Breast cancer is the most frequent cancer type in females in the Western world, affecting approximately one in ten women. It is a complex genetic disease, with the vast majority of sporadic cases currently unaccounted for by our understanding of the genes and pathways involved. To further understand the mechanisms of breast cancer formation, mammary tumors arising in Brca1 p53 mutant mice were analyzed. The high level of genomic instability conferred by the loss of Brca1 and p53 offers a unique opportunity to study recurrent genomic changes that have been selected for in the context of mammary epithelium. The most pronounced feature of these tumors was the high-level DNA amplification of the Met proto-oncogene, observed in 75 percent of the cases. The goal of this proposal is to further characterize the role of Met signaling in breast cancer formation, with the following experimental aims: 1. Functional consequences of Met amplification in vitro. Met signaling levels will be decreased in tumor derived cell lines and the functional consequences and downstream signaling pathways involved will be analyzed. 2. Contribution of Met signaling to mammary tumorigenesis in mouse models. A transgenetic mouse approach will be used to test whether increased Met signaling is necessary and/or sufficient for breast tumorigenesis. ? ? ?
