耐药性仍是乳腺癌HER2靶向治疗的瓶颈, 但具体机制至今未明，上皮——间质转化（EMT）和肿瘤干细胞（CSC）形成是耐药的重要原因。Smad蛋白家族是TGF-β/Smad通路的重要一员，参与EMT和CSC形成。申请人在前期研究中发现HN1是乳腺癌新的癌基因，并发现Smad2/3磷酸化水平上升、Smad4泛素化水平下降和HN1过表达与临床HER2靶向治疗耐药密切相关。进一步的预实验发现HN1和Smad家族存在一定相互作用，并正向调控Smad2/3的磷酸化活性和CSC表型。因此，我们提出假设：HN1通过磷酸化Smad2/3和抑制泛素化降解Smad4, 正向调控Smad2/3/4复合物稳定性，促进其转位入细胞核，激活TGF-β下游通路，介导EMT和CSC形成，从而促进HER2靶向治疗耐药。本研究的完成对深入了解HER2靶向治疗抗拒的分子机制有重要的理论意义，同时为乳腺癌治疗提供新的靶点。

Drug resistance is still the bottleneck of HER2-targeted therapy in breast cancer, however the mechanism remains unknown. Epithelial-mesenchymal transition (EMT) and tumor stem cell (CSC) formation are important cause of resistance. Smad protein family is an important member of TGF-β/Smad pathway, involved in EMT and CSC formation. We devoted ourselves to resistant mechanism of HER2-targeted therapy and translational medicine research in the previous study, and found that HN1 is a new oncogene of breast cancer. We also found that increased phosphorylation levels of Smad2/3, decreased ubiquitination level of Smad4 and overexpression of HN1 were closely related to resistance to HER2-targeted therapy. Further preliminary data showed that the HN1 had some interaction with Smad families， positively regulated phosphorylation activity of Smad2/3 and CSC formation. Therefore, we hypothesize that HN1 may phosphorylate Smad2/3 and inhibit ubiquitination and degradation of Smad4, promote Smad2/3/4 complex to transport into nucleus, active TGF-β downstream pathway，mediate EMT and CSC formation, thereby promoting resistance to HER2-targeted therapy in breast cancer. The completion of this study is of great theoretical significance in understanding the molecular mechanism of resistance to HER2-targeted therapy and provides new targets for breast cancer therapy.