Development and characterization of mouse models of human breast cancer

While previous studies using genetically engineered mice (GEM) have indicated potential effects of several aberrations observed in human breast cancer, the combined role of loss of RB f, P53 and BRCA1 has not been assessed before. As these events frequently occur together in human breast cancer, we use GEMs to show that these pathways have a synergistic tumor suppressor role in the mammary gland. We show that loss of Rbf alone is not enough to promote mammary tumors, but combined loss of Rbf and p53 can lead to mammary adenocarcinoma with a reduction in apoptosis and low latency. In addition to p53 we studied the role of Brca1 loss either in conjunction with loss of Rbf or with both Rb f and p53. We found that these three important tumor suppressors have a synergistic effect in mammary tumor progression and combined loss of all three further reduces mammary tumor latency and leads to progression to distant metastasis. Genomic analysis suggests that the combined loss of Rbf, p53 and Brca1 results in increased genetic instability, overexpression of metastasis promoting genes and an altered micro RNA profile that may also contribute to increased malignancy.;So far analysis of genetic lesions in human cancers has focused on the accumulation of multiple events within the epithelial cell. However it is still unresolved as to why human BRCA1 mutated cancers have their characteristic "basal" like features. We show here for the first time, that the target cell of origin of the Brca1 mutation determines the nature of the tumor that evolves and hence the right combination of genetic mutations and cell of origin is important in modeling human cancers. All of our mouse models generated in this study can be used as preclinical animal models, which both genetically and biologically model the initiation and progression of human breast cancer.