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

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Abstract

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). 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. 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). 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
JournalRadiotherapy and Oncology
Volume101
Issue number1
DOIs
Publication statusPublished - 2011

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