泛素-蛋白酶体系统在肿瘤发生发展中发挥重要作用。寻找针对肿瘤相关蛋白的特定E3泛素连接酶抑制剂，通过选择性调控目标蛋白特异性杀伤肿瘤细胞。Cullin1（Cul1）是SCF E3泛素连接酶的重要组成部分，其表达异常可以导致E3泛素连接酶功能障碍。但Cul1对肿瘤生物学行为的影响尚不清楚。 申请人前期研究发现，沉默Cul1可以上调乳腺癌细胞TIMP-2进而抑制MMP-2表达，最终导致乳腺癌细胞侵袭能力下降。最新研究发现，Cul1可以通过蛋白酶体途径调节TIMP-2的蛋白稳定性。据此提出科学假说：以Cul1为中心形成针对TIMP-2的特异性SCF复合物，调控TIMP-2泛素化，进而影响MMP-2表达，最终影响乳腺癌细胞转移。本课题拟利用我们构建的多种细胞、动物模型，在分子、细胞及整体水平研究Cul1在乳腺癌转移中的分子机制。本研究的开展将为乳腺癌的基因治疗提供新的靶点。

The ubiquitin-proteasome system plays a crucial role in determine the fate of a tumor and its host. People try to looking for inhibitors of specific E3 ubiquitin ligase that targeting tumor-associated protein. These inhibitors can kill tumor cells specifically by regulating target protein. Cullin1 (Cul1) is an important component of SCF E3 ubiquitin ligase. The abnormal expression of Cul1 leads to dysfunction of E3 ubiquitin ligase. But the role of Cul1 in tumor biology behavior is unclear. Our previous results showed that silence Cul1 can increase TIMP-2 and decrease MMP-2 expression, resulting in inhibition of breast cancer cell invasion. Our recent data showed that Cul1 can regulate TIMP-2 protein stability by proteasome pathway. On the basis of these findings, we propose the hypothesis that Cul1 is formed in the center of a specific SCF complex. This complex regulates TIMP-2 ubiquitination, thereby affecting the expression of MMP-2, and ultimately affect breast cancer cell metastasis. This project intends to study the mechanism that Cul1 regulates breast cancer metastasis via a variety of cell and animal models we constructed. The success of this project will provide a new target for breast cancer gene therapy.