近期研究显示EMT和肿瘤干细胞（CSC）在HER2+乳腺癌细胞曲妥珠抵抗中起着关键性的作用，而最新研究发现IL-6炎症信号通路在肿瘤细胞EMT和CSC生成中具有重要地位，结合AT1R拮抗剂ARB能通过抑制多条炎症信号通路的活性广泛应用于心血管疾病的治疗，以及我们前期发现AT1R显著过表达于HER2+曲妥珠耐药细胞株SKBR3/R且与炎症因子IL-6的表达密切相关，因此，本项目拟在SKBR3/R细胞株中研究AT1R在介导SKBR3/R细胞EMT、CSC生成及后续的曲妥珠耐药中的作用及分子信号机制，深入研究AT1R特异性拮抗剂ARB在抑制SKBR3/R细胞EMT、CSC生成及逆转曲妥珠耐药性中的作用，最后从动物移植瘤模型中验证ARB在体内逆转SKBR3/R曲妥珠耐药性的效果，不仅从新的角度阐明HER2+乳腺癌的曲妥珠抵抗机制，且为曲妥珠抵抗HER2+乳腺癌的临床治疗提供新的思路和重要科学依据。

Recent studies have shown a critical role of EMT and cancer stem cell (CSC) in trastuzumab resistance of HER2+ breast cancer cells, and an important role of IL6-mediated inflammatory signal pathway in the induction and maintenance of EMT and CSC. Meanwhile, AT1R antagonist ARB has been extensively used in the treatment of cardiovascular disease through the inhibition of multiple inflammation-related signaling.Our previous research found that AT1R was significantly over-expressed in trastuzumab-resistant HER2-positive breast cancer cell line SKBR3/R as compared with parental SKBR3 cells,and notablely, the increased expression of AT1R was tightly associated with high level of IL6 secretion in SKBR3/R cells. Hence,we further study, in the project, the role and molecular signal mechanism of AT1R in the induction and maintenance of EMT and CSC and the resulted trastuzumab resistance of SKBR3/R cells.Furthermore,we study the potential role and molecular signal mechanism of AT1R antagonist in inhibiting the induction and maintenance of EMT and CSC and overcoming trastuzumab resistance of SKBR3/R cells. At last, we analyse in vivo the effect of ARB on trastuzumab resistance of SKBR3/R. Our project trys to demonstrate a new molecular mechanism of trastuzumab resistance of HER2-positive breast cancer, and provides a innovative strategy and subclinical evidence to overcome resistance to trastuzumab therapy of HER2-positive breast cancer.