title: Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome.
abstract: BACKGROUND
  Breast cancer is a potentially fatal malignancy in females despite the improvement in therapeutic techniques. The identification of novel molecular signatures is needed for earlier detection, monitoring effects of treatment, and predicting prognosis. We have previously used microarray analysis to identify differentially expressed genes in aggressive breast tumors. The purpose of the present study was to investigate the prognostic value of the candidate biomarkers CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 in breast cancer.
  
  
  METHODS
  The expression levels and subcellular localization of the CCNB2, ASPM, CDCA7, KIAA0101, and SLC27A2 proteins were measured using immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Furthermore, the mRNA levels of CCNB2, KIAA0101, and SLC27A2 were subsequently examined by qRT-PCR to validate IHC results. Patient disease-specific survival (DSS) was evaluated in correlation to protein levels using the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of aberrant protein expression of the candidate biomarkers on patient DSS and to estimate the hazard ratio at 8-year follow-up.
  
  
  RESULTS
  Elevated cytoplasmic CCNB2 protein levels were strongly associated with short-term disease-specific survival of breast cancer patients (≤ 8 years; P<0.001) and with histological tumor type (P= 0.04). However, no association with other clinicopathological parameters was observed. Multivariate Cox regression analysis specified that CCNB2 protein expression is an independent prognostic marker of DSS in breast cancer. The predictive ability of several classical clinicopathological parameters was improved when used in conjunction with CCNB2 protein expression (C-index = 0.795) in comparison with a model without CCNB2 expression (C-index = 0.698). The protein levels of ASPM, CDCA7, KIAA0101, and SLC27A2 did not correlate with any clinicopathological parameter and had no influence on DSS. However, a significant correlation between the expression of the CCNB2 and ASPM proteins was detected (P = 0.03).
  
  
  CONCLUSIONS
  These findings suggest that cytoplasmic CCNB2 may function as an oncogene and could serve as a potential biomarker of unfavorable prognosis over short-term follow-up in breast cancer.
authors.affiliation: Sahlgrenska Cancer Center, Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg SE-41345, Sweden. emman.shubbar@gu.se
authors.forename: Emman
authors.initials: E
authors.lastname: Shubbar
authors.forename: Anikó
authors.initials: A
authors.lastname: Kovács
authors.forename: Shahin
authors.initials: S
authors.lastname: Hajizadeh
authors.forename: Toshima Z
authors.initials: TZ
authors.lastname: Parris
authors.forename: Szilárd
authors.initials: S
authors.lastname: Nemes
authors.forename: Katrin
authors.initials: K
authors.lastname: Gunnarsdóttir
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Einbeigi
authors.forename: Per
authors.initials: P
authors.lastname: Karlsson
authors.forename: Khalil
authors.initials: K
authors.lastname: Helou
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018275:Carcinoma, Lobular / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016009:Chi-Square Distribution; D056765:Cyclin B2 / Q000032:analysis* / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C503758:CCNB2 protein, human; D056765:Cyclin B2