Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate

Diane C. Cabelof, Yuji Ikeno, Abraham Nyska, Rita A. Busuttil, Njwen Anyangwe, Jan Vijg, Larry H. Matherly, James D. Tucker, Samuel H. Wilson, Arlan Richardson, Ahmad R. Heydari

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53 Scopus citations

Abstract

This study uses a base excision repair (BER)-deficient model, the DNA polymerase β heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged β-pol+/- mice express 50% less β-pol transcripts and protein (P < 0.05) than aged β-pol+/+ mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in β-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged β-pol+/- mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of β-pol+/- mice exhibited lymphoid hyperplasia, whereas none of the β-pol+/+ exhibited this phenotype. β-pol +/- mice were also more likely to develop adenocarcinoma (2.7-fold increase; P < 0.05) and more likely to develop multiple tumors, as 20% of the β-pol+/- animals died bearing multiple tumors compared with only 5% of the β-pol+/+ animals (P < 0.05). In spite of accelerated tumor development, no gross effect of β-pol heterozygosity was seen with respect to life span. However, the survival curves for the β-pol+/+ and β-pol+/- mice are not identical. A maximum likelihood estimation analysis showed a modest but significant (P < 0.05) acceleration of the age-dependent mortality rate in β-pol +/- mice. Thus, the β-pol+/- mouse represents a model in which mortality rate and tumor development are accelerated and provides evidence supporting the role of genomic maintenance in both aging and carcinogenesis.

Original languageEnglish (US)
Pages (from-to)7460-7465
Number of pages6
JournalCancer Research
Volume66
Issue number15
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Cabelof, D. C., Ikeno, Y., Nyska, A., Busuttil, R. A., Anyangwe, N., Vijg, J., Matherly, L. H., Tucker, J. D., Wilson, S. H., Richardson, A., & Heydari, A. R. (2006). Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate. Cancer Research, 66(15), 7460-7465. https://doi.org/10.1158/0008-5472.CAN-06-1177