Project description:While BRCA-related cancers respond well to double-strand break (DSB) inducing agents, resistance is a serious clinical problem. One mechanism of resistance is reversion of the BRCA1 mutation, suggesting that BRCA1 function is required for resistance. Here we show that secondary Brca1 mutations are not always necessary, since residual activity of the mutant BRCA1 protein can be sufficient for tumor cells to withstand treatment. Genomic profiling and RAD51 foci formation are currently seen as potential biomarkers to stratify patients for therapies targeting homologous recombination deficiency (HRD). However, we show that while mouse mammary tumors with different Brca1 mutations have identical genomic profiles, they respond considerably different to HRD targeted therapy. It may therefore be useful to stratify patients according to functional assays and the underlying BRCA1 mutation. We performed aCGH on mammary tumor DNA from KB1C61GP (n=20), littermate KB1P (n=18) and KP mice (n=19). Spleen DNA of the same animal was used as control material.
