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Molecular Oncology, Markers, Clinical Correlates |
Scott Department of Urology [G. Y., A. F., T. C. T.], Department of Pathology [G. A., T. M. W.], Verna and Marrs McLean Department of Biochemistry and Molecular Biology [J. W. H.], Baylor College of Medicine, Houston, Texas 77030, and Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland [A. D. M.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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p27 levels are regulated by ubiquitin-mediated proteolysis (19) in a process that requires its association with cyclin/Cdk complexes (20 , 21) and phosphorylation on T187 (22) . Ubiquitination of p27 involves a E3 ubiquitin ligase, SCFSkp2, composed of Skp1, Cul1, Rbx1, and the F-box protein Skp2. Skp2 serves as the specificity component for this E3 and binds to p27 in a manner that depends on p27 phosphorylation and on the cofactor Cks1 (23, 24, 25, 26, 27) . Loss of Skp2 in mice leads to increased levels of p27, consistent with a role for Skp2 in p27 turnover (28) . Skp2 levels are cell cycle regulated, and it accumulates during S-phase. Inappropriate expression of Skp2 in G0 cells can promote S-phase entry concomitant with loss of p27 (24) . Skp2 is also found in complexes with cyclin A/Cdk2 in transformed cells (29) , although the significance of this complex is unknown.
A complex relationship also exists between p27 and the tumor suppressor protein PTEN. Loss of PTEN predisposes individuals to transformation in a wide variety of tissues (30) . Interestingly, loss of p27 in PTEN+/- mice greatly enhances the transformation frequency in multiple lineages (31) . This collaboration is most pronounced in the prostate, where transformation is fully penetrant. Interestingly, in vitro studies indicate that loss of PTEN leads to increased levels of Skp2 through an unknown mechanism (32) .
Decreased expression of p27 is frequently observed in human prostate cancer, but the biological basis of this is not known (14 , 16 , 18) . In this study, we have examined the relationship between p27, Skp2, and PTEN expression in human prostate cancer using tissue microarrays. We find that Skp2 levels are dramatically increased in prostate cancer, and this correlates with loss of p27 and with loss of PTEN. Increased levels of Skp2 can be seen in premalignant lesions referred to as PIN, suggesting that Skp2 induction is an early event in transformation. Skp2 levels were also inversely correlated with recurrence-free survival, suggesting that Skp2 may serve as a useful clinical marker. During the course of this work, other studies linking increased Skp2 to reduced p27 levels in colon (33) , lymphoid (34) , and oral epithelial tumors (35) were reported. Our data, together with in vitro data (32) , suggest a model in which loss of PTEN in the prostate promotes destruction of p27 by allowing the accumulation of Skp2.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Array Construction and Tissue Sections.
For each specimen, the index tumor was defined as the most clinically significant cancer focus (the largest and/or most invasive and/or highest Gleason score cancer focus that was identified and mapped on whole-mount sections). Nearly always, the index cancer was the largest tumor focus with the highest Gleason score and most invasive with respect to the capsule and/or seminal vesicle. However, in rare cases, the Gleason score of the index cancer focus was less than other foci of prostate, which were judged less significant for potential clinical impact. The Gleason score of the index cancer was used as the overall surgical Gleason score of the prostatectomy and used in the analysis correlating tumor histological differentiation with protein expression. Two-mm cores were punched from tissue slices and transferred to a recipient block. The tissue microarrays were built using a manual tissue arrayer (Beecher Instruments, Silver Spring, MD). Internal controls were placed in a preestablished pattern throughout each array to assess adequacy of the stain throughout the sections. A database was built for every block produced, including the coordinates of each core and the area and case of origin. For the study of Skp2 expression in HGPIN, a second set of arrays was built using 63 radical prostatectomy specimens in which 2-mm cores were obtained from areas of HGPIN. Additionally, 11 biopsy tissues from patients who had developed HGPIN but no detectable cancer were included in this study as well. Normal prostates from 4 organ donors were used as control tissues. Five-µm sections from the array blocks and tissues were cut for immunostaining.
Immunohistochemistry.
