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

描述（由申请人提供）：MicroRNA-145调控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，肿瘤中存在一小部分癌细胞亚群，它们驱动肿瘤生长，能够自我更新，并负责耐药和复发。异质性乳腺癌中的一个亚群（cd44高/ cd24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，对这些乳腺癌“干细胞”可能的microRNA （miR）调控知之甚少。许多mir在乳腺癌中失调，它们通过调节重要癌症相关通路中基因的表达来促进肿瘤的发生。最近，miR-145被证明对胚胎干细胞（ES）的更新和分化具有关键调控作用。此外，miR-145也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节作用。本研究的假设是，下调乳腺CSC中miR-145可以上调CSC自我更新中重要的基因。我们将通过实验来验证这一假设，以满足我们的具体目标：(1)确定miR-145在癌症干细胞中下调的分子机制；(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认识。此外，拟议的研究将允许在乳腺癌中检查控制正常和肿瘤干细胞多能性的调节机制，并掌握调节基因，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.