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Haploinsufficiency in DNA Polymerase ß Increases Cancer Risk with Age and Alters Mortality Rate

¹ Karmanos Cancer Institute, Developmental Therapeutics Program and ² Department of Pharmacology, Wayne State University School of Medicine; Departments of ³ Nutrition and Food Science and ⁴ Biological Sciences, Wayne State University, Detroit, Michigan; ⁵ Department of Physiology, University of Texas Health Science Center; ⁶ Geriatric Research, Education and Clinical Center, Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas; and ⁷ Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

Requests for reprints: Diane C. Cabelof, Karmanos Cancer Institute, Wayne State University, 110 East Warren, Detroit, MI 48201. Phone: 313-833-0715, ext. 2416; Fax: 313-577-8616; E-mail: d.cabelof{at}wayne.edu.

This study uses a base excision repair (BER)–deficient model, the DNA polymerase ß heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged ß-pol^+/– mice express 50% less ß-pol transcripts and protein (P < 0.05) than aged ß-pol^+/+ mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in ß-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged ß-pol^+/– mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of ß-pol^+/– mice exhibited lymphoid hyperplasia, whereas none of the ß-pol^+/+ exhibited this phenotype. ß-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 ß-pol^+/– animals died bearing multiple tumors compared with only 5% of the ß-pol^+/+ animals (P < 0.05). In spite of accelerated tumor development, no gross effect of ß-pol heterozygosity was seen with respect to life span. However, the survival curves for the ß-pol^+/+ and ß-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 ß-pol^+/– mice. Thus, the ß-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. (Cancer Res 2006; 66(15): 7460-5)

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