Abstract

The phosphatidylinositol 3-kinase (PI3K)–AKT–mechanistic target of rapamycin (mTOR) signaling axis represents one of the most important oncogenic pathways in breast cancer and a major driver of therapeutic resistance, particularly in hormone receptor-positive and triple-negative subtypes. Although PI3K and mTOR inhibitors such as alpelisib and everolimus have improved clinical outcomes in selected patients, their broader application is limited by toxicity and adaptive resistance mechanisms. Increasing attention has therefore been directed toward medicinal plant-derived phytochemicals as multi-target modulators of this pathway. This mini-review summarizes current mechanistic evidence showing how selected phytochemicals—including flavonoids, polyphenols, and isothiocyanates—interfere with PI3K–AKT–mTOR signaling at multiple nodes, suppress compensatory survival pathways, and enhance the efficacy of endocrine therapy, chemotherapy, and targeted agents. Rather than acting as standalone therapies, these compounds are increasingly viewed as adjunctive modulators or lead scaffolds for anticancer drug development. This mini-review uniquely integrates emerging evidence on phytochemical modulation of the PI3K–AKT–mTOR axis with mechanisms of therapeutic resistance and rational combination strategies with targeted therapies. It also highlights recent advances in nanoformulation technologies that may improve phytochemical bioavailability and facilitate clinical translation in precision breast cancer therapy.

Key words: PI3K–AKT–mTOR signaling; breast cancer; phytochemicals; drug resistance; targeted therapy; nanoformulation