PI4K and PIPK families in breast cancer: subtype-specific oncogenic mechanisms and precision therapeutic strategies.

Breast cancer exhibits profound subtype heterogeneity, with luminal A/B, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) showing distinct biological behaviours and therapeutic responses. Despite advances in targeted therapies, primary and acquired resistance remain a major clinical challenge. Phosphatidylinositol 4-kinases (PI4Ks) and phosphatidylinositol phosphate kinases (PIPKs) are key regulators of lipid signalling, metabolic reprogramming, cytoskeletal remodelling, and immune modulation-processes frequently dysregulated in breast cancer. This review summarizes their oncogenic mechanisms: luminal subtypes are frequently characterized by PI4KB amplification and PIP5K1A overexpression, promoting phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) activation and endocrine resistance; HER2-positive subtypes are frequently associated with PI5P4Kβ co-amplification with ERBB2 and PI4KIIα-mediated HER2 signalling to enhance angiogenesis; TNBC is characterized by PIKfyve-mediated immune escape, PI4P5Kγ-driven glycolysis, and PI5P4Kα/β-regulated peroxisomal fatty acid β-oxidation (FAO). We discuss subtype-tailored therapies (small-molecule inhibitors, proteolysis-targeting chimeras (PROTACs), drug repurposing) and combination strategies, analyze resistance mechanisms (target compensation, metabolic adaptation), and propose overcoming strategies. Finally, we outline clinical translation via a multi-omics-guided precision matching model. This review provides insights into PI4K/PIPK roles in breast cancer progression and offers novel ideas for more effective precision therapies.