E3泛素连接酶通过对细胞内重要蛋白质的降解参与机体的生理与病理甚至肿瘤的发生发展过程。而E3泛素连接酶Hrd1在乳腺癌中的作用与功能尚不清楚。本课题前期发现： Hrd1在乳腺癌组织中呈高表达；Hrd1的表达与正常乳腺上皮细胞发生EMT及抑制乳腺癌细胞增殖与迁移有关； Hrd1可与IGF-1R在乳腺癌细胞中直接结合。据此，我们推测Hrd1可能通过降解细胞内的IGF-1R而发挥抑制乳腺癌的作用。为验证此假说，本课题拟运用体内、体外模型，围绕Hrd1对乳腺癌发生发展的影响，重点阐明Hrd1介导IGF-1R的降解机制，进而探讨其对IGF-1R信号通路活性的影响，证明Hrd1抑制乳腺正常细胞的恶性转化及促进乳腺癌细胞的转移和侵袭，同时从Hrd1的角度对雌激素引起乳腺癌发生发展的机制进行深入的认识，本课题结果为针对E3泛素连接酶为靶点开发抗癌药具有重要的理论和实践意义。

Understanding the process of breast cancer development has long been an essential research interest. In recent years, E3 ubiquitin ligases are regarded associated with the various diseases, including cancers. The preliminary data from the current research project demonstrated that expression of Hrd1 is significantly higher in the peri-cancerous tissues than in the cancerous tissues. The results from the in vitro study indicated that Hrd1 expression downregulates Insulin-like Growth Factor-1 Receptor (IGF-1R) expression by their direct interaction, affecting the epithelial mesenchymal transformation of normal breast cells and proliferation as well as migration of breast cancer cells. In this project, we will focus on the mechanism of IGF-1R degradation mediated by Hrd1 in both normal breast epithelial cells and breast cancer cells. Based on this, we intend to further clarify the effects of Hrd1 on the tumorigenesis, proliferation and metastasis of breast cancer. Meanwhile, the tumorigenetic effect of estrogen will be studied from its impact on Hrd1 expression in breast epithelial cell. The findings from our current study help us to develop antitumor drugs targeting E3 ubiquitin ligases.