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Decoding breast cancer treatment resistance through genetic, epigenetic, and immune-regulatory mechanisms: from molecular insights to translational perspectives

Suryendu Saha,Samikshya Mahapatra,Sinjan Khanra,Barnalee Mishra,Biswajit Swain,Diksha Malhotra,Swarnali Saha,Venketesh K Panda,K. Kumari,Sarmistha Jena,S. Thakur,Pawan Singh,Gopal C Kundu

Published 2025 in Cancer Drug Resistance

ABSTRACT

Breast cancer continues to be the primary cause of cancer-related deaths among women globally, with increased rates of incidence and mortality, highlighting the critical need for effective treatment strategies. Recent developments have introduced a variety of treatment options that address the molecular diversity of breast cancer; nonetheless, drug resistance remains a significant barrier to achieving favorable results. This review explains the crucial role of genetic and epigenetic changes in contributing to therapeutic resistance, in addition to other factors such as increased drug efflux, enhanced DNA repair, evasion of senescence, tumor heterogeneity, the tumor microenvironment (TME), and epithelial-to-mesenchymal transition (EMT). Genetic modifications, including mutations in oncogenes and tumor suppressor genes, disrupt essential signaling pathways, facilitating resistance to chemotherapy and targeted therapies. At the same time, epigenetic modifications - like DNA methylation, alterations to histones, and dysregulation of non-coding RNAs - reprogram gene expression, supporting adaptive resistance mechanisms. These molecular abnormalities contribute to the plasticity of tumors, allowing cancer cells to evade therapeutic approaches. This review consolidates recent discoveries regarding how these genetic and epigenetic modifications affect treatment responses and resistance in breast cancer, highlighting their interaction with disease advancement. By pinpointing new drug targets, including immunotherapeutic strategies, this article seeks to shed light on the molecular underpinnings of chemoresistance, aiding in the refinement of existing treatment protocols. A more profound understanding of these mechanisms offers the potential for developing precision therapies to overcome resistance, reduce relapse rates, and improve clinical outcomes for breast cancer patients.

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