TAD1822-7 induces ROS-mediated apoptosis of HER2 positive breast cancer by decreasing E-cadherin in an EphB4 dependent manner.

Abstract

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.