In summary, we demonstrated that the PI3K/AKT/mTOR pathway plays an important role in resistance of breast cancer cells to single-agent HER2 therapy, and combination therapy with HER2 and PI3K/AKT/mTOR inhibitors could overcome the PI3K/AKT/mTOR pathway-mediated resistant mechanism in HER2+ breast cancers. This evidence concerns the gene PIK3CA and breast cancer.