INHIBITION OF P185(C-ERBB-2) PROTOONCOGENE EXPRESSION BY ANTISENSE OLIGODEOXYNUCLEOTIDES DOWN-REGULATES P185-ASSOCIATED TYROSINE-KINASE ACTIVITY AND STRONGLY INHIBITS MAMMARY TUMOR-CELL PROLIFERATION

The c-erbB-2 proto-oncogene codes for a 185-kd putative growth factor receptor that is highly homologous to but distinct from the epidermal growth factor (EGF) receptor. Amplification and overexpression of c-er bB-2 occurs in a number of human tumors, in some of which it is a nega tive prognostic factor. This study investigates the possibility of inh ibiting tumor-cell proliferation by blocking c-erbB-2 expression in th e human mammary carcinoma cell line SK-Br-3 using chemically modified antisense oligodeoxynucleotides. Expression of the p185(c-erbB-2) prot ein product was selectively reduced within 48 hours and resulted in a growth arrest of SK-Br-3 cells. Biochemical studies of tyrosine-kinase and SG-kinase activities after antisense inhibition of c-erbB-2 show that p185(c-erbB-2) activates the SG-kinase signalling pathway in a no nlinear, dose-dependent manner. This may be relevant for the design of therapeutic strategies involving the inhibition of c-erbB-2 (proto-) oncogene expression.