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

描述(申请人提供)：microRNA-145调节乳腺癌干细胞的自我更新一个重要的问题，挑战乳腺癌的治疗管理是耐药。癌症干细胞(CSC)假说认为，在肿瘤内存在一小部分癌细胞，这些细胞驱动肿瘤生长，能够自我更新，并对耐药和复发负责。在异质性乳腺癌中发现了一个亚群(CD44High/CD24low)，该亚群具有高度致瘤性、自我更新能力和耐药特性。对这一亚群的广泛研究揭示了有关肿瘤发生和耐药的新细节，然而，关于这些乳癌干细胞可能的microRNA(MiR)调控知之甚少。许多MIR在乳腺癌中调节失调，它们通过调节重要的癌症相关途径中的基因表达而参与肿瘤的发生。最近，miR-145被证明对胚胎干细胞(ES)的更新和分化具有重要的调控作用。此外，miR-145还被发现调节间充质干细胞的分化。然而，目前尚不清楚miR-145对肿瘤干细胞的潜在调控作用。目前研究的假设是，乳腺CSCs中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的特定目标的实验来验证这一假设：(1)确定癌症干细胞miR-145下调的分子机制；(2)检测miR-145调控对乳腺CSC自我更新和体内肿瘤形成的影响。拟议研究的完成将伴随着对miR调节在乳腺CSC功能中的重要性的新的理解。此外，拟议中的研究将允许在乳腺癌中检查控制多能性的调控机制，并掌握正常和肿瘤干细胞中的调控基因，这反过来将提供CSCs和ES细胞之间的联系。最后，了解控制乳腺CSCs的途径可能会揭示克服耐药性的新的治疗策略。

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.