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Skp2 Protein Expression in Soft Tissue Sarcomas

Andre M. Oliveira, Scott H. Okuno, Antonio G. Nascimento, Ricardo V. Lloyd

From the Department of Laboratory Medicine and Pathology and the Department of Oncology, Mayo Clinic, Rochester, MN.

Address reprint requests to Ricardo V. Lloyd, MD, PhD, Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, 200 First St. SW, Rochester, MN 55905; email: lloyd.ricardo{at}mayo.edu.

Background: p45 S phase kinase-associated protein-2 (p45^skp2), a member of the F-box family of proteins, is an important component of the Skp1-Cullin-F-box protein (SCF) ubiquitin-ligase complex (SCF^skp2). The latter has been implicated in the ubiquitination and degradation of p27^kip1 (p27) and G₁-S cell cycle progression. The expression and prognostic role of Skp2 in a large series of soft tissue sarcomas has not been previously investigated.

Methods: Clinicopathologic features and immunohistochemical expression of Skp2, p27, and Ki-67 proteins were studied in 182 cases of soft tissue sarcomas (American Joint Committee on Cancer stages II and III). Survival analyses were performed using the Kaplan-Meier method and the Cox regression model.

Results: The male to female ratio was 1.2:1, and the median age at the diagnosis was 53 years. The tumors were predominantly located in the lower extremities (n = 163; 90%) and had a median size of 9 cm. High Skp2 expression ( 10% of the cells) was identified in 68 tumors (37%), and was correlated with high grade histology (P = .002) and Ki-67 proliferative index (r = 0.44; P < .0001), but not with p27 expression (r = -0.02; P = .80). By univariate analysis, high Skp2 expression was associated with decreased metastasis-free, disease-free, and overall survival. In a multivariate model, high Skp2 expression was an independent predictor for decreased local recurrence-free, disease-free, and overall survival.

Conclusion: These results indicate that Skp2 expression is associated with cell proliferation and a worse prognosis in soft tissue sarcomas. The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors.

Andre M. Oliveira is currently at the Institute of Medical Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

This work was presented at the Sarcoma Scientific Session of the 2002 Annual Meeting of the American Society of Clinical Oncology.

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