Opposing Functions of BRD4 Isoforms in Breast Cancer

BRD4 同工型在乳腺癌中的相反功能

• 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
• 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

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 正常和受扰细胞中的程序通常会导致需要医疗护理的病理表型。 确定这些异常的基因靶点和途径是至关重要的，尤其是在癌细胞中。 为疾病治疗开发适当的治疗方案。然而，癌细胞的异质性 这使得制定一个适用于每个患者的通用治疗计划变得困难。 在过去的10年里，溴域包含蛋白4(BRD4)已经成为一种很有前途的癌症 由于其与调节转录程序的活性增强子的广泛关联而成为治疗靶点 与癌症的发生和发展有关，更重要的是，小分子化合物抑制剂的可用性 靶向BRD4及其相关家族成员，在人类中还包括BRD2、BRD3和BRDT。这些 溴结构域和末端外(BET)家族蛋白抑制剂，如JQ1和I-BET，在 逆转培养细胞和动物模型的癌症表型。其中几个复合衍生品是 目前正在进行治疗各种类型癌症和炎症性疾病的临床试验，以及它们的治疗靶点 主要归因于BRD4长亚型(BRD4-L，AA1-1362)。最近我们发现，通过异构体- 特异的敲除和内源蛋白检测随着转基因表达的减少而减少 BRD4短亚型(BRD4-S，aa1-722)实际上是致癌的，而BRD4-L在乳腺中具有抑瘤作用 癌细胞的增殖和迁移以及在乳腺肿瘤形成和转移中的作用。我们的中央 假设BRD4亚型具有相反的功能，尽管它们确实有一些共同的属性， 在肿瘤发展方面，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.确定BRD4亚型唯一和共同调控的基因靶点和途径 由于异构体特异性BRD4抗体和一类新的以磷酸化BRD4为靶向的化合物 与BET溴域抑制剂不同的分子作用现已成功地在我的 在实验室，我们处于一个独特的位置，可以解决BRD4靶向癌症治疗中涉及的紧迫问题。我们的 目前的目标是确定每个BRD4亚型唯一和共同调节的细胞通路 使用生化和分子工具、合成化学以及全基因组表达和结合图谱 目的：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 近期有效治疗乳腺癌的分子途径和新的基因靶点。

项目成果

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.

• DOI: 10.1126/sciadv.abf7346
• 发表时间: 2021-05
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Kim SK;Liu X;Park J;Um D;Kilaru G;Chiang CM;Kang M;Huber KM;Kang K;Kim TK
• 通讯作者: Kim TK