化疗耐药是乳腺癌治疗中的难题，其机制仍未完全阐明。前期我们发现NR5A2促进了乳腺癌化疗耐药，初步表明NR5A2与NCOA3相互作用上调了MDC1的转录水平，并降低化疗药诱导的DNA损伤而介导耐药。本课题将开展的工作：1.完善NR5A2通过MDC1促进乳腺癌化疗耐药的功能验证；2.阐明NR5A2和NCOA3相互作用上调MDC1的机制：找出NR5A2结合在MDC1启动子的位点，阐明NR5A2与NCOA3互作结构域，挖掘与NR5A2互作调节MDC1转录的新因子，阐明新因子与NR5A2互作形式及调节MDC1表达机制；3.探讨NR5A2通过MDC1促进DNA损伤修复的机制，从同源重组修复和非同源末端连接修复机制探讨，搜寻与MDC1互作介导DNA修复的新因子，阐明新因子与MDC1互作形式与机制。本课题将为乳腺癌化疗耐药机制提供新的理论，为耐药乳腺癌提供潜在的诊断标志物及药物治疗靶点。

Despite recent advances in the treatment of human breast cancer by chemotherapy, resistance to chemotherapeutic agents is still a major problem. However, the mechanisms of chemotherapy resistance have not been fully elucidated. Our preliminary experiments found that NR5A2 promoted chemoresistance in breast cancer. In addition, the interaction of NR5A2 and NCOA3 up-regulated the expression of MDC1, and attenuated DNA damage induced by chemotherapy drugs. This project will carry out the following work: 1) to verify the function of NR5A2 promotes breast cancer chemotherapy resistance by inducing MDC1 expression; 2) to clarify the mechanisms of NCOA3 interacts with NR5A2 and induces MDC1 expression, to verify the MDC1 gene promoter sites bound by NR5A2, to clarify the interaction domain between NR5A2 and NCOA3, to find some new factors which interacts with NR5A2 and regulate the transcription of MDC1, to clarify the mechanisms that the new factors interact with NR5A2 and regulate the expression of MDC1; 3) to investigate the homologous recombination repair and non homologous end of link repair mechanism by NR5A2 and MDC1, to find some new factors which interacts with MDC1 and promotes DNA repair, to clarify the mechanisms that the new factors interact with MDC1 and promote DNA repair. This study will provide a novel theory for the mechanisms of breast cancer chemotherapy resistance, and provide potential diagnostic markers and therapeutic targets for breast cancer.