The impact of Skp2 overexpression on recurrence-free survival
following radical prostatectomy
Paul L. Nguyen, M.D.*, Douglas I. Lin, A.B., Junyi Lei, M.D., Ph.D.,
Michelangelo Fiorentino, M.D., Elke Mueller, M.D., Michael H. Weinstein, M.D., Ph.D.,
Michele Pagano, M.D., Massimo Loda, M.D.
Harvard Radiation Oncology Program, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA 02115, USA
Received 16 February 2009; received in revised form 18 March 2009; accepted 19 March 2009
Background: In several human cancers, overexpression of Skp2 (S-phase kinase associated protein 2), which targets p27 for degrada-
tion, 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 ϭ 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 ϭ
0.002), more advanced pathological stage (P ϭ 0.01), and higher MIB-1 index (P ϭ 0.03), but a more favorable PSA proﬁle (P ϭ 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 ϭ 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. © 2011 Elsevier Inc. All rights reserved.
Keywords: Skp2; Biomarker; Prostate cancer; Recurrence
For patients with localized prostate cancer, the identiﬁ-
cation of molecular markers that are prognostic for outcome
can be useful both to improve risk stratiﬁcation beyond the
current paradigm of prostate-speciﬁc antigen (PSA), Glea-
son score, and T-category, and to identify potential targets
for novel therapeutic agents . In several human cancers,
overexpression of Skp2 (S-phase kinase associated protein
2) has been associated with poorer tumor differentiation,
more advanced stage at presentation, and ultimately poorer
clinical outcome . Skp2 is an F-box protein that acts as
the substrate recognition subunit of a complex that specif-
ically targets p27 and their substrates for ubiquitylation and
consequent degradation. Skp2-dependent degradation ap-
pears to be the major regulator of p27, which acts as a cell
cycle inhibitor and a tumor suppressor by preventing Cdk1
and Cdk2 from driving the cell division cycle [3–5].
As Skp2 appears to be overexpressed only in tumor cells, it
could represent an attractive candidate for targeting by novel
anti-cancer agents. The purpose of this study is to examine the
relationship between Skp2 expression and severity of disease
in prostate cancer and to determine whether expression of Skp2
adds additional information beyond what is known from the
PSA, T-stage, and Gleason score, to the prediction of outcome
among men treated with radical prostatectomy.
Presented in abstract form at the ASCO 2008 Meeting.
M.L. has consulted for Novartis.
* Corresponding author. Tel.: ϩ1-617-732-6310; fax: ϩ617-732-7347.
E-mail address: pnguyen@LROC.harvard.edu (P.L. Nguyen).
Urologic Oncology: Seminars and Original Investigations 29 (2011) 302–308
1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved.