Understanding the Function of TRIM 24 in Mammary Epithelial Cells

描述(申请人提供)：每八名美国女性中就有一人会在一生中被诊断出患有浸润性乳腺癌，根据美国癌症协会的数据，仅今年一年就有4万名女性死于这种疾病。乳腺癌是一种复杂的疾病，有多个亚型和侵袭性，每种亚型都有自己独特的基因特征。在过去的十年里，研究人员已经开始利用个人癌症的基因图谱来确定适当的治疗过程。虽然有一些研究非常充分的标记物正在临床上使用，如HER-2和BRCA-1，但这些只代表了所有乳腺癌病例的一小部分。慢性阻塞性肺疾病的诊断和治疗效果 其他原癌基因还远未被发现。这项建议旨在确定乳腺癌中一种可能的癌基因TRIM24的分子机制，目的是将其用作诊断标记和治疗靶点。三方基序蛋白24(Triartite Motif Protein 24，TRIM24)是一种环状结构域的E3泛素连接酶，以P53为靶标进行蛋白酶体降解，也是一种PhD/Bromodomain组蛋白阅读器，负责招募雌激素受体(ER？)并调节乳腺癌细胞中的特定基因。TRIM24在乳腺癌中过度表达，且与患者生存呈负相关，提示TRIM24是乳腺癌中的癌基因。然而，关于TRIM24在正常乳腺发育中的作用以及它在乳腺癌中所起作用的分子机制，人们的认识存在着巨大的差距。为了解决这一知识缺口，我将确定TRIM24在小鼠乳腺发育、妊娠和哺乳期的正常表达模式和功能；b)确定TRIM24的过度表达是否足以赋予乳腺上皮细胞促癌表型；以及c)阐明TRIM24的特定结构域在体内如何发挥作用。初步数据表明，TRIM24在发育中的乳腺中高表达，并在乳腺管腔上皮的正常发育中发挥作用。本申请中提出的实验将定义TRIM24在正常乳腺生物学以及乳腺癌恶性肿瘤中的功能。这一信息对TRIM24作为诊断标记物和治疗靶点的潜在使用具有价值。

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.