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: 8707400
• 负责人: Celina G Kleer
• 金额: $ 32.76万
• 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/8707400
• 关键词: African; African American; Automobile Driving; Biological Markers; Breast; Breast Cancer Cell; Breast Carcinogenesis; 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; 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%，但导致大部分乳腺癌患者死亡。 死亡人数，特别是非洲裔美国妇女。描述驱动这些的基因 肿瘤的快速发展可能会发现新的生物标志物来指导目前的治疗， 治疗目标，减少健康差距。虽然TN癌的细胞起源是 已知的是，最近的研究强烈表明它们来源于管腔祖细胞。我们已经确定 EZH 2作为一个关键的癌基因，在ER阴性癌及其转移中特异性上调， 与正常乳腺组织相比。EZH 2的表达在肿瘤发生过程中增加，并且在肿瘤发生过程中显著增加。 与不良临床结局相关。值得注意的是，TN乳腺癌细胞系中的EZH 2下调 降低它们在体内的生长并提高存活率。我们最近发现EZH 2的过度表达 扩大了致瘤干细胞群，其中管腔祖细胞数量特异性增加， 依赖诺奇的态度我们的中心假设是EZH 2的表达失调促进TN 通过增加乳腺干细胞群，特别是管腔祖细胞，促进乳腺癌的发生。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 妇女我们的目标是：目标1。为了阐明EZH 2在维持干细胞和管腔的功能中的作用， 产生TN浸润性癌的祖细胞;和Aim 2.评估EZH 2的临床效用 作为TN浸润癌生存生物标志物的管腔祖细胞的过表达和检测 白种人非裔美国人和西非女性该提案结合了使用独特的， 来自加纳的高加索人、非洲裔美国人和西非患者的注释良好的人体组织 用TN乳腺癌的体内和体外模型。我们的目标是， TN乳腺癌中的EZH 2将确定驱动这些侵袭性肿瘤的新途径， 治疗和可能的靶向干预，以防止转移的发展。 相关性（参见说明）： 三阴性（雌激素、孕激素和HER 2阴性）浸润性乳腺癌占乳腺癌的10%， 所有乳腺癌，但非洲裔美国妇女的发病率和死亡率增加。本研究将 阐明EZH 2如何调节三阴性乳腺癌的发展以及EZH 2的临床效用。 EZH 2和管腔祖细胞作为根据种族群体的存活的生物标志物。

项目成果

Breast Cancer and African Ancestry: Lessons Learned at the 10-Year Anniversary of the Ghana-Michigan Research Partnership and International Breast Registry.

• DOI: 10.1200/jgo.2015.002881
• 发表时间: 2016-10-01
• 期刊: Journal of global oncology
• 作者: Jiagge, Evelyn;Oppong, Joseph Kwaku;Awuah, Baffour
• 通讯作者: Awuah, Baffour

Protocol for the examination of specimens from patients with invasive carcinoma of the breast.

乳腺浸润性癌患者标本的检查方案。

• DOI: 10.5858/133.10.1515
• 发表时间: 2009
• 期刊: Archives of pathology & laboratory medicine
• 影响因子: 4.6
• 作者: Lester,SusanC;Bose,Shikha;Chen,Yunn-Yi;Connolly,JamesL;deBaca,MonicaE;Fitzgibbons,PatrickL;Hayes,DanielF;Kleer,Celina;O'Malley,FrancesP;Page,DavidL;Smith,BarbaraL;Tan,LeeK;Weaver,DonaldL;Winer,Eric;MembersoftheCan
• 通讯作者: MembersoftheCan