|Year : 2015 | Volume
| Issue : 7 | Page : 153-157
Prognostic role of s-phase kinase-associated protein 2 in breast cancer: A meta-analysis
Y Shi1, N Li2, H Ren3, X Guo4, Q Li5, S Ma6, D Wang7
1 Department of Breast thyroid, The Second Hospital of Jilin University, Jilin, China
2 Department of Outpatient, Changchun Obstetrics Gynecology Hospital, Jilin, China
3 Department of General Surgery, The Second Hospital of Jilin University, Jilin, China
4 Department of Nursing, The Second Hospital of Jilin University, Jilin, China
5 Department of Orthopedics, The Second Hospital of Jilin University, Jilin, China
6 Department of Rheumatology and Immunology, The First Affiliated Hospital of Jilin University, Jilin, China
7 Department of Breast, The Second Hospital of Jilin University, China
|Date of Web Publication||20-Jul-2016|
Department of Breast, The Second Hospital of Jilin University
Department of Rheumatology and Immunology, The First Affiliated Hospital of Jilin University, Jilin
Source of Support: None, Conflict of Interest: None
OBJECTIVE: Emerging evidence has shown that the F-box protein S-phase kinase-associated protein 2 (Skp2) plays an important role in the pathogenesis of breast cancer (BC). Our study aimed to evaluate the prognostic value of Skp2 in BC patients using meta-analysis based on the published studies. MATERIALS AND METHODS: Eligible studies were identified by searching the online databases such as PubMed, EMBASE, and Web of Science up to October 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between Skp2 expression and indicators of BC clinical outcomes, including overall survival (OS), disease-free survival (DFS), and BC-specific survival. RESULTS: In total, nine studies with 1820 BC patients were included for final analysis. The meta-analysis suggested that Skp2 overexpression was associated with poor OS (HR = 2.58, 95% CI: 1.83-3.63, P = 0.000) and poor DFS (HR = 2.12, 95% CI: 1.48-3.05, P = 0.000) in BC patients. CONCLUSIONS: This meta-analysis indicates that enhanced Skp2 is an independent prognostic factor for poor cancer survival.
Keywords: Breast cancer, meta-analysis, overall survival, prognosis, S-phase kinase-associated protein 2
|How to cite this article:|
Shi Y, Li N, Ren H, Guo X, Li Q, Ma S, Wang D. Prognostic role of s-phase kinase-associated protein 2 in breast cancer: A meta-analysis. Indian J Cancer 2015;52, Suppl S3:153-7
|How to cite this URL:|
Shi Y, Li N, Ren H, Guo X, Li Q, Ma S, Wang D. Prognostic role of s-phase kinase-associated protein 2 in breast cancer: A meta-analysis. Indian J Cancer [serial online] 2015 [cited 2020 Jun 3];52, Suppl S3:153-7. Available from: http://www.indianjcancer.com/text.asp?2015/52/7/153/186559
| » Introduction|| |
Breast cancer (BC) is the most common female malignancy and the second leading cause of cancer-related death after lung cancer in the United States and China.  BC has been clinically characterized by the expression of hormone and growth factor receptors such as estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2.  Current therapies for BC include surgery, radiation, chemotherapy, hormonal, and biological therapies. Even though BC recurrence rates have been significantly decreased due to early detection and adjuvant therapies, BC still causes high mortality.  Therefore, further understanding of the molecular mechanisms underlying the development of BC, especially the critical events of the metastatic spread, is essential to identify new therapeutic targets for achieving better treatment of BC.
The S-phase kinase-associated protein 2 (Skp2), an indispensable member of the SKP1/CUL1/F-box protein (SCF) ubiquitin ligase complex, was identified as a protein that interacts with cyclin A and CDK2 and controls G1-S progression.  Early studies have shown that Skp2 regulates many cell cycle regulators that may contribute to cancer progression, including c-Myc, cyclin E, p57Kip2, p21WAP1, and E2F1. ,, Subsequent studies with human cancer samples revealed that Skp2 is overexpressed in a variety of human cancers ,,,,,,, suggesting that Skp2 overexpression may have essential functions in human cancer development. In BC, though there are several clinical researches which had investigated the relationships between Skp2 and some clinicopathological parameters, their conclusions were still controversial. Therefore, this meta-analysis is aimed to assess the clinical value of Skp2 in BC patients.
| » Materials and Methods|| |
Literature search and selection criteria
We searched the literatures from the electronic databases such as PubMed, EMBASE, and Web of Science, and the searching deadline were October 2015. The keywords were searched by using the following terms and their combinations: Skp2, breast, mammary gland, carcinoma, and cancer.
