Abstract
<div>Abstract<p>Although disruption of DNA repair capacity is unquestionably associated with cancer susceptibility in humans and model organisms, it remains unclear if the inherent tumor phenotypes of DNA repair deficiency syndromes can be regulated by manipulating DNA repair pathways. Loss-of-function mutations in <i>BLM</i>, a member of the <i>RecQ</i> helicase family, cause Bloom's syndrome (BS), a rare, recessive genetic disorder that predisposes to many types of cancer. BLM functions in many aspects of DNA homeostasis, including the suppression of homologous recombination (HR) in somatic cells. We investigated whether BLM overexpression, in contrast with loss-of-function mutations, attenuated the intestinal tumor phenotypes of <i>Apc<sup>Min/+</sup> and Apc<sup>Min/+</sup>;Msh2<sup>−/−</sup></i> mice, animal models of familial adenomatous polyposis coli (FAP). We constructed a transgenic mouse line expressing human BLM (<i>BLM-Tg)</i> and crossed it onto both backgrounds. <i>BLM-Tg</i> decreased adenoma incidence in a dose-dependent manner in our <i>Apc<sup>Min/</sup></i><sup>+</sup> model of FAP, although levels of GIN were unaffected and concomitantly increased animal survival over 50%. It did not reduce intestinal tumorigenesis in <i>Apc<sup>Min/</sup></i><sup>+</sup>;<i>Msh2<sup>−/−</sup></i> mice. We used the pink-eyed unstable (<i>p<sup>un</sup></i>) mouse model to demonstrate that increasing BLM dosage <i>in vivo</i> lowered endogenous levels of HR by 2-fold. Our data suggest that attenuation of the <i>Min</i> phenotype is achieved through a direct effect of <i>BLM-Tg</i> on the HR repair pathway. These findings demonstrate that HR can be manipulated <i>in vivo</i> to modulate tumor formation at the organismal level. Our data suggest that lowering HR frequencies may have positive therapeutic outcomes in the context of specific hereditary cancer predisposition syndromes, exemplified by FAP. <i>Cancer Prev Res; 8(7); 650–6. ©2015 AACR</i>.</p></div>
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