HER2 gene amplification occurs in many breast cancer patients and is associated with poor clinical prognosis. Trastuzumab is a therapeutic monoclonal antibody binding to HER2 and inhibits growth of HER2-positive breast cancer cells and used as a principal treatment for HER2-positive breast cancer. Unfortunately, some HER2-positive breast cancers eventually relapse after trastuzumab treatment. To investigate the molecular mechanism of trastuzumab resistance, we generated trastuzumab-resistant cells using a mouse model and found ECM1 protein is increased in trastuzumab-resistant cells. ECM1 was shown to increase EGFR signaling via upregulated matrix metalloproteinase 9/galectin-3/mucin pathway. To further find the novel mediators of HER2-driven signaling pathways in breast cancer, we investigated the upregulated proteins in HER2-overexpressing breast cancer cells using a proteomics approach and found that KRT19 is strongly upregulated in HER2-positive breast cancer cells and it activates HER2 signaling by binding to HER2 and stabilizes the receptor on the cell membrane. Moreover, we found that treatment of KRT19 antibody resulted in reduced cell viability of trastuzumab-resistant HER2-positive breast cancer cells as well as trastuzumab-sensitive cancer cells both in vitro and in vivo.
Keywords: ECM1; EGFR; HER2; KRT19; Trastuzumab.