title: Genetic Manipulation of Homologous Recombination In Vivo Attenuates Intestinal Tumorigenesis.
abstract: 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 BLM, a member of the RecQ 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 Apc(Min/+) and Apc(Min/+);Msh2(-/-) mice, animal models of familial adenomatous polyposis coli (FAP). We constructed a transgenic mouse line expressing human BLM (BLM-Tg) and crossed it onto both backgrounds. BLM-Tg decreased adenoma incidence in a dose-dependent manner in our Apc(Min/) (+) model of FAP, although levels of GIN were unaffected and concomitantly increased animal survival over 50%. It did not reduce intestinal tumorigenesis in Apc(Min/) (+);Msh2(-/-) mice. We used the pink-eyed unstable (p(un)) mouse model to demonstrate that increasing BLM dosage in vivo lowered endogenous levels of HR by 2-fold. Our data suggest that attenuation of the Min phenotype is achieved through a direct effect of BLM-Tg on the HR repair pathway. These findings demonstrate that HR can be manipulated in vivo 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.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio. joanna.groden@osumc.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McIlhatton
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Kevin
authors.initials: K
authors.lastname: Murnan
authors.affiliation: Clermont College, University of Cincinnati, Batavia, Ohio.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carson
authors.affiliation: Department of Pathology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Boivin
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Joanna
authors.initials: J
authors.lastname: Groden
mesh_terms: D000236:Adenoma / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D001816:Bloom Syndrome / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D018628:Gene Dosage; D005821:Genetic Techniques; D059765:Homologous Recombination; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D053484:RecQ Helicases / Q000235:genetics*
chemical_list: C097151:Bloom syndrome protein; D053484:RecQ Helicases