申请人自2003 年起专注于DNA 损伤介导的NF-kB 通路激活及其在肿瘤化疗耐药中的相关病理生理机制研究，并已在该领域取得了数项突破性进展。申请人的研究首次揭示了核内DNA损伤如何通过调控信号分子NEMO的序列修饰传导活化信号至胞浆激活NF-kB 通路从而促进肿瘤细胞的化疗耐药性。通过与吴炅教授的合作研究，申请人实验室进一步证实化疗药物诱导的miRNA及促炎症因子在三阴性乳腺癌化疗耐药和侵袭上起重要作用, 并对预测乳腺癌化疗疗效及预后具有潜在的指导意义。本课题拟在前期合作的基础上进一步筛选验证可预测化疗耐药的生物指标， 并研究其影响化疗耐药的分子机制，为三阴性乳腺癌化疗疗效及预后预测提供新的易于检测的生物学标志物。

We have been working on the molecular mechanisms involved in regulating DNA damage-induced NF-kB signaling pathway and their pathophysiological functions in mediating cancer therapeutic response since 2003. Our previous studies demonstrated that NEMO sequential modifications of SUMOylation, phosphorylation and ubiquitylation play critical roles in transducing nuclear DNA damage signal to cytoplasmic NF-kB activating kinase IKK, thereby initiating NF-kB signaling cascade and promoting cancer therapeutic resistance. In collaboration with Dr. Jiong Wu at Fudan University, we further showed that genotoxic drug-induced inflammatory cytokines, such as IL-6, and miRNAs, such as miR-21 and miR-181a, played important roles in mediating NF-kB-dependent chemotherapeutic resistance and metastasis in triple negative breast cancer (TNBC) cells. The alteration of these genes may help to predict therapeutic response and prognosis in TNBC patients. In this proposed studies, we will further validate these findings and screen additional biomarkers which may hold prognostic values in predicting therapeutic response in TNBC patients receiving chemotherapy. The involved molecular mechanisms to modulate therapeutic response will be also investigated.

化疗药物诱导的miRNA等非编码RNA及促炎症因子在乳腺癌化疗耐药和侵袭上起重要作用, 并对预测乳腺癌化疗疗效及预后具有潜在的指导意义。特别是三阴性乳腺癌虽然在治疗早期一般对化疗药物比较敏感，然而有效期普遍较短并易发生化疗耐药。因此，寻找新的针对三阴性乳腺癌的治疗靶点及评价其预后和药物干预效果的生物标记物就显得尤为重要。本课题拟在前期合作的基础上进一步筛选验证可预测化疗耐药的生物指标，并研究其影响化疗耐药的分子机制，为乳腺癌化疗疗效及预后预测提供新的易于检测的生物学标志物。我们按计划通过高通量基因芯片和二代测序技术分析筛选在乳腺癌病人接受新辅助化疗前/后的组织学和血清学样本中基因表达差异，着重于非编码基因如miRNA 和LincRNA，并与病人新辅助化疗疗效进行比较分析。并进一步研究所筛选基因发生改变后影响乳腺癌化疗疗效的具体生理病理学机制，从而找到潜在的针对乳腺癌化疗耐药和转移的新靶点。