锌指转录因子Snail在多数恶性肿瘤组织中过表达。作为调控细胞上皮-间质转化（EMT）的关键因子，Snail参与了EMT介导的肿瘤干细胞生成、肿瘤细胞播散及转移的调节。迄今，内源性Snail在恶性肿瘤发生发展中的作用仍不清楚。为此，我们构建了自发性乳腺肿瘤、Snail条件性敲除转基因小鼠。初步的研究表明，组织特异性Snail敲除显著抑制了乳腺肿瘤的发生、发展及转移。为深入探讨Snail在恶性乳腺肿瘤发生发展中的作用及其分子机制，本项目拟开展如下研究：1）Snail敲除对癌前及肿瘤组织中肿瘤干细胞（也称起动细胞）扩增及活性的影响；2）Snail基因对肿瘤细胞增殖、凋亡、分化、EMT、集体侵润、血管外渗及转移等的调控；3）Snail对“看家”抑癌基因p53的调控及Snail/p53信号轴在肿瘤发生发展中的作用。本研究将为乳腺肿瘤病理诊断及Snail相关的上皮性肿瘤治疗策略提供重要的理论基础。

The zinc-finger transcription factor Snail is inappropriately expressed in various types of malignant tumors. As a key molecule that regulates cell epithelial-mesenchymal transition (EMT), Snail is involved in EMT-mediated regulation of cancer stem cell generation and tumor cell dissemination and metastasis. Currently, it is still unclear whether endogenously-derived Snail expression plays a functional role in regulating tumor initiation and progression. As such, we have generated Snail floxed/floxed mice and crossed these transgenic lines into the MMTV-PyMT mouse model of breast cancer. Preliminary studies demonstrate that tissue specific deletion of Snail markedly represses tumor initiation, progression and metastasis. To further investigate the fundamental role of Snail in controlling tumor initiation and progression as well as the potential molecular mechanisms, we propose the following studies: 1) the effect of Snail conditional deletion on expansion and activity of cancer stem cells (i.e. tumor initiating cells) in preneoplastic tissue and established tumors; 2) the impact of Snail on tumor cell proliferation, apoptosis, differentiation, EMT, collective invasion, extravasation and distal metastasis; 3) the regulatory effect of Snail on “housekeeping” tumor suppressor gene p53 and the functional role of Snail/p53 signaling axis in controlling tumor initiation and progression. These studies should provide an important theoretical basis for diagnosis of breast cancer as well as Snail-related cancer therapeutic strategy.