Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2–AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future. This evidence concerns the gene PIK3CA and breast cancer.