Discovery of cancer genes and pathways operative in PI3K activated mammary cancer reveals clinically relevant genotype-phenotype correlations

Here we used Sleeping Beauty (SB) transposon mutagenesis in mice on a Pik3caH1047R activated mutant background to model mammary cancer development in two different mammary epithelial compartments. Both the target cell for mutagenesis and the specific transposon-induced mutations present correlated with specific tumor phenotypes, including whether the tumors were estrogen receptor (ER) positive or negative. RNA sequencing of 232 resultant tumors and whole exome sequencing of 164 tumors and matched normal tissues revealed novel genotype-phenotype correlations implicating specific transposon-altered gene drivers of high cell cycle activity, ER dependent gene expression, and white blood cell exclusion from the tumor. Many transposon implicated genes are altered at the gene copy number or epigenetic/methylation level in human breast cancer (BRCA) and JUP, a top common insertion site gene, was functionally validated. These models provide a source of genetically heterogenous mouse mammary tumors with a uniform initiating mutation, Pik3caH1047R, useful for identifying cooperating pathways and drivers of specific tumor phenotypes.