Sections were deparaffinized and rehydrated. They were then heated in citrate buffer (0.01 M, pH 8.0) in an 800 W microwave oven for 12 min for antigen retrieval. Endogenous peroxidase in sections was inactivated in 2% H2O2 for 10 min. The sections were then blocked in 3% normal horse serum in 0.2 M PBS (pH 7.4) and followed by incubation with a mouse monoclonal antibody to Skp2 (33)
, generously provided by M. Pagano (New York University, New York, NY) or a rabbit anti-PTEN antibody from Zymed. Anti-Skp2 was used at a dilution of 1:100 in PBS with 0.5% normal horse serum. Sections were incubated in primary antibody for 2 h at room temperature. They were then processed following a standard ABC immunostaining (Vector Laboratory, Burlingame, CA). Immunoreactive products were visualized using 3,3'-diaminobenzidine/H2O2. To verify the specificity of the immunoreactions, some sections were incubated with either PBS or normal mouse IgG replacing Skp2 antibody. Some sections were also immunolabeled with a monoclonal p27 antibody (diluted at 1:100; kindly provided by Dr. Xin Lu (Ludwig Institute, Imperial College, London, UK); Ref. 18
) or with anti-Ki67 (diluted at 1:200; Immunotech, Inc.). Additionally, polyclonal antibody to cyclin A (37)
diluted at 1:1000 was also used to stain some sections following a standard ABC procedure.
Quantitation of Immunohistochemistry.
Nuclear Skp2 immunostaining in cancer was evaluated microscopically and recorded as the percentage of Skp2-positive cells (labeling frequency %) as well as labeling intensity scored as 0–3, where 0 was defined as lack of staining, 1 weak but distinct staining, 2 moderate staining, and 3 intense staining seen at low power. A LI defined as the function of labeling frequency and the labeling intensity was determined for each cancer specimen. p27 and cyclin A immunostaining in cancer was quantified as labeling frequency (%) as described (18)
. All specimens were evaluated without any knowledge of the patients’ clinical information.
Statistical Analysis.
The differences in Skp2 labeling frequencies were compared between normal prostate, HGPIN, and cancer specimens by using the Mann-Whitney test. The relationship of Skp2 expression with patients’ clinical and pathological variables was evaluated using the Spearman correlation coefficient. The Spearman correlation coefficient testing was also used to determine the relationship of Skp2 with PTEN and p27 levels. The significance of Skp2 and cyclin A as predictors for recurrence-free survival time was determined using the Kaplan-Meier actuarial analysis and the log-rank test. In addition, the Cox proportional hazard regression model was used to calculate hazard ratios for all univariate analyses of recurrence-free survival time markers and to determine whether Skp2 is an independent predictor to time to recurrence in the presence of other pathological and clinical markers. The hazard ratio and its 95% confidence interval were recorded for each marker. P < 0.05 was considered statistically significant in all of our analyses. All analyses were performed using SPSS 11.0 statistical software (SPSS, Inc., Chicago, IL).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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containing specimens from >600 individuals including 4 normal prostates from organ donors, 622 prostate cancers, as well as 74 HGPIN lesions (Fig. 1
; Table 1
). The Skp2 immunoreactivity was predominantly localized to the nuclei of prostatic cells (Fig. 1)
. Skp2 positive stromal cells were rarely seen. In 5% of the cancer specimens examined, a weak or moderate cytoplasmic immunoreactivity could be seen in addition to predominant nuclear reactivity in cancer cells.
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. In normal prostate, Skp2 immunoreactivity was rare. Positive nuclear staining was seen only in a small proportion of glandular epithelial cells because most cells were completely negative for antibody reactivity (Fig. 1B)
. Infrequent Skp2 expression was also seen in histologically normal prostatic epithelium adjacent to cancer in array specimens (15 of 65 cases). The expression was weak and most commonly associated with atrophy. Basal epithelial cells were infrequently positive. In contrast to normal prostatic epithelium, increased Skp2 levels were demonstrated in cancer specimens (Fig. 1C)
. Skp2 was detected in 557 of 622 (89.2%) patients, and the Skp2 labeling frequency in cancer [mean, 36.32; median, 30] was significantly higher than either normal prostate epithelium [mean, 0.50; median, 0.50; n = 4; P = 0.0037, Mann-Whitney test] or the HGPIN (mean, 21.30; median, 10.00; n = 74; P < 0.0001, Mann-Whitney test; Table 1
). In specimens containing HGPIN lesions, increased Skp2 expression, relative to the normal epithelium, was also seen (Fig. 1D)
. In HGPIN, the Skp2 labeling frequency was significantly higher than that found in the normal glandular epithelia (P = 0.0252; Mann-Whitney test).
