Oncogenic mutations select and sculpt conditional cooperative networks in breast cancer

Many cancers show recurrent copy number aberrations (CNA) affecting large regions of the genome. To identify genes responsible for this we performed Sleeping Beauty (SB) screens in eight different mouse models of breast cancer. Transposon insertion site analysis identified ~1000 cancer genes, most of which are driver- and/or histotype-specific and appear to have sustained loss-of-function insertions in a single allele. This list greatly exceeds the number identified through searches for recurrent focal mutations. Many SB-targeted genes were identified that function on the same driver-specific pathway responsible for tumor initiation. Some pairs of genes were co-targeted in tumors, and when tested, two such pairs of hemizygous loss-of-function mutations showed significant cooperative interaction with respect to mammary tumor induction. Thus, oncogenic mutations, including haploinsufficient tumor suppressors located in common regions of CNA, form conditional cooperative networks that select and sculpt “just enough and just right” levels of oncogenic signaling in transformation. Overall design: Sleeping Beauty (SB) screens in multiple models of breast cancer