Understanding the Function of TRIM 24 in Mammary Epithelial Cells

了解 TRIM 24 在乳腺上皮细胞中的功能

• 批准号: 8753071
• 负责人: Aundrietta De Van Duncan
• 金额: $ 3.51万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-16 至 2015-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753071
• 关键词: Address; Affect; Aging; American; American Cancer Society; Binding; Biological Assay; Biology; Breast; Breast Cancer Cell; Breast Epithelial Cells; Bromodomain; Carmine; Cell Death; Cells; Chromatin; Clinic; Complex; Data; Development; Diagnosis; Diagnostic; Disease; Drug Targeting; ERBB2 gene; Ectopic Expression; Epithelium; Epitopes; Estrogen Receptors; Gene Amplification; Genes; Goals; Hematoxylin and Eosin Staining Method; Histones; Hormones; House mice; Human; In Vitro; Individual; Knowledge; Lactation; Lead; Location; Maintenance; Malignant Neoplasms; Mammary gland; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Modeling; Molecular; Mus; Mutation; Oncogenes; Oncogenic; Patients; Pattern; Phenotype; Play; Pregnancy; Proteins; Proto-Oncogenes; Reader; Recruitment Activity; Research Personnel; Role; Signal Transduction; Staging; Staining method; Stains; TRIM Gene; TRIM Motif; The Cancer Genome Atlas; Time; Tissues; Transgenic Mice; Translations; Treatment Efficacy; Tumor Suppressor Proteins; Western Blotting; Woman; Work; aluminum sulfate; cohort; embryonic stem cell; genetic profiling; in vivo; malignant breast neoplasm; mammary epithelium; mammary gland development; mouse model; mutant; outcome forecast; public health relevance; receptor function; reconstruction; research study; therapeutic target; transcription factor; tumor; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): One in eight American women will be diagnosed with invasive breast cancer in her lifetime, and according to the American Cancer Society an estimated 40,000 women will die from the disease this year alone. Breast cancer is a complex disease with multiple subtypes and aggressiveness, each expressing its own unique genetic profile. Over the past decade, researchers have begun to take advantage of the genetic profiles of an individual's cancers in order to determine the appropriate course of therapy. While there are some very well studied markers being used in the clinic, such as HER-2 and BRCA-1, these only represent a fraction of all cases of breast cancer. The diagnostic and therapeutic efficacy of other proto-oncogenes is vastly unexplored. This proposal aims to determine the molecular mechanisms of a putative oncogene in breast cancer, TRIM24, with the goal of using it as both a diagnostic marker and therapeutic target. Tripartite Motif protein 24 (TRIM24) is a RING-domain, E3 ubiquitin ligase, which targets p53 for proteasomal degradation, as well as a PHD/Bromodomain histone reader that recruits Estrogen Receptor ¿ (ER¿) and regulates specific genes in breast cancer cells. TRIM24 is over-expressed in human breast cancers, and correlates negatively with patient survival, suggesting that TRIM24 is an oncogene in breast cancer. However, a vast gap in knowledge exists regarding the role of TRIM24 in normal mammary gland development and the molecular mechanism involved in its role in breast cancer. To address this gap in knowledge I will determine the normal expression patterns and functions of TRIM24 in the mouse mammary gland during development, pregnancy and lactation; b) determine if over-expression of TRIM24 is sufficient to confer cancer-promoting phenotypes on mammary epithelial cells, and c) elucidate how specific domains of TRIM24 function in vivo. Preliminary data suggest that TRIM24 is highly expressed in the developing mammary gland and plays a role in proper development of mammary gland luminal epithelium. The experiments proposed in this application will define the function of TRIM24 in normal breast biology as well as breast cancer malignancy. This information can be value in the potential use of TRIM24 as a diagnostic marker and therapeutic target.

描述（由申请人提供）：八分之一的美国妇女将在她的一生中被诊断患有浸润性乳腺癌，根据美国癌症协会估计，仅今年就有40，000名妇女死于这种疾病。 乳腺癌是一种复杂的疾病，具有多种亚型和侵袭性，每种亚型都表达自己独特的遗传特征。在过去的十年中，研究人员已经开始利用个体癌症的遗传特征来确定适当的治疗方案。虽然有一些非常好的研究标记物正在临床上使用，如HER-2和BRCA-1，但这些仅代表所有乳腺癌病例的一小部分。的诊断和治疗效果 其他的原癌基因还未被探索。该提案旨在确定乳腺癌中假定癌基因TRIM 24的分子机制，目的是将其用作诊断标志物和治疗靶点。 TRIM 24是一种RING结构域E3泛素连接酶，靶向p53进行蛋白酶体降解，也是一种PHD/Bromodomain组蛋白阅读器，招募雌激素受体（ER）并调节乳腺癌细胞中的特定基因。 TRIM 24在人乳腺癌中过表达，并且与患者存活率负相关，表明TRIM 24是乳腺癌中的癌基因。然而，关于TRIM 24在正常乳腺发育中的作用以及其在乳腺癌中的作用所涉及的分子机制，存在巨大的知识缺口。 为了解决这一知识空白，我将确定TRIM 24在发育、妊娠和哺乳期间在小鼠乳腺中的正常表达模式和功能; B）确定TRIM 24的过表达是否足以赋予乳腺上皮细胞促癌表型，以及c）阐明TRIM 24的特定结构域如何在体内发挥作用。 初步数据表明，TRIM 24在发育中的乳腺中高度表达，并在乳腺腔上皮的正常发育中起作用。 本申请中提出的实验将定义TRIM 24在正常乳腺生物学以及乳腺癌恶性肿瘤中的功能。该信息对于TRIM 24作为诊断标记物和治疗靶点的潜在用途可能很有价值。