The association between overexpression of skp2 and the risk of recurrence following prostatectomy

Abstract

11052 Background: Decreased expression of the cell cycle inhibitor p27 is associated with a poor prognosis in several human cancers. Skp2 is a substrate recognition unit specifically targeting p27 for degradation and may therefore represent a therapeutic target in cancers with low p27. We sought to determine whether Skp2 overexpression is associated with p27 suppression and an increased risk of recurrence among men with prostate cancer treated with prostatectomy. Methods: We identified 110 men who received a prostatectomy for non-metastatic, node-negative prostate cancer from 1985–1996. Immunohistochemistry (IHC) staining for Skp2, p27, and MIB-1 were performed on paraffin-embedded material. Stains were scored based on the percent of cells showing nuclear staining, averaged by counting 100 tumor cells in 5 different areas. A threshold of >30% was used for high p27 staining, and a threshold of ≥5% was used for high Skp2 and high MIB-1. The primary endpoint was time to prostate-specific antigen (PSA) failure. Results: Overall 12 tumors (11%) had high Skp2 expression. These 12 all had correspondingly low p27 expression (p=0.006, Chi-Square). 40% of tumors with high Skp2 also had high MIB-1 expression, while only 13% of tumors with low Skp2 had high MIB-1 (p=0.035). Skp2 overexpression was associated with higher Gleason score (p=0.001) and more advanced pathological T-category (p=0.004). Median follow-up from the time of surgery was 67 months (range: 0.2 to 218 months). On Cox multivariable analysis, Skp2 overexpression was associated with a significantly shorter time to PSA failure (adjusted hazard ratio 5.2 (95% C.I. 1.9–14, p=0.001) after adjusting for PSA, pathologic T-category, and prostatectomy Gleason score. The median time to PSA failure was 4 months among those with Skp2 overexpression compared to 54 months among those who did not overexpress Skp2. Conclusions: Skp2 overexpression was associated with low levels of p27, poor prognostic features, and increased risk of recurrence. These results support the concept of Skp2-mediated degradation of p27, suggest a possible role for Skp2 in tumor progression, and raise the possibility that Skp2 could be a potential therapeutic target, particularly for tumors which underexpress p27. No significant financial relationships to disclose.