HER2/neu antisense targeting of human breast carcinoma

Overexpression of the HER2/neu oncogene is observed in approximately 30% of human breast carcinoma specimens. HER2/neu overexpression is a negative pr ognostic factor in breast cancer patients. Cancer cells that overexpress HE R2/neu may also be less sensitive to chemotherapy. In order to further defi ne mechanisms by which HER2/neu overexpression drives neoplastic cell growt h and chemoresistance, antisense oligonucleotides (ODNs) have been utilized to selectively down-regulate HER2/neu expression in human breast cancer ce lls. Such antisense ODNs suppress HER2/neu mRNA and protein levels in a dos e-dependent, sequence-specific manner. Down-regulation of HER2/neu expressi on in HER2/neu overexpressing breast cancer cells inhibits cell cycle progr ession in G(0)/G(1) and results in apoptotic cell death. In tissue culture studies, combined treatment of HER2/neu overexpressing breast cancer cells with HER2/neu antisense ODNs and conventional chemotherapeutic agents resul ts in synergistic inhibition of cancer cell growth and activation of apopto tic cell death mechanisms. These studies have been extended to demonstrate synergistic antitumor effects following systemic treatment with antisense O DNs plus doxorubicin in nude mice bearing human breast carcinoma xenografts . Collectively these findings demonstrate that HER2/neu overexpression stim ulates anti-apoptotic cell survival mechanisms and suggest that HER2/neu an tisense ODNs may be of use in cancer therapeutics.