Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation

Connor, Frances; Bertwistle, David; Mee, P. Joseph; Ross, Gillian; Swift, Sally; Grigorieva, Elvira V.; Tybulewicz, Victor L. J.; Ashworth, Alan

doi:10.1038/ng1297-423

Cited by 395 publications

(296 citation statements)

References 46 publications

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“…Notably, osteosarcoma development in both male and female Brca2 À/À rats occurred at a frequency of 20%, a site not common in the limited surviving mice having terminal deletions of exon 11 (Connor et al, 1997;Friedman et al, 1998). Homozygous deletion of exon 27 in mice resulted in the development of various epithelial carcinomas, lymphomas and sarcomas however, no osteosarcomas and only one ovarian tumor were reported (McAllister et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Homozygous mice with severe truncations of the Brca2 protein before exon 11 or resulting in the deletion of this exon are embryonic lethal (reviewed by Moynahan, 2002). Homozygous Brca2 knockout mice with some of the BRC repeats in exon 11 left intact are infertile, have a limited life span and develop thymic lymphoma (Connor et al, 1997;Friedman et al, 1998). In contrast, truncation of a small region of the carboxyl end of Brca2 results in fertile animals with no gross abnormalities that are predisposed to cancer (McAllister et al, 2002), although there is B30% reduced viability than expected for homozygous mice.…”

Section: Introductionmentioning

confidence: 99%

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Characterizing a rat Brca2 knockout model

et al. 2006

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Evidence exists that BRCA2 carriers may have an elevated risk of breast, ovarian, colon, prostate, and pancreatic cancer. In general, carriers are defined as individuals with protein truncating mutations within the BRCA2 gene. Many Brca2 knockout lines have been produced and characterized in the mouse. We previously produced a rat Brca2 knockout strain in which there is a nonsense mutation in exon 11 between BRC repeats 2 and 3, and a truncated protein is produced. Interestingly, while such a mutation in homozygous mice would lead to limited survival of approximately 3 months, the Brca2 À/À rats are 100% viable and the vast majority live to over 1 year of age. Brca2 À/À rats show a phenotype of growth inhibition and sterility in both sexes. Aspermatogenesis in the Brca2 À/À rats is due to a failure of homologous chromosome synapsis. Long-term phenotypes include underdeveloped mammary glands, cataract formation and lifespan shortening due to the development of tumors and cancers in multiple organs. The establishment of the rat Brca2 knockout model provides a means to study the role of Brca2 in increasing cancer susceptibility and inducing a novel ocular phenotype not previously associated with this gene.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterizing a rat Brca2 knockout model

et al. 2006

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“…Germline mutations in the breast-cancer susceptibility gene BRCA2 confer susceptibility to familial early-onset breast and ovarian cancers (Wooster et al, 1994(Wooster et al, , 1995Tavtigian et al, 1996;Brody and Biesecker, 1998;Rahman and Stratton, 1998). Extensive studies have indicated that BRCA2 has an important function in DNA repair (Connor et al, 1997;Mizuta et al, 1997;Sharan et al, 1997;Wong et al, 1997;Chen et al, 1998;Patel et al, 1998). Recent reports indicate that BRCA2 acts in the homology-directed recombinational repair of double-strand DNA breaks (Davies et al, 2001;Moynahan et al, 2001;Xia et al, 2001;Kraakman-van der Zwet et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

DSS1 is required for the stability of BRCA2

et al. 2005

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DSS1 is an evolutionarily conserved acidic protein that binds to BRCA2. However, study of the function of DSS1 in mammalian cells has been hampered because endogenous DSS1 has not been detectable by Western blotting. Here, we developed a modified Western blotting protocol that detects endogenous DSS1 protein, and used it to study the function of DSS1 and its interaction with BRCA2 in mammalian cells. We found that essentially all BRCA2 in human cell lines is associated with DSS1. Importantly, we found that RNAi knockdown of DSS1 in human cell lines led to dramatic loss of BRCA2 protein, mainly due to its increased degradation. Furthermore, the stability of BRCA2 mutant devoid of the DSS1-binding domain is unaffected by the depletion of DSS1. Most notably, like BRCA2 depletion, DSS1 depletion also led to hypersensitivity to DNA damage. These results demonstrated that the stability of BRCA2 protein in mammalian cells depends on the presence of DSS1. Deletion or mutation of DSS1 or suppression of its expression by other mechanisms are therefore potential causative mechanisms for human breast and ovarian cancer. Such mechanisms may be relevant to sporadic as well as familiar breast cancer where BRCA1 and BRCA2 mutations are not present.

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“…Tumorigenesis in carriers of germ-line mutations in BRCA1 and BRCA2 is invariably accompanied by loss of the wild-type allele (Smith et al, 1992;Neuhausen and Marshall, 1994;Collins et al, 1995;Gudmundsson et al, 1995;Kelsell et al, 1996) suggesting that the proteins encoded by the two genes operate as tumour suppressors. An increasing-body of evidence favours a role for both BRCA1 and BRCA2 in cellular response to DNA damage (Connor et al, 1997;Scully et al, 1997;Patel et al, 1998). It is postulated that the BRCA genes act as caretakers, functioning to maintain genomic stability, rather than as gatekeepers which regulate cellular proliferation (Brugarolas and Jacks, 1997;Kinzler and Vogelstein, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…The molecular basis for this is not known. Analysis of ®broblasts derived from mice homozygous for a truncating mutation in BRCA2 has revealed a proliferation defect associated with p53-dependent induction of p21 Waf1 expression, and a DNA repair defect (Connor et al, 1997). In another study, mouse embryo ®broblasts carrying BRCA2 truncations, were shown to be signi®cantly more sensitive to UV irradiation and the alkylating agent methylmethanesulphonate than wild-type controls, leading to the suggestion that BRCA2 may be associated with a nucleotide excision repair pathway (Patel et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

et al. 1998

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The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P50.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16 INK4 , Ki-ras and b-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not re¯ect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF b type II receptor (TGF b IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21 Waf1 was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21 Waf1 . These data do not support, therefore, the simple model based on studies of BRCA7/7 embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21 Waf1 expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.

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Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation

Cited by 395 publications

References 46 publications

Characterizing a rat Brca2 knockout model

Characterizing a rat Brca2 knockout model

DSS1 is required for the stability of BRCA2

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

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