CKB介导的BTF3调控三阴性乳腺癌对氧化磷酸化抑制剂敏感性的作用与机制研究

三阴性乳腺癌（TNBC）因缺乏有效的治疗靶点成为乳腺癌中预后最差的一种病理类型，开发新型靶点并探寻增强药物敏感性的关键因子是靶向治疗领域的重要手段。申请人前期研究发现：通用转录因子3(BTF3)在TNBC中具有促癌作用，而敲减该因子则可下调肌酸激酶B(CKB)的表达，并导致肿瘤细胞更加依赖氧化磷酸化通路。由此提出假设：BTF3通过转录调控CKB，不仅能够改变肿瘤细胞内磷酸肌酸的储存，还能降低糖酵解水平，提高氧化磷酸化活性，并进而增强细胞对氧化磷酸化抑制剂——这一重要的靶向治疗药物的敏感性，可能成为提高TNBC靶向治疗的关键调控因子。本项目拟通过CHIP-qPCR，双荧光素酶报告基因实验，海马代谢呼吸实验等手段深入阐明BTF3通过CKB调控TNBC糖酵解和氧化磷酸化之间的代谢转换以及对氧化磷酸化抑制剂敏感性的分子机制，并将结合临床样本以及小鼠肿瘤模型加以验证，为有效治疗TNBC提供新策略。

Triple negative breast cancer (TNBC) is one of the pathological types with the worst prognosis due to the lack of effective therapeutic targets. Developing new targets and exploring the key factors to enhance drug sensitivity are important means of targeted therapy. Previous studies demonstrated the basic transcription factor 3(BTF3) play an oncogenic role in TNBC, and knockdown of BTF3 can down-regulate the expression of creatine kinase B (CKB), and lead to tumor cells becoming more dependent on the oxidative phosphorylation pathway. Therefore hypothesized that BTF3 can not only alter phosphocreatine storage in tumor cells through transcriptional regulation of CKB, also can reduce the glycolysis level, improve the activity of oxidative phosphorylation, and further sensitivity the cell to oxidative phosphorylation inhibitors - an important targeted therapy drug. BTF3 may be a key regulatory factor for improving TNBC targeted therapy. By means of ChIP-qPCR, dual luciferase reporter gene, and hippocampal metabolic respiration test, this project intends to further clarify the molecular mechanism of BTF3 regulating TNBC metabolic transformation and sensitivity to oxidative phosphorylation inhibitors through CKB, and to verify it in combination with clinical samples and mouse tumor models, so as to provide a new strategy for the effective treatment of TNBC.