The impact of Skp2 overexpression on recurrence-free survival following radical prostatectomy

Abstract

Background In several human cancers, overexpression of Skp2 (S-phase kinase associated protein 2), which targets p27 for degradation, portends a poorer prognosis. We examined whether Skp2 overexpression is associated with recurrence following radical prostatectomy (RP) for prostate cancer. Methods Immunohistochemical staining for Skp2, p27, and MIB-1 was performed on 109 men with node-negative prostate cancer surgically managed from 1985 –1996. Associations between the stains were tested and Cox regression was used to determine the association between Skp2 expression and time to biochemical recurrence following RP. Results The 12 tumors (11%) with Skp2 overexpression all had correspondingly low p27 expression ( P = 0.006), and a similar inverse Skp2/p27 relationship was seen in vitro in LNCap cells. Skp2 overexpression in tissue was associated with higher Gleason score ( P = 0.002), more advanced pathological stage ( P = 0.01), and higher MIB-1 index ( P = 0.03), but a more favorable PSA profile ( P = 0.04). Five men received a TURP. Among 104 who received RP, median follow-up was 67 months (range: 0.2 –218). After adjusting for PSA, pathologic stage, and Gleason score, Skp2 overexpression remained significantly associated with a shorter time to biochemical recurrence (adjusted hazard ratio 4.8 (95% C.I. 1.6 –14, P = 0.004)). The median time to recurrence with high vs. low Skp2 was 4 vs. 54 months. Conclusions Skp2 overexpression was seen in a significant minority of surgically-managed men and was independently associated with a higher risk of recurrence, raising the possibility that Skp2 could be useful as a prognostic biomarker and as a potential molecular target for novel systemic agents in prostate cancer.