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Opposing Functions of BRD4 Isoforms in Breast Cancer

BRD4 同工型在乳腺癌中的相反功能

基本信息

批准号：
10028204
负责人：
CHENG-MING CHIANG
金额：
$ 45.85万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10028204
关键词：
Acute Myelocytic Leukemia Address Animal Model Antibodies BRD2 gene Binding Biochemical Biological Biological Assay Breast Cancer Cell Breast Cancer Treatment Bromodomain Burkitt Lymphoma Cancer Cell Growth Cancer Patient Cathepsins Cell Proliferation Cell model Cells Chemicals Cholesterol Chromatin Classification Clinical Clinical Trials Cultured Cells Cystatins DNA DNA Sequence Alteration Detection Development Disease Drug resistance ERBB2 gene Enhancers Epidermal Growth Factor Receptor Epigenetic Process Estrogen Receptor alpha Estrogen receptor positive Extracellular Matrix Family member Fos-Related Antigens Future Gene Cluster Gene Expression Gene Targeting Genes Genetic Genetic Heterogeneity Genetic Transcription Genomics Goals Hematologic Neoplasms Hematopoietic Neoplasms Histologic Homeobox Human In Vitro Individual Inflammatory Lead Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mammary Neoplasms Metastatic breast cancer Modeling Molecular Mucins Multiple Myeloma Mus Neoplasm Metastasis Nonmetastatic Normal Cell Oncogenes Oncogenic Outcome Pathologic Pathway interactions Patients Pharmacology Pharmacotherapy Phenotype Positioning Attribute Property Protein Family Protein Isoforms Proteins Proteomics Regimen Regulation Role Solid Neoplasm Specimen Stress Surveys Synthesis Chemistry TP53 gene Testing Variant Work base c-myc Genes cancer cell cancer classification cancer gene expression cancer heterogeneity cancer initiation cancer subtypes cancer therapy cancer type cell motility drug development gain of function genetic signature genome wide association study genome-wide in vivo inhibitor/antagonist knock-down malignant breast neoplasm medical attention mevalonate molecular marker mouse model mutant personalized medicine pre-clinical progesterone receptor positive programs protein protein interaction public health relevance targeted cancer therapy targeted treatment therapeutic target tool trait transcription factor transcriptome transcriptomics transgene expression treatment planning triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression tumorigenesis whole genome

项目摘要

Abstract Genetic mutation and non-mutational epigenetic control of gene expression that alter transcription programs in normal and perturbed cells often lead to pathological phenotypes requiring medical attention. Identifying the gene targets and pathways underlying these abnormalities, particularly in cancer cells, is crucial for developing appropriate regimens for disease treatment. Nevertheless, the heterogeneity of cancer cells makes it difficult to develop a universal treatment plan that works for every patient. Over the past 10 years, bromodomain-containing protein 4 (BRD4) has emerged as a promising cancer therapeutic target due to its broad association with active enhancers that modulate transcription programs implicated in cancer initiation and progression, and importantly, the availability of small compound inhibitors targeting BRD4 and its related family members that also include BRD2, BRD3, and BRDT in humans. These bromodomain and extra-terminal (BET) family protein inhibitors, such as JQ1 and I-BET, show great promise in reversing cancer phenotypes in cultured cells and animal models. Several of these compound derivatives are now in clinical trials for treating various types of cancer and inflammatory disease, and their therapeutic targets have been attributed mainly to the BRD4 long isoform (BRD4-L, aa 1-1362). Recently we found, by isoform- specific knockdown and endogenous protein detection along with transgene expression, that the less abundant BRD4 short isoform (BRD4-S, aa 1-722) is in fact oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration as well as in mammary tumor formation and metastasis. Our central hypothesis is that BRD4 isoforms have opposing functions, although they do share some common properties, in tumor development, which will be stringently tested by addressing the following three specific aims: 1. To define the biological role of BRD4-L and BRD4-S in different breast cancer cells and mouse models 2. To elucidate the mechanistic action of BRD4 isoforms and their coregulators in breast cancer subtypes 3. To identify gene targets and pathways uniquely and commonly regulated by BRD4 isoforms Since isoform-specific BRD4 antibodies and a new class of phospho-BRD4-targeting compounds with molecular action distinct from the BET bromodomain inhibitors have now been successfully developed in my lab, we are in a unique position to address pressing issues implicated in BRD4-targeted cancer therapy. Our immediate goals are to identify cellular pathways uniquely and commonly regulated by each BRD4 isoform using biochemical and molecular tools, synthetic chemistry, and genome-wide expression and binding profiling to elucidate BRD4-L and BRD4-S involvement in breast cancer. Our eventual goals are to provide validated molecular pathways and new gene targets for effective breast cancer treatment in the near future.

摘要改变转录的基因表达的遗传突变和非突变表观遗传控制正常和受干扰细胞中的程序经常导致需要医疗关注的病理表型。确定这些异常的基因靶点和途径，特别是在癌细胞中，用于开发适当的疾病治疗方案。然而，癌细胞的异质性这使得很难制定一个适用于每个患者的通用治疗计划。在过去的10年里，含溴结构域蛋白4（BRD4）已经成为一种有前途的癌症由于其与调节转录程序的活性增强子的广泛关联，与癌症的发生和发展有关，重要的是，靶向BRD4及其相关家族成员，还包括人类中的BRD2、BRD3和BRDT。这些布罗莫结构域和额外末端（BET）家族蛋白抑制剂，如JQ1和I-BET，显示出巨大的前景，在培养细胞和动物模型中逆转癌症表型。这些化合物衍生物中的几种是目前正在临床试验中用于治疗各种类型的癌症和炎性疾病，以及它们的治疗靶点主要归因于BRD4长同种型（BRD4-L，aa 1 - 1362）。最近我们发现，通过同种型- 特异性敲低和内源性蛋白检测沿着转基因表达，即丰度越低 BRD4短同种型（BRD4-S，aa 1 - 722）实际上是致癌的，而BRD4-L在乳腺癌中是肿瘤抑制的。癌细胞增殖和迁移以及乳腺肿瘤的形成和转移。我们的中央假设是BRD4同种型具有相反的功能，尽管它们确实具有一些共同的性质，在肿瘤发展中的作用，将通过解决以下三个具体目标进行严格测试： 1.确定BRD4-L和BRD4-S在不同乳腺癌细胞和小鼠模型中的生物学作用 2.阐明BRD4亚型及其共调节因子在乳腺癌亚型中的作用机制 3.鉴定BRD4亚型独特和共同调控的基因靶点和途径由于同种型特异性BRD4抗体和一类新的磷酸-BRD4靶向化合物，与BET布罗莫结构域抑制剂不同的分子作用现在已经在我的研究中成功地开发出来。实验室，我们在解决BRD4靶向癌症治疗中涉及的紧迫问题方面处于独特的地位。我们当前的目标是鉴定由每种BRD4同种型独特和共同调节的细胞通路利用生物化学和分子工具、合成化学、全基因组表达和结合分析阐明BRD4-L和BRD4-S参与乳腺癌。我们的最终目标是提供经过验证的分子途径和新的基因靶点在不久的将来有效的乳腺癌治疗。