The impact of Skp2 overexpression on recurrence-free survival following radical prostatectomy.
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.
Nguyen
Paul L
PL
Harvard Radiation Oncology Program, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA 02115, USA. pnguyen@LROC.harvard.edu
Lin
Douglas I
DI
Lei
Junyi
J
Fiorentino
Michelangelo
M
Mueller
Elke
E
Weinstein
Michael H
MH
Pagano
Michele
M
Loda
Massimo
M
D000368:Aged; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000401:mortality* / Q000601:surgery; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000601:surgery; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C436291:CDKN1B protein, human; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27