Aurka结合蛋白Bora通过P53降解促进休眠乳腺癌细胞激活的分子机制研究

休眠乳腺癌细胞激活是乳腺癌转移的关键环节，然而休眠细胞激活的分子机制未明。申请人发现细胞周期相关基因集提示肿瘤不良预后(EbioMedicine 2019)，有丝分裂期激酶Aurka结合蛋白Bora在乳腺癌高表达并提示不良预后，且Bora在肿瘤非分裂期表达，促进细胞G0/G1向S期转变及乳腺癌增殖(Oncotarget 2017)。前期发现乳腺癌三维模型中休眠细胞Bora表达降低，p21升高；实验证实干扰Bora促进乳腺癌细胞p21表达，诱导细胞衰老，提示Bora抑制P53-p21通路、促进休眠细胞激活的功能。据此，本项目拟利用三维乳腺癌休眠模型，明确Bora促进休眠乳腺癌细胞激活的功能，阐明Bora协同Aurka通过P53-S315磷酸化并降解P53，抑制p21，导致休眠细胞激活的分子机制，鉴定Bora促进休眠细胞激活及乳腺癌转移的潜在靶点，为靶向休眠乳腺癌、抑制乳腺癌转移提供新策略。

Activation of dormant cancer cell is a critical step in breast cancer metastasis. However, the mechanisms underlying dormant cell activation remains ill defined. We have previously found that cell cycle gene sets are associated with poor prognosis in cancer (EbioMedicine, 2019). We have identified that Bora, a mitotic kinase Aurka-binding protein, is highly expressed in breast cancer and indicates poor clinical outcomes. Moreover, Bora is expressed in non-mitotic cells, promoting cell cycle G0/G1 transition to S phase and cell proliferation in breast cancer (Oncotarget, 2017). Our preliminary data show that the expression of Bora is decreased, whereas p21 is increased in the breast three-dimensional dormant model. Indeed, we have confirmed that knocking down Bora results in elevated p21 expression and cellular senescence. These preliminary results suggest that Bora may promote dormant breast cancer cell activation via P53-p21 axis. This study aims to identify the function of Bora in dormant breast cancer cell activation in a three-dimensional dormant model. We will determine the mechanisms whereby Bora activate dormant breast cancer through Aurka-dependent phosphorylation of P53 at S315, which destabilizes P53 and downregulates p21. We will identify the potential targets for this molecular cascade to block dormant cell activation and metastasis in breast cancer.