The roles of TRIM24 in breast cancer

TRIM24 在乳腺癌中的作用

基本信息

批准号：
10117196
负责人：
GUILLERMINA LOZANO
金额：
$ 40.2万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117196
关键词：
Address Amino Acid Motifs Apoptosis Biological Biological Models Breast Breast Cancer Model Breast Cancer Patient Breast Carcinoma Breast Epithelial Cells Bromodomain Cell Line Cells Cessation of life Choristoma Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Cohort Studies Cultured Cells Cytometry Data Data Set Development Disease Epigenetic Process Estrogen Receptors Estrogens Excision Gene Expression Genetic Transcription Goals Growth Histones Human Image Impairment In Vitro Knowledge Laboratories MCF7 cell Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mediating Metabolism Modeling Molecular Molecular Analysis Molecular Profiling Mus Mutagenesis Mutate Mutation Nuclear Receptors Oncogenic Outcome Pathway interactions Patient-derived xenograft models of breast cancer Patients Phenotype Physiological Post-Translational Protein Processing Process Proteins Reader Reading Recurrence Regulation Role Small Interfering RNA Specificity TP53 gene TRIM Motif Testing The Cancer Genome Atlas Therapeutic Transgenes Tumor stage Tumor-Derived Ubiquitination Work base breast tumorigenesis c-myc Genes cancer subtypes carcinogenesis chromatin immunoprecipitation cohort embryonic stem cell genetic regulatory protein histone modification inhibitor/antagonist innovation malignant breast neoplasm mammary mammary epithelium mouse model overexpression patient derived xenograft model recruit small molecule inhibitor therapeutic target transcriptome sequencing tumor tumor initiation tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Breast cancer is a deadly disease and new strategies are needed to fulfill the goals of treatment and eradication. Recent development of epigenetic-based inhibitors offers new avenues of potential therapeutics for breast and other human cancers. Our work using a new mouse model of breast cancer that parallels the aberrant expression of TRIM24 in all breast cancer sub-types will be used to gain a deeper understanding of tumor development and treatment. Epigenetic regulators are frequent targets of aberrant regulation, amplification or mutation in all human cancers. Histone “writers”, “erasers” and “readers” are epigenetic regulators that catalyze addition, removal and/or interaction, respectively, with post-translational modifications (PTMs) of histones or other modified proteins, with subsequent regulatory outcomes for gene expression. Our laboratory discovered Tripartite Motif Protein 24 (TRIM24) as a histone reader and showed that TRIM24: (i) ubiquitinated p53 and siRNA-depletion of TRIM24 led to p53-dependent apoptosis of embryonic stem cells and breast cancer-derived cells (MCF7), (ii) recruited estrogen receptor to chromatin by PHD/bromodomain reading of a unique signature of histone PTMs (H3K4me0; H3K23ac) to co-regulate estrogen-dependent transcription, (iii) induced transformation of immortalized human mammary epithelial cells (iHMECs) by altering metabolism and up-regulating c-Myc expression when ectopically expressed, and (iv) a small molecule inhibitor of the TRIM24 bromodomain disrupts chromatin interactions in vitro. Importantly, we found that aberrant expression of TRIM24 negatively correlates with breast cancer patient survival. TRIM24 is over expressed in all sub-types of breast cancer and is highest in basal breast cancers. We developed a mouse model of TRIM24-expressing breast cancers by conditional over-expression of a Trim24 transgene in mammary epithelia. We saw that aberrant, tissue-specific expression of TRIM24 is sufficient for tumor initiation, development and progression to highly heterogeneous mammary carcinomas. We hypothesize that our proposed, multi-faceted studies, including mouse models, cultured cells and in vitro analyses will uncover how aberrant expression of TRIM24 drives heterogeneous tumor development in mammary/breast epithelia, and that our findings will further development of epigenetic-based therapeutics to treat breast cancers. Our long-term goal is to leverage a deep mechanistic understanding of TRIM24 functions toward innovative therapeutic approaches to treat breast and other cancers in humans.

项目概要乳腺癌是一种致命的疾病，需要新的策略来实现治疗和治疗的目标基于表观遗传的抑制剂的最新发展提供了潜在治疗的新途径。我们的工作使用与乳腺癌相似的新小鼠模型。 TRIM24 在所有乳腺癌亚型中的异常表达将用于更深入地了解肿瘤的发展和治疗是异常调节的常见目标。所有人类癌症中的组蛋白“书写者”、“擦除者”和“阅读者”的扩增或突变都是表观遗传的。分别通过翻译后修饰催化添加、去除和/或相互作用的调节剂组蛋白或其他修饰蛋白的翻译后修饰 (PTM)，以及随后的基因表达调控结果。实验室发现三联基序蛋白 24 (TRIM24) 作为组蛋白读取器，并表明 TRIM24： (i) 泛素化的 p53 和 TRIM24 的 siRNA 耗竭导致胚胎干细胞的 p53 依赖性凋亡乳腺癌衍生细胞 (MCF7)，(ii) 通过 PHD/bromodomain 读取将雌激素受体募集至染色质组蛋白 PTM 的独特特征（H3K4me0；H3K23ac）共同调节雌激素依赖性转录， (iii) 通过改变代谢诱导永生化人乳腺上皮细胞 (iHMEC) 的转化并在异位表达时上调 c-Myc 表达，以及 (iv) c-Myc 的小分子抑制剂重要的是，TRIM24 溴结构域在体外破坏染色质相互作用。 TRIM24 的表达与乳腺癌患者的生存呈负相关 TRIM24 在所有亚型中均过度表达。我们开发了表达 TRIM24 的小鼠模型。我们发现，乳腺上皮细胞中 Trim24 转基因的条件性过度表达可导致乳腺癌。 TRIM24 的异常、组织特异性表达足以导致肿瘤的发生、发展和进展我们认为我们提出的多方面研究，包括小鼠模型、培养细胞和体外分析将揭示 TRIM24 的异常表达如何驱动乳腺/乳腺上皮细胞异质肿瘤的发展，我们的发现将进一步我们的长期目标是开发基于表观遗传学的疗法来治疗乳腺癌。对 TRIM24 功能的深入机制了解，以实现乳腺治疗的创新治疗方法以及人类的其他癌症。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy.

HDAC6：线粒体与周围神经病变发展之间的关键联系。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
English, Krystal;Barton, Michelle Craig
通讯作者：
Barton, Michelle Craig

Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer.

Trim24 的乳腺特异性表达建立了人类化生性乳腺癌的小鼠模型。

DOI：
发表时间：
2021-09-10
期刊：
影响因子：
16.6
作者：
Shah, Vrutant V;Duncan, Aundrietta D;Jiang, Shiming;Stratton, Sabrina A;Allton, Kendra L;Yam, Clinton;Jain, Abhinav;Krause, Patrick M;Lu, Yue;Cai, Shirong;Tu, Yizheng;Zhou, Xinhui;Zhang, Xiaomei;Jiang, Yan;Carroll, Christopher L;Kang, Zhiju
通讯作者：
Kang, Zhiju