HER-2/neu is rate-limiting for ovarian cancer growth - Conditional depletion of HER-2/neu by ribozyme targeting

Amplification and overexpression of the HER-2/neu proto-oncogene frequently coincide with an aggressive clinical course of certain human adenocarcinomas. To assess whether HER-2/neu plays a rate-limiting role in ovarian cancer, we used human SK-OV-3 ovarian cancer cells as a model, We applied a conditional mRNA depletion strategy of HER-2/neu with anti-HER-2/neu-targeted hammerhead ribozymes expressed under the con control of a tetracycline-regulated promoter system, In these ovarian cancer cells, we reduced HER-2/neu mRNA, protein expression, and tumor growth in nude mice by transfection with HER-a!neu-targeted ribozymes and generated cell lines expressing different levels of HER2/neu. Expression of the most effective ribozyme (Rz3) quenched HER-2/neu mRNA levels by >90%. Concomitantly, fluorescence-activated cell sorting analysis revealed that expression of the HER-2/neu encoded surface glycoprotein was almost completely abrogated, In nude mice, tumor growth was dramatically inhibited in the HER-2/neu-depleted Rz3-expressing SK-OV-3 cells, Furthermore, already established tumors started to regress when Rz3 expression was activated midstream by withdrawal of the tetracycline treatment, This study supports the thesis that HER-S/neu can be rate-limiting for the malignant phenotype of ovarian cancer in a gene dose dependent manner.