MicroRNA-145 Regulation of Breast Cancer Stem CEll Self-Renewal

MicroRNA-145对乳腺癌干细胞自我更新的调节

• 批准号: 8649641
• 负责人: Gabriel Lee Eades
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-21 至 2016-04-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649641
• 关键词: Address; Adult; Automobile Driving; Biological Assay; Biology; Breast; Breast Cancer Cell; Breast Epithelial Cells; CD44 gene; Cancer Etiology; Cancer cell line; Cell physiology; Cells; Cessation of life; Characteristics; Chondrocytes; Clinical; Color; DNA; Development; Disease; Down-Regulation; Drug Targeting; Drug resistance; Embryo; Epigenetic Process; Fatty acid glycerol esters; Fluorescence-Activated Cell Sorting; Gene Expression; Genes; Goals; Gold; Growth; Hematoxylin and Eosin Staining Method; Histones; Immunodeficient Mouse; Immunohistochemistry; In Situ Hybridization; Lead; Link; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mesenchymal Stem Cells; Messenger RNA; Methylation; MicroRNAs; Molecular; Molecular Profiling; National Research Service Awards; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Nude Mice; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Promoter Regions; Recurrence; Regulation; Regulator Genes; Reporter; Reporting; Role; Sampling; Sequence Analysis; Sorting - Cell Movement; Staging; Staining method; Stains; Stem cells; Surface; Testing; Therapeutic; Tissues; Transplantation; Tumor Stem Cells; Tumor Tissue; Tumor Volume; Tumorigenicity; Up-Regulation; Woman; Xenograft procedure; adult stem cell; base; bisulfite; cancer cell; cancer stem cell; chromatin immunoprecipitation; chromatin remodeling; design; embryonic stem cell; fetal; improved; in vivo; malignant breast neoplasm; mammary epithelium; neoplastic cell; new technology; novel; novel strategies; novel therapeutics; pluripotency; prevent; promoter; prostate cancer cell; public health relevance; research study; restoration; self-renewal; stem; stem cell biology; stem cell differentiation; stem cell division; stemness; trait; tumor; tumor growth; tumorigenesis; tumorigenic; vector control

DESCRIPTION (provided by applicant): MicroRNA-145 Regulation of Breast Cancer Stem Cell Self-Renewal An important issue challenging the therapeutic management of breast cancer is drug resistance. The cancer stem cell (CSC) hypothesis argues for existence within tumors of a small subpopulation of cancer cells driving tumor growth, capable of self-renewal, and responsible for drug-resistance and recurrence. A subpopulation (CD44high/CD24low) within heterogeneous breast cancers has been identified that is highly tumorigenic, capable of self-renewal, and possess drug-resistant characteristics. Extensive study of this subpopulation has revealed new details concerning tumorigenesis and drug resistance, however, little is known concerning possible microRNA (miR) regulation of these breast "cancer stem cells". Many miRs are dysregulated in breast cancer where they contribute to tumorigenesis by regulating expression of genes in important cancer-related pathways. Recently, miR-145 was shown to critically regulate embryonic stem (ES) cell renewal and differentiation. Furthermore, miR-145 has also been found to regulate mesenchymal stem cell differentiation. However, nothing is currently known concerning potential miR-145 regulation of neoplastic stem cells. The hypothesis of the current study is that down-regulation of miR-145 within breast CSCs allows up-regulation of genes important in CSC self-renewal. We will test this hypothesis with experiments designed to address our specific aims: (1) to determine a molecular mechanism for miR-145 down-regulation in cancer stem cells and (2) to examine the impact of miR-145 regulation of breast CSC self-renewal and tumorigenesis in vivo. Completion of the proposed studies will be accompanied with new understanding of the importance of miR regulation in breast CSC function. Additionally, proposed studies will allow an examination, in breast cancer, of regulatory mechanisms that control pluripotency and master regulatory genes in normal and neoplastic stem cells, which in turn will provide a link between CSCs and ES cells. Finally, understanding pathways controlling breast CSCs may reveal new therapeutic strategies for overcoming drug resistance.

描述（由申请人提供）：MicroRNA-145调节乳腺癌干细胞自我更新一个挑战乳腺癌治疗管理的重要问题是耐药性。癌症干细胞（CSC）假说认为，在肿瘤内存在一小群癌细胞，这些癌细胞驱动肿瘤生长，能够自我更新，并负责耐药性和复发。异质性乳腺癌中的一个亚群（CD 44高/CD 24低）已被确定为高度致瘤性，能够自我更新，并具有耐药特征。对该亚群的广泛研究揭示了有关肿瘤发生和耐药性的新细节，然而，关于这些乳腺“癌症干细胞”可能的microRNA（miR）调节却知之甚少。许多miR在乳腺癌中失调，它们通过调节重要癌症相关途径中的基因表达而促成肿瘤发生。最近，miR-145被证明对胚胎干（ES）细胞的更新和分化具有重要的调节作用。此外，还发现miR-145调节间充质干细胞分化。然而，目前还没有任何关于潜在的miR-145调节肿瘤干细胞的信息。目前研究的假设是，乳腺CSC内miR-145的下调允许CSC自我更新中重要基因的上调。我们将通过旨在解决我们特定目标的实验来验证这一假设：（1）确定癌症干细胞中miR-145下调的分子机制和（2）检查miR-145调节乳腺CSC自我更新和体内肿瘤发生的影响。完成拟议的研究将伴随着对miR调节在乳腺CSC功能中的重要性的新理解。此外，拟议的研究将允许在乳腺癌中检查控制多能性和正常和肿瘤干细胞中的主调节基因的调节机制，这反过来将提供CSC和ES细胞之间的联系。最后，了解控制乳腺CSC的途径可能会揭示克服耐药性的新治疗策略。