CRL4A E3泛素连接酶在多类肿瘤中过度活化，介导抑癌蛋白降解促进肿瘤的发生发展，选择性靶向CRL4A E3泛素连接酶成为理想肿瘤治疗策略。在CRL4A E3泛素连接酶复合体中，底物识别蛋白决定了底物的特异性。我们发现在乳腺癌中，CRL4A E3泛素连接酶底物识别蛋白DWD-box家族中POC1A过度表达，而在乳腺癌细胞中靶向POC1A，则可诱导p27蛋白积聚，引起细胞周期S期阻滞。据此我们提出假说：在乳腺癌中，过表达的POC1A作为CRL4A E3底物识别蛋白促进抑癌蛋白p27的降解，促进肿瘤细胞的增殖分裂，进而促进乳腺癌的发生与发展；反之，在乳腺癌中靶向POC1A则可诱导p27蛋白积聚，引起细胞周期S期阻滞，从而发挥抗肿瘤效应。本项目旨在验证该假说，阐明靶向DWD-box蛋白POC1A调控P27积聚的分子机制及其在乳腺癌发生发展中的作用，为乳腺癌抗癌分子靶点鉴定提供科学依据。

CRL4A E3 ubiquitin ligases have been reported to over-activate in various types of cancers and mediate the degradation of a numerous of tumor suppressors to promote tumorigenesis. Targeting CRL4A E3 ubiquitin ligases has become a novel anticancer strategy. In CRL4A E3 ubiquitin ligase complexes, receptor proteins determine the specificity of certain substrates. We demonstrated that in breast cancer, POC1A, one of CRL4A E3 ubiquitin ligase substrate receptor DWD-box family proteins, is overexpressed, while downregulation of POC1A in breast cancer cells induces the accumulation of p27 and arouses cell cycle S phase arrest. Accordingly, we hypothesize that overexpressed POC1A mediates the degradation of tumor suppressor p27 to promote the cell proliferation, through which promotes the tumorigenesis and development of breast cancer; Conversely, targeting POC1A in breast cancer would lead to the accumulation of p27 to induce cell cycle S-phase arrest and exert antitumor effects. To verify this hypothesis, we will carry out intensive studies in this project to elucidate the underlying mechanism of targeting DWD-box protein POC1A in regulating the accumulation of p27 and provide a scientific basis for the identification of anticancer target for breast cancer.