title: Human homologue for Caenorhabditis elegans CUL-4 protein overexpression is associated with malignant potential of epithelial ovarian tumours and poor outcome in carcinoma.
abstract: BACKGROUND
  CUL-4 plays a critical role in DNA replication in Caenorhabditis elegans, and interacts with p53 and p21 proteins in cell cycle regulation and response to genomic instability. However, the role of CUL-4 in human carcinomas is widely unknown.
  
  
  OBJECTIVE
  To investigate the expression of CUL-4 protein and its association with p53 and p21, and to determine its prognostic relevance in invasive ovarian carcinoma.
  
  
  METHODS
  CUL-4, p53 and p21 protein expression was determined retrospectively by immunohistochemistry in 140 specimens of human epithelial ovarian tumours (98 invasive carcinomas and 42 tumours of low malignant potential; LMP).
  
  
  RESULTS
  Overexpression of CUL-4 was observed in 41 (41.8%) of carcinoma samples and in 10 (23.8%) LMP tumours. CUL-4 was significantly more often overexpressed in invasive carcinomas compared with LMP tumours (p=0.042, χ(2) test, OR 2.302, 95% CI 1.018 to 5.203). In invasive carcinoma, CUL-4 overexpression was found to be a prognostic factor for overall (p=0.017, Cox regression, HR 2.387, 95% CI 1.17 to 4.869) and disease-free survival (p=0.005, Cox regression, HR 3.5, 95% CI 1.465 to 8.365), respectively. In subgroup analysis, CUL-4 was only of prognostic relevance in carcinomas without p53 expression.
  
  
  CONCLUSIONS
  These data indicate for the first time that CUL-4 might play a relevant role in the development and progression of ovarian carcinoma, warranting further investigations. Degradation of wild-type p53 might be a key mechanism to explain why CUL-4 leads to more aggressive clinical behaviour. Not only CUL-4 itself, but also its associated proteins might represent targets for novel, selective therapeutic strategies.
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schoppmann
authors.forename: Monika
authors.initials: M
authors.lastname: Schindl
authors.forename: Carina
authors.initials: C
authors.lastname: Dinhof
authors.forename: Bettina
authors.initials: B
authors.lastname: Jesch
authors.forename: Anna Sophie
authors.initials: AS
authors.lastname: Berghoff
authors.forename: Sebastian F
authors.initials: SF
authors.lastname: Schoppmann
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D000818:Animals; D001317:Austria / Q000453:epidemiology; D014408:Biomarkers, Tumor / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D003131:Combined Modality Therapy; D044842:Cullin Proteins / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D049670:History, 17th Century; D006801:Humans; D007150:Immunohistochemistry; D008025:Ligases / Q000378:metabolism*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000401:mortality; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C114234:CUL4A protein, human; D029742:Caenorhabditis elegans Proteins; C475682:Cul-4 protein, C elegans; D044842:Cullin Proteins; D008025:Ligases