title: Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesis.
abstract: Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disease characterized by microcephaly, growth retardation, immunodeficiency, chromosomal instability, and predisposition to cancer. Heterozygous NBS patients show increased chromosomal instability and are suspected to be at a high risk for cancer. To study the impact of NBS1 heterozygosity on malignancy susceptibility, we disrupted the murine homologue (Nbn) of NBS1 in mice using gene targeting techniques. While null mutation in the Nbn gene resulted in embryonic lethality at the blastocyst stage because of growth retardation and increased apoptosis, heterozygous knockout (Nbn(+/-)) mice developed a wide array of tumors affecting the liver, mammary gland, prostate, and lung, in addition to lymphomas. Moreover, gamma-irradiation enhanced tumor development in Nbn(+/-) mice, giving rise to a high frequency of epithelial tumors, mostly in the thyroid and lung, as well as lymphomas. These mice also developed numerous tumors in the ovary and testis. Southern and Western blot analyses showed a remaining wild-type allele and nibrin expression in Nbn(+/-) tumors. Sequencing analysis confirmed no mutation in the Nbn cDNA derived from these tumors. Cytogenetic analysis revealed that primary Nbn(+/-) embryonic fibroblasts and tumor cells exhibit increased chromosomal aberrations. These data suggest that haploinsufficiency, not loss of heterozygosity, of Nbn could be the mechanism underlying the tumor development. Taken together, our heterozygous Nbn-knockout mice represent a novel model to study the consequences of NBS1 heterozygosity on tumor development.
authors: International Agency for Research on Cancer, 150 cours Albert Thomas, 69008 Lyon, France.
authors: Valérie
authors: V
authors: Dumon-Jones
authors: Pierre-Olivier
authors: PO
authors: Frappart
authors: Wei-Min
authors: WM
authors: Tong
authors: Giangadharan
authors: G
authors: Sajithlal
authors: Wolfgang
authors: W
authors: Hulla
authors: Gerald
authors: G
authors: Schmid
authors: Zdenko
authors: Z
authors: Herceg
authors: Martin
authors: M
authors: Digweed
authors: Zhao-Qi
authors: ZQ
authors: Wang
mesh_terms: D000818:Animals; D001757:Blastomeres / Q000166:cytology / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011247:Pregnancy
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins