title: Overabundant FANCD2, alone and combined with NQO1, is a sensitive marker of adverse prognosis in breast cancer.
abstract: BACKGROUND
  Defective DNA repair is central to the progression and treatment of breast cancer. Immunohistochemically detected DNA repair markers may be good candidates for novel prognostic and predictive factors that could guide the selection of individualized treatment strategies.
  
  
  METHODS
  We have analyzed nuclear immunohistochemical staining of BRCA1, FANCD2, RAD51, XPF, and PAR in relation to clinicopathological and survival data among 1240 paraffin-embedded breast tumors, and additional gene expression microarray data from 76 tumors. The antioxidant enzyme NQO1 was analyzed as a potential modifier of prognostic DNA repair markers.
  
  
  RESULTS
  RAD51 [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.94, P = 0.0050] and FANCD2 expression (HR 1.50, 95% CI 1.28-1.76, P = 1.50 × 10(-7)) were associated with breast cancer survival. High FANCD2 expression correlated with markers of adverse prognosis but remained independently prognostic in multivariate analysis (HR 1.27, 95% CI 1.08-1.49, P = 0.0043). The FANCD2-associated survival effect was most pronounced in hormone receptor positive, HER2-negative tumors, and in tumors with above-median NQO1 expression. In the NQO1-high subset, patients belonging to the highest quartile of FANCD2 immunohistochemical scores had a threefold increased risk of metastasis or death (HR 3.10, 95% CI 1.96-4.92). Global gene expression analysis indicated that FANCD protein overabundance is associated with the upregulation of proliferation-related genes and a downregulated nucleotide excision repair pathway.
  
  
  CONCLUSIONS
  FANCD2 immunohistochemistry is a sensitive, independent prognostic factor in breast cancer, particularly when standard markers indicate relatively favorable prognosis. Taken together, our results suggest that the prognostic effect is linked to proliferation, DNA damage, and oxidative stress; simultaneous detection of FANCD2 and NQO1 provides additional prognostic value.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Fagerholm
authors.forename: K
authors.initials: K
authors.lastname: Sprott
authors.forename: T
authors.initials: T
authors.lastname: Heikkinen
authors.forename: J
authors.initials: J
authors.lastname: Bartkova
authors.forename: P
authors.initials: P
authors.lastname: Heikkilä
authors.forename: K
authors.initials: K
authors.lastname: Aittomäki
authors.forename: J
authors.initials: J
authors.lastname: Bartek
authors.forename: D
authors.initials: D
authors.lastname: Weaver
authors.forename: C
authors.initials: C
authors.lastname: Blomqvist
authors.forename: H
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D052236:Fanconi Anemia Complementation Group D2 Protein; D016660:NAD(P)H Dehydrogenase (Quinone); D018719:Erb-b2 Receptor Tyrosine Kinases; C499905:FANCD2 protein, human; C447479:NQO1 protein, human; C508053:ERBB2 protein, human
keywords: DNA repair; FANCD2; NQO1; breast cancer; prognosis