Overexpression of the Human Homologue for Caenorhabditis elegans cul-4 gene is Associated with Poor Outcome in Node-negative Breast Cancer

Abstract

Background: Cul-4, a member of the Caenorhabditis elegans “cullin” ubiquitin-ligase gene family, plays a critical role in regulation of DNA-replication in this nematode. It has been suggested that cul-4 might have an important role in the development and progression of human cancer, but no data on this subject exist. The aim of this study was to investigate the expression and prognostic relevance of CUL-4 protein in lymph node-negative breast cancer, one of the most common malignancies worldwide. Materials and Methods: CUL-4 protein expression was determined with immunohistochemistry in 167 specimens of human node-negative invasive breast cancer with long term follow-up. Results were correlated with overall and disease-free survival of patients. Results: Strong expression of CUL-4 protein was observed in 32 cases (19.2%), moderate expression in 59 (35.3%), weak expression in 64 (38.3%), and in 12 tumors (7.2%) no expression of CUL4 was observed. Patients with strong expression of CUL4 had a significantly shorter overall and disease-free survival (p=0.04 and p=0.029, respectively; Cox regression) compared to all other cases. Conclusion: Our data provide evidence for the first time that CUL-4 could play an important role in the development and progression of human cancer.