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

摘要

Substantial evidence exists supporting direct roles for ErbB-2/neu and src tyrosine kinase activation in breast cancer. CHK is a kinase that phosphorylates and negatively regulates Src kinase activity. Our studies reveal that CHK expression was observed in 70 out of 80 primary breast cancer specimens, but not in normal breast tissues (0/19). CHK participates in signaling in breast cancer cells by associating, via its SH2 domain, with ErbB-2 following heregulin stimulation. CHK-SH2 binds to Tyrl248 of human ErbB-2. Interestingly, autophosphorylation at this site confers oncogenicity to this receptor. Moreover, CHK was able to downregulate ErbB-2-activated Src kinases, and overexpression of CHK in MCF-7 breast cancer cells markedly inhibited cell growth and proliferative response to heregulin as well as decreased colony formation in soft agar. CHK also inhibits tumor growth of MCF- 7 cells implanted in nude mice. These results strongly suggest that CHK is a potential novel negative growth regulator in human breast cancer. New information gained from these studies on the role of CHK as a putative tumor suppressor gene may provide a basis for utilizing this novel tyrosine kinase to oppose the malignant process of breast cancer.