Prognostic impact of Skp2 and p27 in human breast cancer

Purpose. The cell cycle is controlled by cyclin-dependent kinases and one of the key players is the cyclin-dependent kinase inhibitor p27. The F-box protein Skp2 is a regulator of G1-S transition and promotes specifically the ubiquitin-mediated proteolysis of p27 via the proteasome pathway. In breast carcinomas, overexpression of Skp2 has been implicated in cell transformation and oncogenesis, but no data are available on the association of Skp2 and p27. The purpose was to evaluate the prevalence of Skp2 and p27 expression and determine whether a combined index has prognostic power in breast carcinomas. Experimental design. Three hundred and thirty-eight breast cancer specimens were analyzed for Skp2 and p27 expression by immunohistochemistry. Results were compared with classical histopathological criteria as well as other prognostic markers (ER, PR, HER2, p53, Ki-67) and correlated with the clinical outcome. Results. Thirty-four percent of breast cancers analyzed showed both a high expression for Skp2 and a low expression for p27. In univariate Kaplan-Meier analysis, this combination was found to be significantly associated with a worse clinical course (p < 0.0001). Including staging, grading and the other tested marker, the Skp2/p27 index proved to be of prognostic relevance in multivariate analysis. Conclusions. The combined assessment of Skp2 and p27 identifies aggressive breast cancer. In long-term follow-up, high Skp2 and low p27 indicate an unfavorable course. Beyond the prognostic importance of the Skp2/p27 index, it could serve as a predictive marker for new molecular targeted therapies aiming at Skp2.