title: Enhanced RAD21 cohesin expression confers poor prognosis in BRCA2 and BRCAX, but not BRCA1 familial breast cancers.
abstract: BACKGROUND
  The RAD21 gene encodes a key component of the cohesin complex, which is essential for chromosome segregation, and together with BRCA1 and BRCA2, for high-fidelity DNA repair by homologous recombination. Although its expression correlates with early relapse and treatment resistance in sporadic breast cancers, it is unclear whether familial breast cancers behave in a similar manner.
  
  
  METHODS
  We performed an immunohistochemical analysis of RAD21 expression in a cohort of 94 familial breast cancers (28 BRCA1, 27 BRCA2, and 39 BRCAX) and correlated these data with genotype and clinicopathologic parameters, including survival. In these cancers, we also correlated RAD21 expression with genomic expression profiling and gene copy-number changes and miRNAs predicted to target RAD21.
  
  
  RESULTS
  No significant differences in nuclear RAD21 expression were observed between BRCA1 (12 (43%) of 28), BRCA2 (12 (44%) of 27), and BRCAX cancers (12 (33%) of 39 (p = 0.598). No correlation was found between RAD21 expression and grade, size, or lymph node, ER, or HER2 status (all P > 0.05). As for sporadic breast cancers, RAD21 expression correlated with shorter survival in grade 3 (P = 0.009) and but not in grade 1 (P = 0.065) or 2 cancers (P = 0.090). Expression of RAD21 correlated with poorer survival in patients treated with chemotherapy (P = 0.036) but not with hormonal therapy (P = 0.881). RAD21 expression correlated with shorter survival in BRCA2 (P = 0.006) and BRCAX (P = 0.008), but not BRCA1 cancers (P = 0.713). Changes in RAD21 mRNA were reflected by genomic changes in DNA copy number (P < 0.001) and by RAD21 protein expression, as assessed with immunohistochemistry (P = 0.047). High RAD21 expression was associated with genomic instability, as assessed by the total number of base pairs affected by genomic change (P = 0.048). Of 15 miRNAs predicted to target RAD21, mir-299-5p inversely correlated with RAD21 expression (P = 0.002).
  
  
  CONCLUSIONS
  Potential use of RAD21 as a predictive and prognostic marker in familial breast cancers is hence feasible and may therefore take into account the patient's BRCA1/2 mutation status.
authors.affiliation: Department of Anatomical Pathology, Prince of Wales Hospital, Barker Street, Randwick, 2031, Australia.
authors.forename: Max
authors.initials: M
authors.lastname: Yan
authors.forename: Huiling
authors.initials: H
authors.lastname: Xu
authors.forename: Nic
authors.initials: N
authors.lastname: Waddell
authors.forename: Kristy
authors.initials: K
authors.lastname: Shield-Artin
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McKay
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006579:Heterozygote; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C553452:MIRN299 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D010750:Phosphoproteins; C429022:RAD21 protein, human