title: Constitutive expression of γ-H2AX has prognostic relevance in triple negative breast cancer.
abstract: OBJECTIVE
  Constitutive γ-H2AX expression might indicate disruption of the DNA damage repair pathway, genomic instability, or shortened telomeric ends. Here, we quantified expression of endogenous γ-H2AX and its downstream factor 53BP1 in a large number of breast cancer cell lines (n=54) and a node-negative breast cancer cohort that had not received adjuvant systemic treatment (n=122).
  
  
  METHODS
  Formalin fixed paraffin embedded breast cancer cell lines and tumors were immunohistochemically analyzed for γ-H2AX and 53BP1 expression, and related to cell line, patient and tumor characteristics and to disease progression.
  
  
  RESULTS
  In breast cancer cell lines, γ-H2AX positivity was associated with the triple negative/basal like subgroup (p=0.005), and with BRCA1 (p=0.011) or p53 (p=0.053) mutations. Specifically in triple negative breast cancer patients a high number of γ-H2AX foci indicated a significantly worse prognosis (p=0.006 for triple negative vs. p=0.417 for estrogen receptor (ER), progesterone receptor (PR) or HER2 positive patients). A similar association with disease progression was found for 53BP1. In a multivariate analysis with tumor size, grade, and triple negativity, only the interaction between triple negativity and γ-H2AX remained significant (p=0.002, Hazard Ratio=6.77, 95% CI=2.07-22.2).
  
  
  CONCLUSIONS
  Constitutive γ-H2AX and 53BP1 staining reveals a subset of patients with triple negative breast tumors that have a significantly poorer prognosis.
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anika
authors.initials: A
authors.lastname: Nagelkerke
authors.forename: Simon J A
authors.initials: SJ
authors.lastname: van Kuijk
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.forename: Mieke A
authors.initials: MA
authors.lastname: Timmermans
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001707:Biopsy, Needle; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D016019:Survival Analysis; D016610:Tissue Embedding; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D000071857:Tumor Suppressor p53-Binding Protein 1; C468783:H2AX protein, human; C498301:TP53BP1 protein, human