Increased Skp2 Protein Levels Are Associated with Poor Histological Differentiation of Prostate Cancer.
Relationships of Skp2 levels with pathological and clinical variables including ECE, seminal vesicle invasion, surgical margin, positive lymph node, Gleason score, preoperative PSA levels, as well as clinical stage were evaluated (Table 2)
. Although not statistically significant, cancer with positive lymph node deposits, ECE, positive seminal vesicle invasion, or a higher clinical stage appeared to have a higher Skp2 labeling frequency (Table 2)
. However, ECE and clinical stage were significantly correlated with the Skp2 LI (Table 3)
. A significant correlation was found between the Skp2 labeling frequency and the Gleason score in radical prostatectomy specimens (rho = 0.150; P = 0.0002; Table 3
). Cancers with higher Gleason scores tended to have a higher level of Skp2 expression (Fig. 2)
. Preoperative PSA levels were also positively correlated with Skp2 frequency (rho = 0.80; P = 0.0499; Table 3
).
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10 (n = 36; mean, 2.54; median, 2.12; Mann-Whitney test, P = 0.0408). These results indicate that cancers with a higher Skp2 level tend to display higher proliferation rates. However, it should be noted that the cancers with high-level Skp2 expression had a broad range of Ki-67 labeling indices (from 0.31 to 16.25%). The Ki-67 labeling index was not significantly correlated with the continuous Skp2 labeling frequency (Spearman’s rho = 0.197; P = 0.0658) or the continuous Skp2 labeling index (Spearman’s rho = 0.155; P = 0.1494). Thus, Skp2 expression is not simply linked to proliferation in prostate cancer tissues.
Increased Skp2 Levels Predict a Shorter Recurrence-free Survival Time.
Further analysis was performed to determine the value of using Skp2 expression as a predictive marker for patients’ recurrence-free survival. Of 622 patients examined, 616 had follow-up data for this analysis. These patients were followed up after radical prostatectomy for a time ranging from 0.36 to 167.74 months (mean, 42.7; median, 40.6 months). One hundred twenty-two had biological recurrence (a blood PSA level 
0.4 ng/ml) during follow-up. A lower quartile of the Skp2 labeling index was used as the breakpoint between relatively low versus high Skp2, creating subgroups at 10. At this cutoff point, 222 cases were in the low category (LI, 10). Three hundred and ninety-four patients had an index >10 (LI, >10).
As shown on the Kaplan-Meier plot (Fig. 3)
, the probability of recurrence-free survival in the high LI group was significantly lower than that in the low LI group (P = 0.0363; Log-rank test). Using the Cox proportional hazard model, we showed that patients with a high Skp2 LI (>10) were 50% more likely to have an earlier recurrence than patients with low Skp2 labeling index. Other pathological markers were analyzed univariately for predictive value. As expected, ECE, seminal vesicle invasion, lymph node metastasis, surgical margin status, and Gleason score were all significant predictors of time to recurrence (Table 4)
. However, the Skp2 labeling index was not an independent predictor of other pathological markers of recurrence-free survival time based on multivariate analysis (P = 0.8724).
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was well demonstrated in a subset of the 622 specimens (n = 175). As we observed in a previous study (18)
, nuclear p27 levels in histologically normal glandular epithelial cells adjacent to cancer were significantly higher when compared with that in cancer (Fig. 1E)
. Nuclear p27 staining in cancer cells was quantified for each cancer specimen and expressed as p27 labeling frequencies (%). They were then compared with the Skp2 labeling frequencies in the same set of specimens (Fig. 4A)
. A statistically significant inverse relationship between p27 and both Skp2 labeling frequencies and labeling index was evident (Spearman’s rho = -0.310; P = 0.0003 for cell labeling frequency; Spearman’s rho = -0.262; P = 0.0021 for cell LI).
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. Interestingly, we found that increased Skp2 expression is significantly correlated with loss of PTEN staining (Fig. 4B
; Spearman’s rho = -0.14; P = 0.0444); tumors that induce Skp2 lack PTEN staining, whereas specimens maintaining PTEN expression tend to maintain low Skp2 levels.
Absence of Linkage of Cyclin A and Skp2 Expression in Prostate Cancer.