Studies in this meta-analysis had to meet the following inclusion criteria: (1) Inclusion of patients with BC; (2) evaluation of the association between Skp2 and clinical prognosis; (3) sufficient data to estimate hazard ratio (HR) and 95% confidence interval (CI); and (4) publication as a full paper in English. Studies were excluded based on the following criteria: (1) Duplicated studies, reviews, letters, unpublished data, and comments; (2) published in a language other than English; (3) data that could not be extracted or calculated from the original article; and (4) nonhuman subjects. Study selection was achieved by two investigators independently according to the inclusion and exclusion criteria by screening the title, abstract, and full text.
The data of eligible studies were extracted in duplicate by two investigators independently. The following details were extracted: Name of the first author, year of publication, country of origin, total number of patients, median follow-up time, clinical stage, detection method of Skp2, and cut-off values, as well as the HR and the corresponding 95% CI for overall survival (OS), disease-free survival (DFS), and BC-specific survival (BCSS). If available, HRs with their 95% CIs data were provided by the authors. If not, we calculated the HRs and CIs from the Kaplan-Meier survival curves using the HR digitizer software Engauge 4.1 (NY, USA) as described previously.  The literature search, study selection, and data abstraction were performed independently by two reviewers, and disagreements between the reviewers were solved by discussion.
HRs with their 95% CIs were calculated on the basis of the association between Skp2 expression and the OS and DFS of BC patients. The χ2 test and the I2 statistic were used to evaluate the heterogeneity among studies. If the heterogeneity was significant between studies (I2 > 50% or P < 0.05), the random effects model was used; otherwise, the fixed effects model was used.  Sensitivity analysis was also conducted by sequential omission of individual studies to evaluate the stability of the results. Publication bias was estimated by Begg's linear regression test with a funnel plot.  The statistical analysis was performed using STATA Version 12.0 software (Stata Corporation, Collage Station, TX, USA).
| » Results|| |
The literature selection process is shown in [Figure 1]. Finally, we identified nine eligible studies ,,,,,,,, based on the inclusion criteria.
[Table 1] summarizes the main characteristics of the included studies. All studies included a high-Skp2 expression arm and a low-Skp2 expression arm, whereas the cut-off values considered in the studies were inconsistent due to variations in the detection methods or discrepancies in the cut-off definitions. A total of eleven HRs were analyzed. There were four studies ,,, that assessed OS, six that ,,,,, assessed DFS, and one  that assessed BCSS in the meta-analysis. HRs with 95% CIs were reported directly in five studies, ,,,,, and extrapolated from Kaplan-Meier curves in three studies. ,,,
The main results of this meta-analysis are listed in [Table 2]. Our analysis suggested that Skp2 overexpression was associated with poor OS in BC patients (HR = 2.58, 95% CI: 1.83-3.63, P = 0.000) with heterogeneity (I2 = 0.0%, P = 0.667) [Figure 2]a. When stratifying by HR estimate, significant relevance was observed both in "reported directly from articles" subgroup (HR = 2.38, 95% CI: 1.57-3.60, P = 0.000) and "survival curves" subgroup (HR = 3.05, 95% CI: 1.66-5.60, P = 0.000) [Figure 3]a. Six studies comprising 1248 patients reported HRs for DFS and showed that Skp2 expression exceeding the cut-off value was more likely to be associated with an obviously shorter DFS (HR = 2.12, 95% CI: 1.48-3.05, P = 0.000) with heterogeneity (I2 = 60.5%, P = 0.027) [Figure 2]b. When stratifying by HR estimate, significant relevance was observed both in "reported directly from articles" subgroup (HR = 2.08, 95% CI: 1.25-3.46, P = 0.005) and "survival curves" subgroup (HR = 2.34, 95% CI: 1.58-3.48, P = 0.000) [Figure 3]b. To further explore the source of the heterogeneity, a meta-regression was performed using HRs from univariate/multivariate analyses to analyze the heterogeneity [Table 2]. However, none of the examined factors accounted for the inter-study heterogeneity in the meta-regression.
