Honma K et al. (2008) RPN2 gene confers docetaxel resistance in breast cancer. Nat Med 14: 939–948

Docetaxel has been shown to be beneficial in the treatment of breast cancer; however, almost half of treated patients do not respond to it and many tumors develop resistance. At present no method exists to predict response to docetaxel or to detect resistance. Moreover, target molecules to increase the efficacy of chemotherapy in breast cancer have not yet been identified.

Honma and colleagues used gene-expression profiling of 44 patients with breast cancer (22 of whom had a pathologic response to docetaxel) to determine the regulatory network responsible for docetaxel resistance in breast cancer cells and to identify molecular targets for therapy. The authors used an atelocollagen-based, small-interfering-RNA (siRNA) transfection array to identify the genes responsible for drug resistance.

Of the genes whose expression was elevated in patients who did not respond to docetaxel, inhibition of the ribophorin II (RPN2) gene promoted docetaxel-dependent apoptosis and inhibited cell growth in a docetaxel-resistant human breast cancer cell line (MCF7-ADR). Silencing of RPN2 resulted in decreased glycosylation and membrane localization of the P-glycoprotein efflux pump, which caused increased sensitization of MCF7-ADR cells to docetaxel. In drug-resistant models of mice given docetaxel, in vivo delivery of RPN2-specific siRNA substantially reduced tumor growth.

The authors conclude that the introduction of RPN2-specific siRNA to cancer cells results in a hypersensitive response to docetaxel. RPN2 could, therefore, have clinical applications as a target for RNA-interference-based therapeutics in drug-resistant tumors.