化学治疗使乳腺癌患者最重要的辅助治疗之一，但由于部分患者对乳腺癌化疗不敏感而预后较差，因此对乳腺癌化疗敏感性的研究，选用合理有效的化疗药物至关重要。已有研究证实DNA损伤和修复机制的完整是影响以DNA为作用靶点的化疗药物疗效的重要因素，而其中一种特殊的修复方式——断裂诱导复制（BIR）是对乳腺癌细胞进行化疗药物干预时的主要修复方式。我们在前期工作中发现BRIT1是乳腺癌相关的肿瘤抑制基因，与DNA损伤修复机制密切相关，而且可调节Mus81的表达来调控BIR修复通路，从而影响基因组稳定性。BRIT1基因的缺失导致BIR修复的减少，使用ATR抑制剂，可阻断DNA损伤修复的其他途径，从而使肿瘤细胞染色体得不到修复而死亡。因此，BRIT1缺失的乳腺癌细胞，对ATR抑制剂更加敏感。本项目将进一步阐明BRIT1调节Mus81的作用机制和效应靶点以及鉴定ATR抑制剂治疗BRIT1缺陷乳腺癌的临床意义。

The chemical treatment is one of the most important adjuvant therapy of patients with breast cancer, but the prognosis is poor if patients are not sensitive to chemotherapy. Therefore, it is very important to select reasonable and effective chemotherapeutic agents and study on breast cancer chemotherapy sensitivity. It has been proved that DNA damage and the integrity of repair mechanism is an important factor that affects the effect of Chemotherapeutic drugs targeting DNA. One of the special repair manner, BIR(break induced repair), is the main way to repair breast cancer cells with chemotherapy drugs. In our previous work, we found that BRIT1 is a tumor suppressor gene associated with breast cancer, closely related to DNA damage repair mechanism. Moreover, BRIT1 can regulate the expression of Mus81 to control the BIR repair pathway, thus affecting the stability of genome. Deletion of the BRIT1 gene leads to a reduction in BIR repair, other pathways of DNA damage repair may be blocked by using of ATR inhibitors, thus tumor cells will die without DNA repair. Therefore, BRIT1 deficient breast cancer cells are more sensitive to ATR inhibitors. This project will further clarify the mechanism of BRIT1 in the regulation of Mus81 and the clinical significance of ATR inhibitors in the treatment of BRIT1 deficient breast cancer.