ACTB in Breast Cancer: Molecular Mechanisms, Oncogenic Pathways, and Therapeutic Potential

Abstract

Breast cancer remains a leading cause of cancer-related mortality worldwide, with an estimated 316,950 new invasive cases and 42,170 deaths projected in the United States alone for 2025. Globally, it accounted for approximately 670,000 deaths in 2022, underscoring the urgent need for novel therapeutic targets that address metastatic progression. Among these, β-actin (encoded by ACTB), a core component of the actin cytoskeleton, has emerged as a pivotal regulator of cytoskeletal dynamics, epithelial-mesenchymal transition (EMT), and metastasis in breast cancer. This review synthesises recent evidence on ACTB's functional roles, demonstrating how its dysregulation promotes invasive phenotypes through actin polymerisation and remodelling, enabling cancer cell migration, extravasation, and colonisation of distant sites. We delineate ACTB's interaction networks, including crosstalk with Rho/ROCK for stress fibre formation, PI3K/Akt for survival and motility enhancement, and MAPK for proliferative signalling, which collectively amplify oncogenic pathways. Leveraging bioinformatics and network pharmacology, we integrate multi-omics data from databases such as STRING for protein-protein interactions, KEGG for pathway enrichment, and Cytoscape for modular network analysis, revealing ACTB-centred hubs co-expressed with EMT markers (e.g., vimentin, MMPs) and prognostic signatures in triple-negative breast cancer (TNBC). ACTB overexpression correlates with poor prognosis across subtypes, particularly in aggressive TNBC, positioning it as a biomarker and druggable target. This mechanistic framework highlights opportunities for isoform-specific inhibitors and combination therapies targeting upstream regulators like ROCK, offering a foundation for precision oncology in metastatic breast cancer.