; Reporting; Resistance; Role; Route; Stretching; Testing; Tissues; Xenograft Model; activating transcription factor; aurora B kinase; cancer cell; cancer genome; cancer subtypes; cancer type; cdc Genes; cell growth; chemotherapy; epigenetic regulation; improved; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; mimetics; neoplastic cell; novel; novel strategies; novel therapeutic intervention; prevent; protein function; public health relevance; receptor; response; senescence; targeted treatment; taxane; transcription factor; transcriptome; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor growth

 DESCRIPTION (provided by applicant): For over a decade it has been known that breast cancer subtypes are dictated by their expressed genomes or transcriptomes and that these expression profiles dictate tumor aggressiveness and patient outcomes. Despite this conceptual breakthrough, the creation of targeting approaches to alter these transcriptomes has not yet been feasible due to our limited understanding of the factors that activate and maintain gene expression in these tumors. This proposal focuses on Bromodomain and Extra Terminal (BET) proteins, which are "readers" of the histone code, and their role in regulating breast cancer growth and progression. We will focus on triple negative breast cancers (TNBC) which lack estrogen, progesterone, and HER2 receptors because patients with these tumors do not reap the benefits of targeted therapies directed to these receptors. Identifying the mechanisms that control the expressed genomes of these tumors should reveal new avenues for ameliorating this relatively untreatable disease. Our preliminary studies have revealed that loss of BET protein function results in extensive suppression of genes involved in mitosis and cytokinesis and causes polyploidy in TNBC cells. This defect is followed either by apoptosis or senescence in numerous cell lines. Furthermore, the BET inhibitor, JQ1, displays significant efficacy and inhibits the growth of tumors in three different xenograft models. We will expand upon these foundational studies to uncover the mechanisms by which suppression of BET proteins inhibits growth and promotes death of TNBC cells. In Aim 1, we will identify the BET proteins and their transcriptional targets that maintain normal ploidy in TNBC cell lines as well as determine if FOXM1 is a major intermediate in BET control of normal cell cycle progression. Aim 2 will focus on deciphering the specific defects induced by BET inhibitors that lead to polyploidy in TNBC cells and assessing whether these can be leveraged to enhance sensitivity to chemotherapies that also target mitosis. Lastly, Aim 3 will identify the specific mechanisms that dictate the decision to apoptose or senesce in response to the loss of BET function in TNBC cells, with the goal of ensuring an apoptotic cell fate in response to BET inhibitors. Together, these studies will provide key mechanistic insights into the roles of BET proteins in TNBC and reveal approaches for enhancing their activity in this disease. These studies should lead to the development of a new therapeutic approach that globally targets the transcriptome of aggressive breast cancers with the goal of improving patient outcomes.

 描述（由适用提供）：十多年来，众所周知，乳腺癌亚型由其表达的基因组或转录组决定，并且这些表达谱决定了肿瘤的侵袭性和患者结果。尽管存在这种概念上的突破，但由于我们对激活这些肿瘤中激活和维持基因表达的因素的有限理解，改变了改变这些转录组的靶向方法尚不可行。该提案的重点是溴结构域和额外末端（BET）蛋白，这些蛋白是组蛋白代码的“读者”及其在控制乳腺癌生长和进展中的作用。我们将专注于缺乏雌激素，孕激素和HER2受体的三重阴性乳腺癌（TNBC），因为这些肿瘤的患者无法获得针对这些受体的靶向疗法的好处。确定控制这些肿瘤表达基因组的机制，应揭示新的途径，以改善这种相对不可治疗的疾病。我们的初步研究表明，BET蛋白功能的丧失会导致广泛抑制有丝分裂和细胞因子的基因，并在TNBC细胞中引起多倍体。在许多细胞系中，这种缺陷之后是凋亡或感应。此外，BET抑制剂JQ1显示出明显的效率，并抑制了三种不同的异种移植模型中肿瘤的生长。我们将扩展这些基础研究，以发现抑制BET蛋白抑制生长并促进TNBC细胞死亡的机制。在AIM 1中，我们将确定在TNBC细胞系中保持正常倍性的BET蛋白及其转录靶标，并确定FOXM1是否是对正常细胞周期进程的BET控制的主要中间体。 AIM 2将集中于解解由导致TNBC细胞多倍体的BET抑制剂引起的特定缺陷，并评估是否可以利用这些缺陷来提高对也靶向有丝分裂的化学疗法的敏感性。最后，AIM 3将确定针对TNBC细胞中BET功能丧失的凋亡或传感器决定的具体机制，目的是确保响应BET抑制剂的凋亡细胞命运。这些研究将在一起 提供有关BET蛋白在TNBC中作用的关键机械洞察力，并揭示了增强其在该疾病中活性的方法。这些研究应导致一种新的治疗方法的发展，该方法在全球范围内针对侵略性乳腺癌的转录组，以改善患者预后。