Cytoskeletal dynamics in breast cancer: mechanistic insights and therapeutic opportunities

Breast cancer (BC) progression, metastasis, and therapy resistance are intricately linked to the cytoskeletal dynamics. The cytoskeleton, a central hub of cellular architecture, is composed of three primary filament systems: microtubules (MTs), actin filaments (AFs), and intermediate filaments (IFs). These filaments are not passive scaffolds but active, integrated systems that govern the processes of cell division, invasion, and migration, thereby providing the direct mechanistic basis for tumor growth, metastasis, and therapy resistance. Therefore, this review examines the pivotal roles of MTs, AFs, and IFs in mediating drug resistance by adapting to the breast cancer (BC) microenvironment (BC-ME). This review summarizes recent insights into how key signaling pathways, such as PAKs (p21-activated kinases), FAK (Focal adhesion kinase), and the ARF (ADP-ribosylation factor) signaling, regulate actin dynamics, focal adhesion turnover, and cytoskeletal organization. Furthermore, the review highlights the control of microtubule (MT) assembly and stability by microtubule-associated proteins (MAPs), detailing the distinct contributions of tumor suppressors, such as ATIP3 and Tektins, and oncogenes, including MASTL and Tau. Aberrations in the pathways controlling cytoskeletal dynamics and MAP expression significantly contribute to metastatic potential and resistance to conventional therapies. Emerging therapeutic strategies targeting specific cytoskeletal regulators, including PAKs, FAK, and MASTL inhibitors, are discussed as promising approaches to mitigate resistance and metastasis. Furthermore, targeting ARF has been highlighted as a potential means to sensitize TNBC cells to EGFR inhibitors. Finally, a cytoskeleton dynamics-based 3P medicine approach for breast cancer was discussed. Future perspectives emphasize the development of specific inhibitors, the establishment of robust predictive biomarkers (e.g., ATIP3, TEKT4 variants, Tau levels), the exploitation of vulnerabilities created by MAP alterations, and the rational optimization of combination therapies to overcome resistance and improve BC treatment outcomes, especially in aggressive subtypes like TNBC.