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

EZH2在AF女性雌激素受体阴性乳腺癌中的作用

• 批准号: 8532854
• 负责人: Celina G Kleer
• 金额: $ 31.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532854
• 关键词: African; African American; Automobile Driving; Biological Markers; Breast; Breast Cancer Cell; Breast Carcinoma; Cancer cell line; Carcinoma; Caucasians; Caucasoid Race; Cessation of life; Clinical; Detection; Development; Down-Regulation; ERBB2 gene; EZH2 gene; Estrogen receptor negative; Estrogens; Genes; Ghana; Goals; Growth; Incidence; Instruction; Intervention; Maintenance; Mammary Gland Parenchyma; Neoplasm Metastasis; Oncogenes; Outcome; Pathway interactions; Patients; Progesterone; Race; Role; Stem cells; Woman; breast tumorigenesis; carcinogenesis; health disparity; human tissue; improved; in vitro Model; in vivo; malignant breast neoplasm; mortality; new therapeutic target; novel; outcome forecast; overexpression; prevent; progenitor; prognostic; stem cell population; triple-negative invasive breast carcinoma; tumor; tumorigenesis; tumorigenic

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 ijnknown, recent studies strongly suggest that they derive from luminal progenitor cells. We have identified EZH2 as a critical oncogene specifically upregulated 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 downregulation in TN breast cancer cell lines decreased their growth in vivo and improved survival. We recently discovered that EZH2 overexpression 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 overexpression 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. RELEVANCE (See instructions): Triple negative (estrogen, progesterone, and HER2 negative) invasive breast carcinomas comprise 10% of all breast cancers but have increased incidence and mortality in African American women. This study will elucidate how EZH2 regulates the development of triple negative breast cancer and the clinical utility of EZH2 and luminal progenitor cells as biomarkers of survival according to racial groups.

三阴性(TN)浸润性乳腺癌占乳腺癌的10%，但在 死亡人数，特别是非洲裔美国妇女。描述了驱动这些基因的特征 肿瘤的快速发展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 治疗目标，并减少健康差距。尽管TN癌的细胞起源是 众所周知，最近的研究强烈表明它们起源于腔前体细胞。我们已经确定了 EZH2作为一种关键癌基因在ER阴性癌及其转移中特异性上调 与正常乳房组织相比。EZH2在肿瘤发生过程中表达增加，并显著 与不良的临床结果相关。值得注意的是，EZH2在TN乳腺癌细胞系中表达下调 减少了它们在体内的生长并提高了存活率。我们最近发现EZH2过度表达 通过特定增加腔内祖细胞的数量来扩大成瘤干细胞群 诺奇式的消沉态度。我们的中心假设是EZH2的异常表达促进了TN 通过增加乳腺干细胞数量，特别是腔前体细胞，从而导致乳腺癌的发生。我们 进一步假设EZH2的表达和腔祖细胞的检测可能是新的生物标志物 高加索人、非裔美国人和西非人TN浸润性癌的转移和预后 女人。我们的目标是：目标1.阐明EZH2在干细胞和腔细胞维持中的作用 导致TN浸润性癌的前体细胞；以及目的2.评估EZH2的临床应用 TN浸润性癌中腔祖细胞的过表达及其作为生存生物标志物的检测 来自高加索、非裔美国人和西非女性。这一建议结合了独特的、 来自加纳的高加索人、非裔美国人和西非患者的注释良好的人体组织 建立TN乳腺癌的体内和体外模型。我们的目标是 TN乳腺癌中的EZH2将识别驱动这些侵袭性肿瘤的新途径，并允许定制 治疗，也许是有针对性的干预，以防止转移的发展。 相关性(请参阅说明)： 三阴性(雌激素、孕激素和HER2阴性)浸润性乳腺癌占10% 所有乳腺癌，但增加了非裔美国妇女的发病率和死亡率。这项研究将 阐明EZH2如何调控三阴性乳腺癌的发生及临床应用 根据种族群体，EZH2和腔前体细胞作为生存的生物标记物。