Regulation of ErbB-2 and Signaling by CHK and Csk Tyrosine Kinases in Breast Cancer

摘要

The HER-2/neu/c-erbB2 and Src family members are implicated in the pathogenesis of breast cancer. In this study, we have examined the role of CHK kinase in suppressing the cell transformation mediated by ErbB-2 and src kinases. We generated stable transfected human breast carcinoma MCF-7 cells overexpressing CHK either active or inactive (kinase-dead). We showed that overexpression of active CHK (but not inactive CHK) inhibited in vitro MCF-7 cells growth, transformation (5-fold) and invasion (24% to 33%) induced upon HRG stimulation. In addition, in vitro Lyn tyrosine kinase activity was inhibited (5-fold) and entry into mitosis was delayed. Furthermore, in vivo tumor growth of MCF-7 cells transfected with active CHK (but not inactive CHK) and grafted in nude mice was significantly inhibited (97% to 100%) compared to untransfected MCF-7 cells (P < 0.05 and P < 0.03 for the two clones of MCF-7 cells transfected with active CHK that were tested). In conclusion, our data strongly support the role of CHK as a novel tumor suppressor gene for human breast cancer, acting through downregulation of Lyn kinase activity and regulation of the S-phase of the cell cycle.