应用基因工程小鼠研究转录因子KLF5在乳腺（癌）干细胞中的功能

Breast cancer is one of the commonest malignancies among females in China, while the mechanisms remain unclear. A growing body of evidence supports the notion that breast cancer is initiated from breast stem cells. Deregulation of self-renewal and differentiation of stem cells cause transformation. Previous studies suggest that KLF5 promotes stem cell self-renewal and inhibits stem cell differentiation. We already established a breast specific KLF5 knockout (KO) mouse model and will further investigate the role of KLF5 in breast stem cells and breast cancer. First, we will analyze whether KLF5 regulates breast stem cell self-renewal and differentiation using the KLF5 KO mouse model. Second, we will investigate whether KLF5 affects self-renewal and differentiation of brest cancer stem cells using in vivo and in vitro models. Finally, we will further study how KLF5 fuctions in breast (cancer) stem cells via analyzing its downstream targets. This project will provide in vivo evidence to conclude whether KLF5 is a novel promising molecular target for breast cancer treatment. This study will build foundation for developing future breast cancer targeted therapies.

乳腺癌是一种严重危害女性身心健康的常见恶性肿瘤，其发病机制不明。大量证据表明乳腺癌起源于乳腺干细胞，乳腺干细胞的自我更新和分化紊乱可以引起乳腺癌。研究显示KLF5转录因子促进干细胞自我更新和抑制分化，我们已经建立了KLF5乳腺特异基因敲除小鼠。我们计划进一步研究KLF5在乳腺（癌）干细胞及肿瘤发生中的作用。首先，我们将分析KLF5乳腺特异敲除小鼠的乳腺干细胞数量和功能是否异常。其次，我们会在体内以及体外模型中研究KLF5是否影响乳腺癌干细胞的更新和分化。最后，我们将通过对KLF5下游靶基因的分析进一步探讨KLF5是如何在乳腺（癌）干细胞中发挥作用的。我们的研究将在转基因动物水平证明KLF5能否成为乳腺癌治疗的有效靶标，为后期乳腺癌临床靶向治疗研究打下坚实基础。

KLF5是一个促进乳腺癌发生发展的重要转录因子，有研究显示KLF5转录因子促进干细胞自我更新和抑制分化，但KLF5在乳腺（癌）干细胞及肿瘤发生中的作用尚不明确。本研究证实Klf5 KO小鼠乳腺发育受到明显抑制，乳腺上皮细胞的增殖、生存以及干细胞比例明显均显著下降；我们进一步发现KLF5通过转录调控Slug促进正常乳腺干细胞的维持；另外，我们发现KLF5在乳腺癌干细胞中表达较高，在乳腺癌细胞沉默KLF5的表达显著抑制了癌干细胞的维持和自我更新；最后，应用PyMT病毒诱导的乳腺癌模型我们证实Klf5 KO显著抑制了乳腺癌的形成和生长。这项研究表明，KLF5在乳腺正常以及癌干细胞的维持中都发挥至关重要的作用。