Skp2 was originally identified based on its association with the S-phase cyclin, cyclin A, in complexes with Cdk2 (29)
. Cyclin A levels are known to be increased in prostate cancer (38)
, and we therefore sought to determine whether increased Skp2 and cyclin A levels were correlated. Cyclin A labeling frequencies were determined in 63 specimens and compared with Skp2 indices in the identical specimens. Although a positive correlation coefficient of 0.184 was found (Table 5)
, it was not statistically significant (P = 0.3314). Nevertheless, cyclin labeling frequencies alone significantly correlated with Gleason score, clinical stage, and ECE in this set of clinically confined cancer patients (Table 5)
. Moreover, cyclin A labeling was a predictive marker for recurrence-free survival time (P = 0.0041) as demonstrated in a Kaplan-Meier analysis in which the upper quartile of cyclin A labeling frequency (3.74%) was used as a cutoff level to differentiate between the patients (Fig. 5)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Loss of p27 was previously linked with multiple cancer types, including prostate cancer. The recent identification of Skp2 as the specificity component of the E3 ubiquitin ligase responsible for p27 destruction led us to examine whether Skp2 might be linked to loss of p27 in prostate cancer. Three important findings were established:
(a) We found that Skp2 is overexpressed in premalignant lesions of the prostate (HGPIN) that are generally considered to be precursors of frank malignancies. To our knowledge, overexpression of Skp2 has not been demonstrated in premalignant lesions that have a predisposition toward loss of p27 expression. This temporal relationship implies a mechanistic relationship between increased Skp2 and decreased p27 that can be exploited clinically.
(b) We have found that Skp2 is overexpressed in prostate cancer tissues relative to normal prostate and has prognostic significance with respect to time to recurrence after radical prostatectomy. On the basis of Ki-67 and cyclin A staining, the frequency of Skp2 staining is not simply a result of proliferation. This information further defines Skp2 as being involved in prostate cancer development and progression and documents its prognostic capacities in a clinical setting. However, in multivariate analysis, the Skp2 LI did not provide an additional predictive value independent of other pathological markers for recurrence-free survival time (data not shown).
(c) We have found that Skp2 expression is inversely correlated with the expression of p27, as found previously in other cancer types (33, 34, 35) , but is also inversely correlated with PTEN expression. The relationship between Skp2 expression and loss of PTEN is particularly interesting in light of the finding that deletion of PTEN in mouse fibroblasts leads to increased levels of Skp2 with concomitant reductions in p27 levels (32) . Thus, it would appear that PTEN functions as a negative regulator of the Skp2 pathway that is normally used to control S-phase entry. Moreover, recent studies in the mouse have demonstrated that deletion of p27 in PTEN+/- mice leads to cooperation in transformation, with essentially 100% penetrance in the prostate (31) . These results suggest that the presence of a single copy of PTEN is sufficient to suppress transformation and epithelial cell proliferation when p27 is present. These data together with our clinical analysis suggest that the decrease in p27 seen during prostate transformation involves accumulation of Skp2, possibly mediated by loss of PTEN expression. This model makes the testable hypothesis that transformation by PTEN would require an intact Skp2 gene.
Alterations in the levels of proteins controlled by the ubiquitin-proteasome pathway during transformation are likely to be common, and further studies that define how such posttranscriptional control pathways are altered during transformation may provide additional biomarkers or facilitate the identification of novel therapeutic targets. Currently, there are ongoing clinical trials of small molecule drugs that target the proteasome, a general component of the ubiquitin-mediated proteolysis pathway (40) . The finding that Skp2 is induced in a number of different cancers suggests that drugs directed at this molecule may provide a more selective target for therapeutic development.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by Grant P50-CA58204 from the National Cancer Institute and by a grant from the Welch Foundation. 
2 To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6993; Fax: (713) 796-9438; E-mail: jharper{at}bcm.tmc.edu
3 The abbreviations used are: Cdk, cyclin-dependent kinase; PIN, prostatic intraepithelial neoplasm; PSA, prostate-specific antigen; HGPIN, high-grade PIN; ABC, avidin-biotin complex; LI, labeling index; ECE, extraprostatic extension.
4 G. Avala and A. De Marzo, manuscript in preparation.
Received 2/ 4/02; revised 7/19/02; accepted 8/ 5/02.
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