Constitutive expression of γ-H2AX has prognostic relevance in triple negative breast cancer

Anika Nagelkerke, Simon J A van Kuijk, Fred C G J Sweep, Iris D Nagtegaal, Nicoline Hoogerbrugge, John W M Martens, Mieke A Timmermans, Hanneke W M van Laarhoven, Johan Bussink, Paul N Span*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

56 Citations (Scopus)
3 Downloads (Pure)

Abstract

BACKGROUND AND PURPOSE: 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).

MATERIALS AND 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.

Original languageEnglish
Pages (from-to)39-45
Number of pages7
JournalRadiotherapy and Oncology
Volume101
Issue number1
DOIs
Publication statusPublished - 2011
Externally publishedYes

Keywords

  • Adult
  • Aged
  • Biomarkers, Tumor/metabolism
  • Biopsy, Needle
  • Breast Neoplasms/metabolism
  • Cohort Studies
  • DNA Damage/genetics
  • DNA Repair/genetics
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Histones/metabolism
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Middle Aged
  • Predictive Value of Tests
  • Prognosis
  • Receptor, ErbB-2/metabolism
  • Receptors, Progesterone/metabolism
  • Survival Analysis
  • Tissue Embedding
  • Tumor Suppressor p53-Binding Protein 1

Cite this