|Figure 2: (a) Forest plots for the relationship between lysine-specific demethylase 1 (LSD1) expression and overall survival. (b) Forest plots for the relationship between LSD1 expression and disease-free survival|
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|Figure 3: (a) Subgroup analysis of hazard ratios of overall survival by factor of hazard ratio estimate. (b) Subgroup analysis of hazard ratios of disease-free survival by factor of hazard ratio estimate|
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|Table 2: Results of subgroup analysis of the independent role of S-phase kinase-associated protein 2 in overall survival/disease-free survival |
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Sensitivity analysis and publication bias
We used sensitivity analysis to test whether the inclusion criteria of the meta-analysis affected the final results, and further confirmed whether the entire study was not significantly affected by any single study. Sensitivity analysis indicated that the pooled HRs were not significantly influenced by omitting any single study [Figure 4]. The association between Skp2 and DFS remained stable after the exclusion of the Ravaioli et al.  from the sensitivity analysis [Table 3]. [Table 3] summarizes the sensitivity analysis outcome. Because only seven studies were included, publication bias was not assessed. The shape of the funnel plot did not reveal any evidence of obvious asymmetry [Figure 5].
|Figure 4: Sensitivity analysis of the effect of individual studies on the pooled hazard ratios for increased s-phase kinase-associated protein 2, expression and overall survival (left) and disease-free survival (right) of patients|
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|Figure 5: Funnel plot of publication bias on the relationship between s-phase kinase-associated protein 2 expression and overall survival (left) and disease-free survival (right)|
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| » Discussion|| |
BC is the most common type of cancer and remains the second leading cause of cancer-related death for female in the United States.  It has been known that several signaling pathways and various factors play critical roles in the development and progression of BC, such as ER, Notch, PTEN, human epidermal growth factor receptor 2, PI3K/Akt, BRCA1, and BRCA2. ,, Emerging evidence has shown that the F-box protein Skp2 also plays an important role in the pathogenesis of BC. Therefore, in this meta-analysis, we summarize the novel functions of Skp2 in the pathogenesis of BC.
Skp2 is the specific factor of the SCFSkp2 E3 ligase involved in cell cycle progression through the degradation of its targets. For example, Skp2 is essential for p27 degradation and thereby limiting cells in G1 phase, prior to entry into S-phase.  Till date, in addition to p27, specific substrates of Skp2 have also been identified which include p57, p21, p130, and many others. ,, These substrates are involved in many cellular processes such as cell cycle regulation, proliferation, differentiation, apoptosis, and survival. Without a doubt, Skp2 has important functions in the regulation of these cellular processes due to the degradation of its substrates, most of which are tumor suppressor proteins. Because Skp2 is responsible for the degradation of the abovementioned tumor suppressor proteins, Skp2 is thought to function as oncoprotein.
To the best of our knowledge, this is the first meta-analysis focused on the association between Skp2 expression and BC patients' survival. The present study pooled the survival data of 1820 cancer patients from nine studies and found that Skp2 overexpression was associated with poor OS (HR = 2.58, 95% CI: 1.83-3.63) and poor DFS (HR = 2.12, 95% CI: 1.48-3.05) in BC patients. Except for BC, Skp2 overexpression was also a sign of poor prognosis in nonsmall cell lung cancer, ovarian cancer, melanoma and prostate cancer. ,,,,, For example, overexpression of Skp2 is associated with late metastases to lymph nodes leading to poor survival in colorectal cancer. 
Our meta-analysis also has several limitations that should be acknowledged. First, the number of prognostic studies was relatively small, which might weaken the reliability of our results. Second, we extracted data from survival curves because not all survival data of the enrolled studies were presented directly. These calculated HRs with their 95% CIs might be less reliable than the directly given data. Third, although the method for detecting Skp2 level in most included studies was immunohistochemistry, it was difficult to follow entirely consistent monitoring standards for the dyeing process, antibody concentration, and cut-off value of different tissues. Finally, there were insufficient data to fully confirm the association between Skp2 and its prognostic value in BCSS, and the result should be interpreted with caution.
| » Conclusions|| |
In summary, our meta-analysis provides evidence of an association between positive/high Skp2 and BC patients' survival. These results suggested that Skp2 might be a novel biomarker to predict the prognosis of BC and could be a potential direction for developing diagnostic and therapeutic approaches in BC. However, more comprehensive studies and larger samples are necessary to confirm this association.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]