阿霉素是乳腺癌化疗的基石药物，但耐药问题极大地限制其临床应用。研究表明阿霉素耐药的肿瘤细胞DNA损伤修复能力异常增强，但机制尚未完全阐明。PRMT5是一种甲基转移酶，在多种肿瘤的发生发展中有重要作用。我们前期发现PRMT5在乳腺癌组织中高表达，且其表达水平与肿瘤对阿霉素化疗的敏感性负相关，同时PRMT5过表达可促进肿瘤细胞的DNA损伤修复能力。通过质谱技术我们筛选出可直接与PRMT5相互作用的蛋白ALKBH7，并初步证实PRMT5可甲基化修饰ALKBH7增强其蛋白稳定性，进而促进细胞DNA损伤修复。基于此，本课题将通过分子克隆、细胞动物模型构建及组织样本分析等手段，深入解析PRMT5调控ALKBH7促进DNA损伤修复的分子机制，并分别在细胞和动物水平阐明其功能，最终明确其在乳腺癌治疗中的临床意义。这些研究将进一步揭示PRMT5在乳腺癌中的作用，为解决乳腺癌化疗耐药问题提供新的理论依据。

Doxorubicin was the cornerstone of breast cancer chemotherapy, but the drug resistance in treatment greatly limited its clinical application. Recent studies have shown that the increased chemotherapy resistance of doxorubicin was linked to the enhanced ability of DNA damage repair of breast cancer cells, but the mechanism have not been clarified. Our study have found that PRMT5 was highly expressed in breast cancer tissues, the expression level of PRMT5 was negatively correlated with the chemotherapy response of doxorubicin of breast cancer patients, and the overexpression of PRMT5 promoted DNA damage repair of tumor cells. Through mass spectrometry, we screened out a protein called ALKBH7, which could interact with PRMT5, and initially confirmed that PRMT5 can affect its stability by regulating the methylation status of the protein and promote DNA damage repair of breast cancer cells. On this base, we will analyze the molecular mechanism of the process which PRMT5 promote DNA damage repair by regulating ALKBH7 and clarify the role of PRMT5 in chemotherapy resistance in vitro and in vivo through molecular cloning, biological model construction and tissue sample analysis. We will further identify the clinical significance of PRMT5 in the treatment of breast cancer. These studies can further reveal the role of PRMT5 in breast cancer and provide a new theoretical basis for solving the problem of chemoresistance in breast cancer.