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，尤其是在非洲裔美国妇女中。表征驱动这些肿瘤快速进展的基因可以识别新的生物标志物来指导当前的治疗，可以提供新的治疗靶点，并减少健康差异。虽然TN癌的细胞起源是未知的，最近的研究强烈建议，他们来自管腔祖细胞。我们已经确定EZH 2作为一个关键的癌基因，特别是在ER阴性癌及其转移相比，正常乳腺组织中不受调节。EZH 2表达在肿瘤发生期间增加，并且与不良临床结果显著相关。值得注意的是，TN乳腺癌细胞系中的EZH 2下调降低了它们的体内生长并改善了存活率。我们最近发现，EZH 2的过度表达扩大了致瘤干细胞群，并以Notchi依赖的方式特异性增加了管腔祖细胞的数量。我们的中心假设是EZH 2的表达失调通过增加乳腺干细胞群，特别是管腔祖细胞来促进TN乳腺癌的发生。我们进一步假设EZH 2表达和管腔祖细胞的检测可能是来自高加索人、非洲裔美国人和西非妇女的TN浸润性癌的转移和预后的新生物标志物。我们的目标是：目标1。阐明EZH 2在维持引起TN侵袭性癌的干细胞和腔祖细胞中的作用;和目标2。评估EZH 2过表达和管腔祖细胞检测作为高加索人、非裔美国人和西非妇女TN浸润性癌生存期生物标志物的临床效用。该建议结合使用独特的，注释良好的人类组织从高加索人，非洲裔美国人，和西非患者从加纳在体内和体外模型TN乳腺癌。我们的目标是，EZH 2在TN乳腺癌中的功能表征将确定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.