Targeting BET proteins in Triple Negative Breast Cancer

 描述（由申请人提供）：十多年来，已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肿瘤侵袭性和患者结果。尽管有这一概念上的突破，但由于我们对激活和维持这些肿瘤中基因表达的因素的了解有限，因此创建靶向方法来改变这些转录组尚不可行。这项提案的重点是溴结构域和额外的终端（BET）蛋白，这是“读者”的组蛋白代码，以及它们在调节乳腺癌的生长和进展的作用。我们将重点关注缺乏雌激素、孕激素和HER2受体的三阴性乳腺癌（TNBC），因为这些肿瘤患者无法从针对这些受体的靶向治疗中获益。确定控制这些肿瘤表达基因组的机制应该揭示改善这种相对无法治疗的疾病的新途径。我们的初步研究表明，BET蛋白功能的丧失导致参与有丝分裂和胞质分裂的基因的广泛抑制，并导致TNBC细胞的多倍性。在许多细胞系中，这种缺陷之后是凋亡或衰老。此外，BET抑制剂JQ1在三种不同的异种移植模型中显示出显著的功效并抑制肿瘤的生长。我们将扩展这些基础研究，以揭示BET蛋白抑制TNBC细胞生长和促进TNBC细胞死亡的机制。在目标1中，我们将鉴定在TNBC细胞系中维持正常倍性的BET蛋白及其转录靶标，以及确定FOXM1是否是BET控制正常细胞周期进程的主要中间体。目标2将专注于破译BET抑制剂诱导的导致TNBC细胞多倍体的特定缺陷，并评估这些缺陷是否可以用于增强对也靶向有丝分裂的化疗的敏感性。最后，目标3将确定响应于TNBC细胞中BET功能的丧失而决定凋亡或衰老的特定机制，目的是确保响应于BET抑制剂的凋亡细胞命运。这些研究将 为BET蛋白在TNBC中的作用提供了关键的机制见解，并揭示了增强其在这种疾病中的活性的方法。这些研究应该导致开发一种新的治疗方法，该方法在全球范围内靶向侵袭性乳腺癌的转录组，目的是改善患者的预后。

 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.