¹McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, WI, USA

Correspondence: WF Dove, McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, WI 53706, USA. E-mail: dove@oncology.wisc.edu

²Current address: Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Received 11 May 2007; Revised 19 June 2007; Accepted 3 July 2007; Published online 13 August 2007.

Abstract

The ataxia telangiectasia-mutated (ATM) gene has been implicated as an early barrier to the growth and progression of incipient solid tumors. Here, we show that germ-line nullizygosity for the mouse Atm gene significantly increases the proliferative index, net growth rate and multiplicity of intestinal adenomas in two distinct models of familial colon cancer: Apc^Min/+ and Apc^1638N/+. These effects of Atm deficiency are quantitatively different from deficiency for either of the genomic stability genes Bloom's syndrome helicase or DNA ligase 4, and the effect of Atm loss on tumor multiplicity is largely independent of the effect of ionizing radiation. Furthermore, the loss of heterozygosity rates at the adenomatous polyposis coli (Apc) locus are unaffected by Atm loss. Taken together, these data implicate the Atm gene product as a barrier to dysplastic growth in the early stages of intestinal tumor progression, independent of its effects on genomic stability.