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

描述(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，特别是在非裔美国妇女中。表征驱动这些肿瘤快速发展的基因可能会识别新的生物标记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来自腔前体细胞。我们已经确定EZH2是一个关键的癌基因，与正常乳腺组织相比，它在ER阴性的癌症及其转移中是不受调控的。在肿瘤发生过程中，EZH2的表达增加，并与不良的临床结果显著相关。值得注意的是，TN乳腺癌细胞系中EZH2的下调抑制了它们在体内的生长并提高了存活率。我们最近发现，EZH2的过度表达以一种Notchi不依赖的方式，通过特定增加管腔祖细胞的数量来扩大致瘤干细胞群体。我们的中心假设是，EZH2的异常表达通过增加乳腺干细胞数量，特别是腔前体细胞来促进TN乳腺癌的发生。我们进一步假设，EZH2的表达和腔祖细胞的检测可能是高加索人、非裔美国人和西非妇女TN侵袭性癌转移和预后的新生物标志物。我们的目标是：1.阐明EZH2在维持导致TN浸润性癌的干细胞和腔祖细胞中的作用；以及2.评估EZH2过度表达和检测腔祖细胞作为生物标志物在高加索、非裔美国人和西非女性TN浸润性癌中的临床应用价值。这项建议结合了来自加纳的高加索人、非裔美国人和西非患者独特的、注释良好的人类组织与体内和体外TN乳腺癌模型的使用。我们的目标是，EZH2在TN乳腺癌中的功能特征将确定驱动这些侵袭性肿瘤的新途径，并允许进行量身定制的治疗，或许还可以进行有针对性的干预，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.