HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review

Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. 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.