The Prognostic Value of 14-3-3 Isoforms in Vulvar Squamous Cell Carcinoma Cases: 14-3-3β and ε Are Independent Prognostic Factors for These Tumors

Background: The 14-3-3 family is comprised of highly conserved proteins that are functionally important in the maintenance of homeostasis. Their involvement with the cell cycle, their association with proto-oncogenes and oncogenes, and their abnormal expression in various tumors has linked this family of proteins to the etiology of human cancer. Mounting evidence now indicates that 14-3-3 sigma is a cancer suppressor gene but the roles of the other 14-3-3 isoforms and their interactions in tumorigenesis have not yet been elucidated. In our current study, we examined the expression of 14-3-3 beta, gamma, epsilon, zeta, eta and tau in a large series of vulvar squamous cell carcinomas to evaluate any clinical significance. Methods: Tumor biopsies from 298 vulvar carcinomas were examined by immunohistochemistry for the expression of 14-3-3 beta, gamma, epsilon, zeta, eta and tau. Statistical analyses were employed to validate any associations between the expression of any 14-3-3 isoform and clinicopathologic variables for this disease. Results: High cytoplasmic levels of 14-3-3 beta, gamma, zeta, epsilon and eta were observed in 79%, 58%, 50%, 86% and 54% of the vulvar carcinomas analyzed, respectively, whereas a low nuclear expression of 14-3-3 tau was present in 80% of these cases. The elevated cytoplasmic expression of 14-3-3 beta, gamma, epsilon, zeta and eta was further found to be associated with advanced disease and aggressive features of these cancers. The overexpression of cytoplasmic 14-3-3 beta and epsilon significantly correlated with a poor disease-specific survival by univariate analysis (P = 0.007 and P = 0.04, respectively). The independent prognostic significance of these factors was confirmed by multivariate analysis (P = 0.007 and P = 0.009, respectively). Conclusions: We reveal for the first time that the 14-3-3 beta, gamma, epsilon, zeta, eta and tau isoforms may be involved in the progression of vulvar carcinomas. Furthermore, our analyses show that high cytoplasmic levels of 14-3-3 beta and epsilon independently correlate with poor disease-specific survival.