Dab1在乳腺癌发生发展中的作用及分子机制研究

普通型脆性位点基因位于基因组不稳定区域，该区域修饰活跃，常与肿瘤的发生发展密切相关。Disabled-1（Dab1）是近期发现的普通型脆性位点基因，其功能的研究主要集中在大脑皮层发育过程中神经元的迁移和定位上。有研究表明Dab1在大脑和子宫内膜癌中呈失活状态，然而，其失活的生物学意义并不明确。本研究拟通过收集临床乳腺癌及其癌旁标本，检测Dab1在乳腺癌中的表达变化，研究Dab1的表达与乳腺癌临床分期、分型、转移潜能之间的相关性；序列分析表明Dab1基因存在5’CpG岛，因此我们将探究Dab1在乳腺癌中的表达下调与甲基化修饰的关系；预实验结果显示，乳腺癌组织中Dab1的表达变化与淋巴结转移状态有显著相关性，本项目将进一步利用体外培养的肿瘤细胞、荷瘤鼠模型和恶性肿瘤转移模型，阐明Dab1在乳腺癌恶性进程中的作用及相关分子机制，为临床乳腺癌的治疗提供分子靶点和理论依据。

Common Fragile Site (CFS) genes are located in genomic unstable regions, which are hot-spots for modification, especially in cancer progression. Disabled-1(Dab1) is a CFS gene discovered recently, and many of the studies about Dab1 are focused on its role in neuron migration and position during the development of cerebral cortex. Dab1 is found inactived in brain and endometrial cancer, however, the biological significance of its inactivation is still unclear. In this study, we will investigate the expression of Dab1 in clinical breast cancer tissues related to their paired surrouding tissues, and the relationship between Dab1 and breast cancer staging, subtype and metastatic potential. Sequence analysis reveals that there are 5’CpG islands in Dab1 gene, basing on that, the correlation between the methylation of Dab1 gene and its down-regulation will be analysed. Result of our pre-experiment shows that Dab1 is significantly associated with lymph node metastasis, therefore, the role of Dab1 in breast cancer progression and its molecular mechanism will be investigated by cultured tumor cells, xenograft model and malignant metastasis model, which will elucidate the biological significance of Dab1's down-regulation, providing molecular targets and theoretical basis for the clinical treatment of breast cancer.