MAPK signaling mediates tamoxifen resistance in estrogen receptor-positive breast cancer

Abstract

Tamoxifen is a cornerstone in the treatment of estrogen receptor (ER)-positive breast cancer, yet resistance to this therapy remains a significant clinical challenge. In most cases, the resistance phenotype is not caused by loss or mutation of the ER, but by changes in multiple proliferative and survival pathways. The mitogen-activated protein kinase (MAPK) signaling pathways regulate various cellular processes such as cell growth, proliferation, and apoptosis. This review provides a comprehensive analysis of molecular mechanisms that sustain MAPK activation and promote tamoxifen resistance. We evaluated molecular factors that promote the survival of tamoxifen-resistant cells through the regulation of MAPK signaling, including growth factors, RNA-binding proteins, non-genomic ER variants, and microRNAs. Mitochondrial dynamics and their regulation by MAPK highlight novel adaptive mechanisms employed by resistant cells to survive. Furthermore, MAPK-mediated phosphorylation of ER alpha enhances resistance through ligand-independent activation and sustained cellular proliferation. MAPK and parallel oncogenic pathways, including PI3K/AKT and receptor tyrosine kinases (EGFR, IGF-1R, and FGFR), function synergistically to enhance signaling redundancy and compensatory survival mechanisms. Therapeutic interventions targeting MAPK signaling-ranging from small-molecule inhibitors to RNA-based therapies-offer promising avenues for overcoming tamoxifen resistance.