These data, together with the surprisingly small overlap in gCIS identified as cooperating mutations in Pik3caE545K vs. Pik3caH1047R screens, the selection for non-classical hotspot mutations as second site allelic enhancers in BC, as well as evidence for unique signaling pathways downstream of each mutant58,59, support a model whereby many breast tumors select for just enough and just right signaling within the PI3K signaling pathway(s). This evidence concerns the gene PIK3CA and breast neoplasm.