The Function of EZH2 in Estrogen Receptor Negative Breast Cancer in Women of Af

描述（由申请人提供）：三阴性（TN）浸润性乳腺癌占乳腺癌的10%，但导致大量死亡，特别是在非洲裔美国妇女中。表征驱动这些肿瘤快速发展的基因可能会发现新的生物标志物来指导当前的治疗，可能会提供新的治疗靶点，并减少健康差距。虽然TN癌的细胞起源尚不清楚，但最近的研究强烈表明它们起源于腔内祖细胞。与正常乳腺组织相比，我们已经确定EZH2是在ER阴性癌及其转移中特异性不受调节的关键癌基因。EZH2表达在肿瘤发生过程中增加，并与不良临床预后显著相关。值得注意的是，在TN乳腺癌细胞系中，EZH2的下调降低了它们在体内的生长，提高了它们的存活率。我们最近发现，EZH2过表达以notchi依赖的方式扩大了致瘤性干细胞群，并特异性增加了管腔祖细胞的数量。我们的中心假设是EZH2表达失调通过增加乳腺干细胞群，特别是管腔祖细胞群，促进TN乳腺癌的发生。我们进一步假设EZH2的表达和腔内祖细胞的检测可能是白种人、非裔美国人和西非妇女TN浸润性癌转移和预后的新生物标志物。我们的目标是：阐明EZH2在引起TN浸润性癌的干细胞和管腔祖细胞的维持中的作用；和Aim 2。评估EZH2过表达和检测管腔祖细胞作为白种人、非裔美国人和西非妇女TN浸润性癌存活生物标志物的临床应用。该建议将来自加纳的高加索人、非洲裔美国人和西非患者的独特的、注释良好的人体组织与体内和体外的TN乳腺癌模型相结合。我们的目标是，通过研究EZH2在TN乳腺癌中的功能特征，发现一种驱动这些侵袭性肿瘤的新途径，并允许定制治疗和可能的靶向干预，以防止转移的发展。

DESCRIPTION (provided by applicant): Triple negative (TN) invasive breast carcinomas comprise 10% of breast cancers but result in a large number of deaths, especially among African American women. Characterizing genes that drive these tumors' rapid progression may identify novel biomarkers to guide current treatments, may offer novel therapeutic targets, and decrease health disparities. Although the cellular origin of TN carcinomas is unknown, recent studies strongly suggest that they derive from luminal progenitor cells. We have identified EZH2 as a critical oncogene specifically unregulated in ER negative carcinomas and their metastasis when compared to normal breast tissues. EZH2 expression increases during tumorigenesis and is significantly associated with poor clinical outcome. Of note, EZH2 down regulation in TN breast cancer cell lines decreased their growth in vivo and improved survival. We recently discovered that EZH2 over expression expands the tumorigenic stem cell population with a specific increase in the number of luminal progenitors in a Notchi-depedent manner. Our Central Hypothesis is that dysregulated expression of EZH2 promotes TN breast carcinogenesis by increasing the breast stem cell population, particularly the luminal progenitors. We further hypothesize that EZH2 expression and detection of luminal progenitors may be novel biomarkers of metastasis and prognosis in TN invasive carcinomas from Caucasian, African American, and West African women. Our aims are: Aim 1. To elucidate the role of EZH2 in the maintenance of stem cells and luminal progenitors that give rise to TN invasive carcinomas; and Aim 2. To assess the clinical utility of EZH2 over expression and detection of luminal progenitors as biomarkers of survival in TN invasive carcinomas from Caucasian, African American, and West African women . This proposal combines the use of unique, well-annotated human tissues from Caucasian, African-American, and West-African patients from Ghana with in vivo and in vitro models of TN breast carcinoma. Our goal is that the functional characterization of EZH2 in TN breast cancer will identify a new pathway driving these aggressive tumors, and allow tailored treatment and perhaps targeted intervention to prevent the development of metastases.