MMTV-trBrca1 mice display strain-dependent abnormalities in vaginal development.
The breast cancer susceptibility gene Brca1 encodes a large multi-functional protein which is implicated as a caretaker of the genome, through its role in regulation of DNA damage response pathways, including apoptosis. Here we show that in mice expressing a dominant-negative Brca1 transgene on a BALB/c background, vaginal entrance remodeling is inhibited, and that the incidence of this phenotype is increased on a p53 +/- genotype. Given that this developmental process is mediated primarily by apoptosis, we hypothesized that disruption of BRCA1 may confer a resistance to apoptosis in normal epithelial cells. Consistent with this, we show that expression of this transgene in vitro leads to resistance to ionizing radiation induced cell killing in mammary epithelial cells. This is the first time that BRCA1 has been implicated in an apoptosis-mediated normal developmental process.
Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria, Australia.
Kaylene J
KJ
Simpson
Mas R
MR
Wati
Andrew J
AJ
Deans
Geoffrey J
GJ
Lindeman
Melissa A
MA
Brown
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D019398:Genes, BRCA1; D005838:Genotype; D008321:Mammary Glands, Animal / Q000196:embryology; D015674:Mammary Neoplasms, Animal / Q000235:genetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008957:Models, Genetic; D009154:Mutation; D013997:Time Factors; D019076:Transgenes; D014621:Vagina / Q000196:embryology* / Q000473:pathology