癌细胞侵袭转移是引起乳癌患者死亡的主因，癌相关成纤维细胞(CAF)促进乳癌侵袭转移。前期工作发现：乳癌CAF存在非DNA双链断裂依赖的ATM异常活化、能量代谢变化，但氧化型ATM对低氧诱导的CAFs能量代谢重塑机制和促乳癌侵袭影响不明。本项目拟在前期研究基础上，以CAF和NF为模型，模拟体内乳癌微环境低氧状态，运用磷酸化蛋白质组学技术、生物信息学手段、定点突变技术挖掘氧化型ATM下游能量代谢有关的靶蛋白及其信号途径，以揭示氧化型ATM调控CAFs EMR的内在分子机制；以siRNA沉默、小分子抑制剂干预关键靶蛋白和信号通路，探寻氧化型ATM介导的CAFs EMR对CAFs生物学特性、乳癌侵袭转移的潜在影响，为寻找乳腺癌转移防治新靶点提供新思路和可靠的实验依据，研究结果具有重要理论意义和潜在的临床价值。

Invasion and metastasis of cancer cells are the leading causes resulting in the death of breast cancer patients. The cancer-associated fibroblasts (CAFs) promote the invasion and metastasis of breast cancer cells. Our previous work has found that the aberrant activity of oxidized ATM is independent of DNA double strands breaks and involved in the hypoxia-induced energy metabolism reprogramming (EMR) in CAFs. However, its potential mechanisms and roles in the invasion and metastasis of breast cancer remain unknown. Based on our previous work, we will mimic the hypoxia status in breast cancer microenvironment to reveal the molecular mechanisms (including the target proteins and their associated signaling pathways) of oxidized ATM regulating the EMR of breast CAFs by employing phosphorylated proteomics technology, bioinformatics method and site-directed mutagenesis technology. To further understand its role of CAF EMR mediated by oxidized ATM, the characteristics of CAFs, and the invasion and metastasis of breast cancer cells in the cross-talking with CAFs will be studied by using siRNA and specific chemical inhibitors to EMR-related key targets or signaling pathways. Our results will disclose a novel mechanism of CAF EMR, and provide the novel strategies or find the new molecular targets to prevent and treat the metastasis of breast cancer.