Analysis of the crosstalk between the EphB6 and ErbB2 receptors in breast cancer cells

Abstract

Eph receptor tyrosine kinases and their ligands, ephrins, represent an important signaling system that regulates many fundamental biological processes, including cell proliferation, survival, and migration. Aberrant expression and regulation of these proteins often contribute to cancer aggressiveness and progression, which makes them an attractive target for cancer therapy. Here, we report that EphB6, a kinase-dead member of the Eph receptor group, physically interacts with a well-described oncogene, the ErbB2 receptor, but not its kinase-inactive relative, ErbB3, and modulates cell expansion in ErbB2-positive breast cancer cells. On the mechanistic level, the ligand (NRG1)-activated ErbB2 receptor assured EphB6 tyrosine phosphorylation, while EphB6 presence also enhanced ligand-induced ErbB2 phosphorylation on tyrosine residues. This results in the enhanced downstream signaling through the Akt-mTORC1-S6K pathway, concluding in the increased proliferation and in the inhibition of the apoptotic death in human breast cancer cells. Consistent with this, my experiments reveal that EphB6 enhances the propagation of ErbB2 overexpressing breast cancer cells in response to NRG1 stimulation. Taken together, our data suggest an entirely new role for EphB6 in ErbB2 signaling and in ErbB2-positive breast cancer. Since ErbB2 plays an important role in human malignancies, is overexpressed in 15-25% of breast tumors, and represents the most popular therapeutic target in their treatment, my findings suggest that simultaneous co-inhibition of ErbB2 and EphB6 receptors might benefit the survival of patients with ErbB2-positive breast cancer.