title: Haploinsufficiency of the Nijmegen breakage syndrome 1 gene increases             mammary tumor latency and metastasis.
abstract: Human diseases such as Nijmegen breakage syndrome due to mutations in the             NBS1 gene result in defects in resection of double strand breaks. NBS1 functions             as part of the MRN complex which functions in homologous recombination and non-homologous             end joining. NBS is a rare human autosomal recessive disorder caused by hypomorphic             mutations. At the cellular level, NBS is characterized by radiosensitivity, chromosomal             breakage and defective cell cycle checkpoints. NBS1 null mutations result in early             embryonic lethality in mice, but NBS1 hypomorphic mutants are viable. Cells from             these mice are defective in S phase and G2/M checkpoints. In humans, NBS1 polymorphisms             have been associated with increased risk of breast cancer. MRN expression was             reduced in the majority of breast tumors, and low expression of MRN correlated             with increased histologic grade and estrogen receptor negativity. While these             studies have shown NBS1 to be important in clinical outcomes of patients with             breast cancer, mammary tumors are rare in the NBS1 haploinsufficient mouse. To             better understand the role of NBS1 in mammary tumorigenesis, we examined the NBS1+/-;MMTV-neu             mouse model. Mammary tumor latency was markedly increased in NBS1+/-;neu mice             compared to NBS1+/+;neu control animals. This effect was due to increased apoptosis             in early NBS1+/-;neu mammary tumors. However, NBS1+/-;neu mammary tumors were             highly metastatic and demonstrated clear differences in gene expression profiles             compared to control tumors. We concluded that NBS1 haploinsufficiency results             in increased mammary tumor latency and metastasis.
authors.affiliation: University of Illinois Cancer Center, Chicago, IL 60612, USA.
authors.forename: Rowena
authors.initials: R
authors.lastname: Wan
authors.forename: David L
authors.initials: DL
authors.lastname: Crowe
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D057895:Haploinsufficiency; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics*; D013997:Time Factors
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins