HER2/uPAR通路调控乳腺肿瘤休眠和细胞周期的分子机制

本团队在前期研究中发现HER2、uPAR与乳腺癌细胞休眠相关，具体机制不明。休眠的本质是细胞停滞于G0/G1期，一旦进入S/G2/M期休眠即被打破，而此过程与cyclin/Cdks密切相关。由此推断HER2/uPAR通过各种通路及细胞周期关键节点蛋白影响cyclin/Cdks而实现对休眠的调控。另文献报道HER2、uPAR可能通过ERK/AKT调节p27水平，并抑制cyclinD，最终导致细胞休眠。因此本团队拟通过过表达或敲降HER2/uPAR，检测ERK、AKT及其下游关键因子，同时分析p27、cyclinD的变化，以明确其是否为HER2/uPAR调控休眠的机制之一。并拟采用串联亲和纯化技术、质谱测序分析及数据库对比筛选与HER2、uPAR分子互相作用的蛋白，从中寻找影响休眠的其他通路和关键细胞周期节点蛋白。并在临床标本中进行验证，以期发现预测转移的分子标志及潜在治疗靶点。

In previous studies, we found HER2 and uPAR played an important role in breast cancer cell dormancy, however the mechanism is unknown. The nature of cell dormancy is that cells are stuck in G0/G1 period and the dormant state will be broken if cells enter S/G2/M period, and the whole process is closely related to cyclin/Cdks. So we can infer that HER2/uPAR affects cell dormancy by the regulation of key protein in the cell cycle. According to previous research, HER2, uPAR may regulate p27 and cyclinD level and affect cell dormancy through PI3K or MAPK pathways repectively. Therefore, we intent to confirm whether HER2/uPAR affect dormancy this way by detecting key components of PI3K, MAPK pathways and p27, cyclinD with overexpression or knockout of HER2/uPAR. Furthermore, using tandem affinity purification, mass spectrometry sequence analysis and database comparison, we aim to seek for protein interacting with both HER2 and uPAR and find other pathways and key cell cycle proteins. At last, we will test and verify our findings in the clinical specimens from recurrent and metastatic breast cancer patients in order to find a new tumor markers benificial for clincal follow-up or a new target for anti-dormancy treatment.