Role of EZH2 in Breast Cancer

描述（由申请人提供）：乳腺癌是美国女性癌症相关死亡的主要原因。尽管在早期发现和治疗方面取得了进展，但20%的复发和/或转移患者的死亡率接近100%。不同的基因和蛋白质决定了从前体病变到浸润性癌，最后到转移性疾病的进展。表征调节乳腺癌生长和转移能力的基因可能会发现新的生物标志物，帮助临床医生指导当前的治疗，并可能为治疗干预提供新的靶点。我们最近发现EZH2 （Zeste同源物2的增强子）是一种多梳蛋白（PcG），在侵袭性和转移性乳腺癌中表达上调。在果蝇中，PcG蛋白已被证明在发育过程中通过负调控包括同源基因在内的靶基因座来维持基因表达程序。EZH2在乳腺癌中的作用尚未被研究。我们的中心假设是PcG蛋白EZH2的表达失调通过特异性靶基因的转录沉默促进乳腺癌的生长和侵袭。我们的长期目标是研究EZH2的功能特征，并阐明其作为乳腺癌转移潜力的新型生物标志物的作用。本申请的目的是开始研究EZH2在乳腺癌发展中的作用，并描述其临床应用。本项目的具体目的如下：1。为了确定EZH2作为一种新的侵袭性乳腺癌生物标志物在一大群浸润性乳腺癌中的临床应用，并提供临床和治疗信息。2 .通过在永生化人乳腺上皮细胞和乳腺癌细胞中过表达或抑制EZH2的表达，以及在乳腺上皮中过表达EZH2的转基因小鼠，确定EZH2在体外和体内调节肿瘤特征中的作用；通过对过表达EZH2的永生化乳腺上皮细胞和有或没有过表达EZH2的浸润性癌组织进行转录组分析，鉴定和表征在乳腺癌进展中起作用的EZH2转录靶基因。综上所述，本研究旨在探讨EZH2在乳腺癌进展调控中的临床应用和功能作用。

DESCRIPTION (provided by applicant): Breast cancer is a leading cause of cancer-related deaths in American women. Despite advances in early detection and treatment, mortality for those 20% of patients with recurrences and/or metastases is nearly 100%. Distinct sets of genes and proteins dictate progression from precursor lesions, to invasive carcinoma and finally to metastatic disease. Characterizing genes that regulate the growth and metastatic ability of breast cancer may identify novel biomarkers to help clinicians guide current treatments, and may offer novel targets for therapeutic intervention. We recently identified EZH2 (enhancer of Zeste homolog 2), a polycomb group protein (PcG), as being up-regulated in invasive and metastatic breast cancer. In Drosophila, PcG proteins have been shown to maintain gene expression programs during development by negatively regulating target loci including homeotic genes. The role of EZH2 in breast cancer has not been investigated. Our central hypothesis is that dysregulated expression of the PcG protein EZH2 promotes the growth and invasion of breast cancer by transcriptional silencing of specific target genes. Our long-term goal is to functionally characterize EZH2 and to elucidate its role as a novel biomarker of metastatic potential in breast cancer. The objective of this application is to begin to study the role of EZH2 in the development of breast cancer and delineate its clinical application. The specific aims of this project are as follows: 1. To determine the clinical utility of EZH2 as a novel biomarker of aggressive breast cancer in a large group of invasive carcinomas of the breast with clinical and treatment information, 2. To determine the role of EZH2 in regulating neoplastic characteristics in vitro and in vivo by overexpressing or inhibiting EZH2 expression in immortalized human mammary epithelial cells and in breast cancer cells, and by developing transgenic mice overexpressing EZH2 in the mammary epithelium, and 3. To identify and characterize transcriptional target genes of EZH2 that play a role in breast cancer progression by performing transcriptome analysis on immortalized mammary epithelial cells overexpressing EZH2 and in tissues of invasive carcinomas with and without EZH2 overexpression. In summary, this proposal addresses the clinical utility and functional role of EZH2 in the regulation of breast cancer progression.