HER2-positive breast cancer (HER2-BC) shows the over-expression of tyrosine kinase receptor EphB4 associated with poor disease prognosis. E-cadherin is found as a survival factor in multiple models of breast cancer by suppressing reactive oxygen-mediated apoptosis. This study confirmed that both HER2 and EphB4 are positively correlated with E-cadherin in HER2-BC. Inhibition of HER2 or EphB4 is discovered to induce ROS-dependent apoptosis by decreasing E-cadherin expression in SKBR3 and MDA-MB-453 cells. TAD1822-7 (TAD), a novel biphenyl urea taspine derivative, exhibits good growth inhibition, apoptosis induction and ROS accumulation effects on SKBR3 and MDA-MB-453 cells. Mechanistic investigation revealed that TAD blockades both EphB4 positive signal transduction and activation of HER2 signal transduction, thereby suppressing E-cadherin/TGF-β/p-Smad2/3 signaling axis to elicit ROS-dependent endogenous mitochondrial apoptosis. Together, these findings not only provide a new approach for HER2-BC therapy but also increase our understanding of the regulating effect of E-cadherin by HER2 and EphB4 in ROS-mediated apoptosis.

HER2 阳性乳腺癌 (HER2-BC) 显示酪氨酸激酶受体 EphB4 的过度表达与疾病预后不良相关。通过抑制活性氧介导的细胞凋亡，E-钙粘蛋白被发现是多种乳腺癌模型中的一种生存因子。该研究证实，HER2-BC 中 HER2 和 EphB4 均与 E-cadherin 呈正相关。发现抑制 HER2 或 EphB4 可通过降低 SKBR3 和 MDA-MB-453 细胞中 E-钙粘蛋白的表达来诱导 ROS 依赖性细胞凋亡。TAD1822-7 (TAD) 是一种新型的联苯脲 taspine 衍生物，对 SKBR3 和 MDA-MB-453 细胞具有良好的生长抑制、凋亡诱导和 ROS 积累作用。机理研究表明，TAD 阻断 EphB4 阳性信号转导和 HER2 信号转导的激活，从而抑制 E-cadherin/TGF-β/p-Smad2/3 信号轴以引发 ROS 依赖性内源性线粒体凋亡。总之，这些发现不仅为 HER2-BC 治疗提供了一种新方法，而且还增加了我们对 HER2 和 EphB4 对 E-钙粘蛋白在 ROS 介导的细胞凋亡中的调节作用的理解。