PTEN loss and PIK3CA activation both promote the accumulation of phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3). While these proteins also have distinct biochemical functions, beyond the regulation of PIP3, little is known about the consequences of these differences in vivo. Here, we directly compared cancer signalling in mammary tumors from MMTV-Cre: Pten f/f and MMTV-Cre: Pik3ca LSL-H1047R mice. Using unsupervised hierarchical clustering we found that whereas MMTV-Cre: Pik3ca LSL-H1047R-derived tumors fall into two separate groups, designated squamous-like Ex and class14 Ex, MMTV-Cre: Pten f/f tumors cluster as one group together with PIK3CA H1047R class14 Ex, exhibiting a ‘luminal’expression profile. Gene Set Enrichment Analysis (GSEA) of Pten Δ and PIK3CA H1047R class14 Ex tumors revealed very similar profiles of signalling pathways as well as some interesting differences. Analysis of 18 signalling signatures revealed that PI3K signalling is significantly induced whereas EGFR signalling is significantly reduced in Pten Δ versus PIK3CA H1047R tumors. Thus, Pten Δ and PIK3CA H1047R tumors exhibit discernable differences that may impact tumorigenesis and response to therapy.