Disease relevance of Brca2

• Mouse model for Brca2 mutation shows growth retardation and paradoxical occurrence of thymic lymphomas [1].
• These findings define a function of Brca2 in DNA repair, whose loss precipitates replicative failure, mutagen sensitivity, and genetic instability reminiscent of Bloom syndrome and Fanconi anemia [2].
• Brca2 is an important tumor suppressor associated with susceptibility to breast cancer [3].
• Nevertheless, Brca2-deficient mice developed mammary adenocarcinomas after a long latency (average, 1.6 years) [3].
• Our results support a role for Brca2 in repairing spontaneous DNA lesions, and suggest that loss of Brca2 enhances the susceptibility of mouse T-lineage cells to chromosomal aberrations and deregulation of apoptosis in the absence of p53 [4].

High impact information on Brca2

• We show that Brca2 is required for efficient DNA repair, and our results suggest that loss of the p53 checkpoint may be essential for tumour progression triggered by mutations in BRCA2 [5].
• Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation [5].
• Unlike other mutations in the Brca2 gene, which are lethal early in embryogenesis when homozygous, some of our homozygous mutant mice survive to adulthood [5].
• Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 [6].
• The phenotypic overlap between Fancd2-null and Brca2/Fancd1 hypomorphic mice is consistent with a common function for both proteins in the same pathway, regulating genomic stability [7].

Biological context of Brca2

• In Brca1 mutants, the onset of abnormalities is earlier by one day and their phenotypic features and time of death are highly variable, whereas the phenotype of Brca2 null embryos is more uniform, and they all survive for at least 8.5 embryonic days [8].
• Disruption of the homologous mouse genes Brca1 and Brca2 by targeting showed that they both have indispensable roles during embryogenesis, because nullizygous embryos become developmentally retarded and disorganized, and die early in development [8].
• Thus, the mutations of Bub1 and BubR1 found in Brca2- mutant mice indeed are responsible for the chromosome instability in Brca2-mutated tumors [1].
• Impaired phosphorylation and mis-localization of Bub1 and BubR1 are responsible for the defective mitotic checkpoint function in Brca2-mutant thymic lymphomas [1].
• Brca2 is required for embryonic cellular proliferation in the mouse [9].

Anatomical context of Brca2

• Analysis of these animals showed that Brca2 is not required for epithelial expansion in mammary glands of pregnant mice [3].
• To study the role of Brca2 specifically in mammary epithelium development, we crossed mice bearing the conditionally deficient allele Brca2(flox9-10) to mouse mammary tumor virus- or whey acidic protein-Cre transgenic lines [3].
• Here we report the generation of T-cell lineage-specific Brca2-deficient (tBrca2(-/-)) mice using the Cre-loxP system [4].
• In the testes, Brca1 and Brca2 were expressed in mitotic spermatogonia and early meiotic prophase spermatocytes [10].
• Northern analyses of prepubertal mouse testes revealed that the time course of Brca2 expression was delayed in spermatogonia relative to Brca1 [10].

Associations of Brca2 with chemical compounds

• Increased sensitivity to genotoxic agents, particularly ultraviolet light and methylmethanesulfonate, shows that Brca2 function is essential for the ability to survive DNA damage [2].
• We used mice with a Brca1 mutation on a BALB/cJ inbred background (BALB/cB1+/- mice) or a Brca2 genetic alteration on the 129/SvEv genetic background (129B2+/- mice) to investigate potential gene-environment interactions between defects in these genes and treatment with the highly estrogenic compound diethylstilbestrol (DES) [11].
• These agents/factors included DMBA, gamma-radiation, Brca2 heterozygosity, and steroid hormones [12].

Regulatory relationships of Brca2

• Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/-) mutant mice [3].

Other interactions of Brca2

• This study shows that Brca2, like Brca1, is required for cellular proliferation during embryogenesis [9].
• Mice with a flanked by loxP allele of Brca2 were crossed to transgenic mice bearing Cre recombinase driven by the T cell-specific promoter Lck [4].
• The expression pattern of Brca1 and Brca2 correlates with the localization of proliferating cell nuclear antigen, an indicator of proliferative activity [10].
• Immunoprecipitation experiments showed that Fancd2 did not coprecipitate with the mutated Brca2 [13].
• On the other hand, we did not find any difference during gametogenesis in mice harboring exon 27 truncating mutation of the Brca2 gene and control mice, and in both cases, Rad51 localized to the recombination foci [13].

Analytical, diagnostic and therapeutic context of Brca2

• To study their biological function and to create animal models for these cancer susceptibility genes, several strains of mice mutated in the homologous genes Brca1 and Brca2 have been generated by gene targeting [14].
• Therefore, we compared the non isotopic in situ hybridization expression patterns of Brca1 and Brca2 mRNA in vivo in mitotic and meiotic cells during mouse embryogenesis, mammary gland development, and in adult tissues including testes, ovaries, and hormonally altered ovaries [10].
• We have analyzed by immunohistochemistry Brca1 and Brca2 protein expression in mouse during embryonic development, in adult tissues, and during postnatal mammary gland development [15].
• To elucidate this interaction in an animal model, mice lacking the carboxy terminal domain of Brca2 were crossed with p53 heterozygous mice [16].

References