在靶向Aurora-A治疗乳腺癌中自噬的作用及其诱导机制研究

在乳腺癌的治疗中，放化疗的副作用太大，分子靶向治疗由于其高特异性，毒副作用小而成为当前乳腺癌治疗的热点。在乳腺癌分子靶向治疗中，我们及其他研究组均发现靶向Aurora-A (Aur-A)能够显著抑制乳腺癌。申请人的前期结果表明(Autophagy，2012，IF:12.04)，在乳腺癌细胞中抑制Aur-A活性和干扰其表达诱导了凋亡，同时诱导了自噬，抑制自噬后显著增强Aur-A抑制剂诱导细胞凋亡，但抑制Aur-A诱导自噬的机制尚未阐明。在本课题中，我们将利用乳腺癌三维细胞培养及动物模型，进一步验证抑制Aur-A与自噬的关系，及自噬在抑制Aur-A治疗乳腺癌中的作用。分析联合靶向Aur-A及自噬在乳腺癌中的可行性，为临床治疗乳腺癌提供新的方案。并通过转录组和蛋白质组学分析以阐明抑制Aur-A诱导自噬的的分子机制，为临床靶向Aur-A与自噬治疗乳腺癌提供坚实可靠的理论和实验基础。

Chemotherapy and radiotherapy have many side effects in the treatment of breast cancer. Molecular targeting therapy with low side effects and high specificity has been a novel therapeutic strategy for cancer. Our and other previous studies suggest that targeting Aurora-A (Aur-A) may be of therapeutic use, leading to apoptosis in breast cancer. We found inhibition and depletion of Aur-A induced apoptosis and autophagy in breast cancer cells, moreover repression of autophagy enhanced the apoptosis (Autophagy, 2012, IF:12.04). However, mechanisms of autophagy induced by inhibiting Aur-A have not been found. In this project, we will further examine whether inhibition of Aur-A could induce autophagy, and assess the role of autophagy in targeting Aur-A for breast cancer therapy in 3D (three dimensions) cell culture and animal model. Moreover, we will systematically explore the molecular mechanisms of autophagy induced by targeting Aur-A by transcriptome and proteome analysis. This project will provide a reliable theoretical and experimental basis for clinical treatment of breast cancer.