Wnt/β-catenin信号通路异常活化，会导致三阴性乳腺癌在内多种肿瘤的发生。但目前为止，该信号通路药物靶点的发现及其作用机理研究方面严重滞后，直接导致尚无针对该通路的特异药物用于临床。本申请拟采用基于高通量测序的筛选新技术HTS2，以Wnt/β-catenin信号通路特有的特征基因表达谱（gene expression signature）为药物筛选的检测指标，经过大规模筛选来首先获得该信号通路的特异抑制剂。并充分利用基因组学、细胞生物学、生物化学等手段，进一步找到该抑制剂的直接结合蛋白，即该信号通路的药物靶点，并对该新药物靶点具体作用机理展开深入研究。我们期望通过本研究，利用新方法和新思路，找到Wnt/β-catenin信号通路的特异性抑制剂，进而发现新的药物靶点并研究其作用机制，为抗肿瘤的临床治疗提供理论依据，并提高对该重要信号通路调控生命活动普遍机制的认识。

The dysfunctional hyper-activation of Wnt/β-catenin signaling pathway causes many human diseases including triple negative breast cancer (TNBC), thus this pathway should be a potential and promising drug target. However, the drug discovery specifically targeting Wnt/β-catenin pathway is far behind expected, and there is not even one drug having been approved by FDA or CFDA so far. In this proposal, we plan to utilize a novel and powerful high throughput drug screening technology named HTS2 (High Throughput Sequencing based High Throughput Screening), which was established and is working well in our lab, to discover the specific small molecular inhibitors against this pathway. The direct target and functional mechanisms of these specific inhibitors will be studies by combination of cutting-edge technologies related to genomics, epigenomics, chemical genomics and cell biology. By using these novel technologies and through a new research angle, we anticipate that our work should provide some candidate inhibitors and critical molecular insights into Wnt/β-catenin function and regulation in human diseases. This work may disclose novel drug targets within Wnt/β-catenin pathway and shed light on the treatment of triple negative breast cancer.