BRCA1 is a well-described breast cancer susceptibility gene identified by positional cloning in 1994. Studies from many groups have implicated BRCA1 in DNA damage response, cell cycle control, the induction of apoptosis, maintenance of genomic stability and transcriptional regulation, and also have identified many protein partners. However, functional studies have been limited by cellular instability and lethality associated with BRCA1 deficiency. We now have a unique resource that allows us to circumvent these problems - a recently developed mouse strain with a conditionally targeted deletion in the Brca1 3' transcriptional activation (BRCT) domain (referred to as Brca1-deltaBRCT). This is the first mouse model that mimics a human disease-associated mutation that is engineered to produce a tissue specific deletion, thus maintaining viability. Deng and colleagues (Xu et al., 1999a) have shown that mice with mammary-specific Brca1 defects develop mammary lesions reminiscent of human breast cancers in BRCA1 mutation carriers, thus we expect that this model will be a valuable source of mammary tissue with which to study the effect of BRCA1 loss in tumorigenesis. Using this model we will first harvest mouse embryonic fibroblasts (MEFs) heterozygous and homozygous for a conditional Brca1 construct (referred to as Brca1-fldeltaBRCT) and expose them to recombinant self-excising Cre retrovirus (referred to as retroviral-Cre). Using this model, we will characterize the phenotype associated with the loss of wild-type Brca1 function by studying the effects on DNA damage response, cell cycle regulation, and induction of apoptosis. We will also focus our investigations on Brca1-related changes in mammary epithelium and mammary tumors of Brca1-deltaBRCT/deltaBRCT mice where the BRCT domain is excised by breeding with WAP-Cre mice. Using transcription profiling in MEFs, mouse mammary gland, and mouse mammary tumors heterozygous and homozygous for Brca1-deltaBRCT, we will identify genes and characterize the molecular pathways related to Brca1 function, thus providing potential targets for early detection and prevention strategies for BRCA1- associated cancers.
| Gupta-Abramson, Vandana; Troxel, Andrea B; Nellore, Anoma et al. (2008) Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 26:4714-9 |
