From Clinic to Lab and Back

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Science  05 Sep 2008:
Vol. 321, Issue 5894, pp. 1273
DOI: 10.1126/science.321.5894.1273c

Some breast cancer patients respond to docetaxel chemotherapy, but some do not. Honma et al. have marshaled converging evidence that ribophorin II (RPN2), a mammalian oligosaccharide transferase component, contributes to the development of resistance to docetaxel. Assessing gene expression levels in nonresponders versus responders yielded 85 genes expressed at higher levels in nonresponsive patients. Down-regulating these genes individually by applying small interfering RNAs (siRNAs) to a docetaxel-resistant breast cancer cell line winnowed the candidates to eight, with RPN2 knockdown strongly associated with the inhibition of cell growth (taxanes are antimitotic agents) and activation of apoptotic (programmed cell death) pathways; conversely, docetaxel-resistant cells displayed enhanced expression of RPN2 and also of MDR1, which encodes a multidrug efflux pump. Translating these findings into two animal models—created by implanting two docetaxel-resistant breast cancer cell lines into mice—revealed that RPN2 siRNA delivery restored sensitivity to docetaxel and inhibited tumor growth; these effects were mediated by the diminished maturation and glycosylation of MDR1 and the accumulation of docetaxel within the orthotopic tumors. Finally, in a new, albeit small, set of breast cancer patients, RPN2 expression matched responsiveness to docetaxel treatment. — GJC

Nat. Med. 14, 10.1038/nm.1858 (2008).

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