Down-regulation of HER2/neu expression induces apoptosis in human cancer cells that overexpress HER2/neu.

The HER2/neu oncogene is overexpressed in a significant fraction of human tumors; such overexpression is thought to play a role in the aberrant proliferation of cancer cells. The effects of HER2/neu-specific phosphorothioate antisense oligodeoxyribonucleotides on HER2/neu expression, tumor cell proliferation, and activation of apoptotic cell death pathways have been examined. Antisense treatment down-regulates HER2/neu expression in a dose-dependent and sequence-specific manner. HER2/neu antisense treatment specifically inhibits the growth of tumor lines that overexpress HER2/neu, but it has little effect on the growth of tumor cells that express low levels of HER2/neu. Down-regulation of HER2/neu expression is not only cytostatic, but it also results in the activation of apoptotic cell death pathways in cells that overexpress HER2/neu. These results suggest that, in addition to stimulating tumor cell proliferation, HER2/neu overexpression in cancer cells acts as an antiapoptotic cell survival factor.