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：
10612045
负责人：
CHENG-MING CHIANG
金额：
$ 45.11万
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/10612045
关键词：
Acute Myelocytic Leukemia Address Animal Model Antibodies BRD2 gene Binding Biochemical Biological Biological Assay Breast Cancer Cell Breast Cancer Treatment Bromodomain Bromodomains and extra-terminal domain inhibitor 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 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 Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mammary Neoplasms Metastatic breast cancer Modeling Molecular Mucins Multiple Myeloma Mus NF-kappa B Neoplasm Metastasis Nonmetastatic Normal Cell Oncogenes Oncogenic Outcome Pathologic Pathway interactions Patients 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 c-myc Genes cancer cell cancer gene expression cancer heterogeneity cancer initiation cancer subtypes cancer therapy cancer type cell motility drug development drug resistance development gain of function genetic signature genome wide association study genome-wide in vivo inhibitor knock-down malignant breast neoplasm medical attention mevalonate molecular marker mouse model mutant personalized medicine pharmacologic posttranscriptional 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.

抽象的改变转录的基因表达的基因突变和非突变表观遗传控制正常和受到干扰的细胞中的程序通常会导致需要医疗护理的病理表型。识别这些异常（尤其是癌细胞）背后的基因靶点和途径至关重要制定适当的疾病治疗方案。然而，癌细胞的异质性使得制定适用于每位患者的通用治疗计划变得困难。在过去的 10 年里，含溴结构域蛋白 4 (BRD4) 已成为一种有前途的癌症治疗靶标，因为它与调节转录程序的活性增强子有广泛的关联与癌症的发生和进展有关，重要的是，与小化合物抑制剂的可用性有关靶向 BRD4 及其相关家族成员，其中还包括人类中的 BRD2、BRD3 和 BRDT。这些溴结构域和末端外 (BET) 家族蛋白抑制剂，例如 JQ1 和 I-BET，在逆转培养细胞和动物模型中的癌症表型。其中一些化合物衍生物是目前正在进行治疗各种类型癌症和炎症性疾病及其治疗靶点的临床试验主要归因于 BRD4 长亚型（BRD4-L，aa 1-1362）。最近我们发现，通过异构体- 特异性敲除和内源蛋白检测以及转基因表达，即丰度较低的 BRD4 短亚型（BRD4-S，aa 1-722）实际上具有致癌性，而 BRD4-L 在乳腺中具有肿瘤抑制作用癌细胞增殖和迁移以及乳腺肿瘤形成和转移。我们的中央假设 BRD4 同工型具有相反的功能，尽管它们确实具有一些共同的特性，在肿瘤发展中，这将通过解决以下三个具体目标进行严格测试： 1. 明确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. 识别 BRD4 异构体独特且普遍调控的基因靶标和通路由于异构体特异性 BRD4 抗体和一类新型磷酸化 BRD4 靶向化合物与 BET 溴结构域抑制剂不同的分子作用现已在我的实验室中成功开发出来。实验室，我们处于独特的地位，可以解决 BRD4 靶向癌症治疗中涉及的紧迫问题。我们的近期目标是确定每种 BRD4 异构体独特且普遍调控的细胞通路使用生化和分子工具、合成化学以及全基因组表达和结合分析阐明 BRD4-L 和 BRD4-S 与乳腺癌的关系。我们的最终目标是提供经过验证的在不久的将来有效治疗乳腺癌的分子途径和新基因靶点。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MYC promotes global transcription in part by controlling P-TEFb complex formation via DNA-binding independent inhibition of CDK9 SUMOylation.

DOI：
10.1007/s11427-022-2281-6
发表时间：
2023-09
期刊：
SCIENCE CHINA-LIFE SCIENCES
影响因子：
9.1
作者：
Guan, Qingqing;Chen, Zhaosu;Yu, Fang;Liu, Lingling;Huang, Yuanyong;Wei, Gang;Chiang, Cheng-Ming;Wong, Jiemin;Li, Jiwen
通讯作者：
Li, Jiwen

Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives.

癌症中溴结构域和额外末端蛋白的双靶点抑制剂：从药物化学角度进行综述

DOI：
10.1002/med.21859
发表时间：
2022-03
期刊：
Medicinal research reviews
影响因子：
13.3
作者：
Feng L;Wang G;Chen Y;He G;Liu B;Liu J;Chiang CM;Ouyang L
通讯作者：
Ouyang L

Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site.

DOI：
10.1021/acs.jmedchem.1c01851
发表时间：
2022-02-10
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Liu Z;Li Y;Chen H;Lai HT;Wang P;Wu SY;Wold EA;Leonard PG;Joseph S;Hu H;Chiang CM;Brasier AR;Tian B;Zhou J
通讯作者：
Zhou J

Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients.

DOI：
10.3390/cancers13061246
发表时间：
2021-03-12
期刊：
Cancers
影响因子：
5.2
作者：
Sanz-Álvarez M;Cristóbal I;Luque M;Santos A;Zazo S;Madoz-Gúrpide J;Caramés C;Chiang CM;García-Foncillas J;Eroles P;Albanell J;Rojo F
通讯作者：
Rojo F

Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome.