Mapk Signaling Mediates Tamoxifen Resistance in Estrogen Receptor-Positive Breast Cancer Publisher



S Javankiani SEPIDE ; S Bolandi SOHEIL ; A Soleimani ANVAR ; Mss Meigoli Mohammad Saeed SOLEIMANI ; M Parsafar MAHDIS ; S Safaei SADAF ; M Esmailpour MOJGAN ; S Nadimi SOGOL ; Na Avval Nahal AGHAJAMAL ; Sma Fazayel Seyed Mohammad ALI
Source: Molecular and Cellular Biochemistry Published:2025

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 ERα 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. © 2025 Elsevier B.V., All rights reserved.