以Nanog 转基因小鼠为模型研究多潜能因子Nanog在乳腺癌发生及转移中的作用

Resistance to conventional treatments, recurrence and metastasis are the most serious problems for the breast cancer therapy, leading to the poor prognosis of the cancer patients. Previous studies have identified subpopulations of cells within tumors, termed cancer stem cells (CSCs) or tumor initiation cells, which might drive tumor growth and recurrence, and are responsible for metastasis and resistance to chemotherapy and radiation therapy. However, the molecular basis of CSCs and how this relates to the resistance to conventional therapeutics, cancer recurrence and metastasis, remains unknown. Self-renewal and pluripotency are the common central features of embryonic stem cells (ESCs), adult stem cell and CSCs. The ESC Self-renewal and pluripotency gene Nanog, which is not expressed in normal adult tissues, has been found to be expressed at high levels in human breast cancers, especially in poorly differentiated human breast cancers. However, the function of Nanog in the progression and metastasis of breast cancer is not clear. Here, we have employed LoxP/Cre technology to develop transgenic mice that conditionally express Nanog in their mammary glands. We will use the mouse models and human breast cancer cells to elucidate the potential roles of Nanog in breast cancer development and metastasis. In addition, I will test the hypothesis that disruption of Nanog in breast cancer cells can suppress breast cancer progression and metastasis. Considering the close correlation between Nanog expression and the poor prognosis of human breast cancer patients, my research could have significant impact on developing novel therapeutic strategy to treat breast cancer.

化疗耐受、复发及转移是乳腺癌治疗的主要问题。近来研究表明肿瘤干细胞是乳腺癌治疗问题的潜在根源。阐明乳腺癌干细胞的调节机制，发展针对乳腺癌干细胞疗法将有利于降低乳腺癌耐药，复发及转移。Nanog是维持胚胎干细胞自我更新及多潜能性的主要蛋白，在乳腺癌内高表达并与其分化程度密切相关，这预示了它可能通过对乳腺癌干细胞的调节从而在乳腺癌发生发展中发挥重要作用。利用LoxP/Cre技术，我们建立了可以在乳腺内特异性表达Nanog的条件转基因小鼠，并利用此模型初步发现Nanog促进Wnt-1诱导的乳腺癌肺内转移。本项目拟在此前期基础上，进一步利用该小鼠模型，系统深入探讨Nanog对于乳腺癌干细胞的调节机制，证明Nanog通过调节乳腺癌干细胞从而在乳腺癌的发生及转移中发挥了重要作用，并使其成为治疗乳腺癌的一个潜在药物靶标。

Nanog 是一个促进胚胎干细胞自我更新及维持其全能性的转录因子，它在大多数的成年人组织中都不表达。然而近来的研究显示Nanog在包括乳腺癌在内的许多肿瘤中异常表达。Nanog在肿瘤发生发展中的作用还不清楚。 为了阐明Nanog 在肿瘤的发生发展中的作用，我们构建了利用 LoxP/Cre 调节的可诱导Nanog表达的小鼠模型。我们发现在乳腺组织中过表达Nanog并不会诱导乳腺癌的发生。这一结果表面Nanog并非一个肿瘤发生起始因子。然而，当Nanog与致癌基因Wnt-1同时表达于乳腺组织中，Nanog可以促使Wnt-1诱发的乳腺癌的发生及转移。更进一步的研究显示Nanog可以增加肿瘤细胞的干细胞特征并促进肿瘤细胞的迁移及侵袭。过表达Nanog可以促使上皮细胞间质转型。 通过 微阵列分析我们发现Nanog可以调控与肿瘤形成及转移相关的多个分子的表达从而调节乳腺癌肿瘤的发生及转移。我们的研究显示Nanog参与了乳腺癌的发生及进展，因为Nanog不会在成体组织中表达，我们的发现提示Nanog将可能用于治疗乳腺癌的靶标分子。