This project capitalizes on two unique UNC resources, the Mouse Phase I Unit (MP1U) and the Collaborative Cross (CC), to study the genetics of basal like breast cancer (BBC).
We elected to focus on BBC because this disease has interesting epidemiology, worsened prognosis and lack of active targeted therapeutics. We have shown that a T-Antigen driven murine model (C3TAg) is faithful to human BBC, and has been extensively characterized in the MP1U.
In aim 1 we will complement our preliminary analysis by crossing FVB/n C3TAg mice to 24 additional Recombinant Inbred (RI) strains from the CC, to generate Recombinant Inbred Backcross (RIB) strains. Each RIB strain will be genetically unique and easily regenerated by further (CC x FVB/n) F1 crosses. Progeny from these crosses will be monitored for phenotypic variation including tumor latency, multiplicity and histological subtype. Variability in these phenotypes will be used to map genetic loci associated with these phenotypes. Based on preliminary studies, we expect the phenotypic variability to exceed 20%, and more likely 50%, for each of the primary endpoints of this aim, which should allow for precise (< 1 MB) mapping given a dataset of 40 RIB strains (16 completed, 24 newly analyzed).
In aim 2, we will perform DNA genotyping and RNA expression analysis of tumors from the RIB mice to identify somatic tumor-associated genetic mutations and gene expression patterns associated with the BBC phenotypes studied in aim 1. Results from aim 2 will be merged with mapping results from aim 1 to identify genes and pathways associated with BBC development and progression.