Pharmacological Modulation of DNA Damage Response Pathway in Breast Cancer Therapy: A Comprehensive Review

Abstract

Breast cancer remains a leading cause of cancer-related morbidity and mortality among women worldwide. A
hallmark of cancer cells, genomic instability, often arises from defects in the DNA damage response (DDR)
pathways—complex cellular networks that detect, signal, and repair DNA lesions. This comprehensive review
explores the pharmacological modulation of key DDR pathways, including base excision repair (BER), nucleotide
excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end
joining (NHEJ), in the context of breast cancer therapy. Central to DDR activation are damage sensors such as the
MRN complex and PARP1, which recognize DNA lesions and recruit transducer kinases—ATM, ATR, to
propagate damage signals and coordinate repair. The review also discusses mechanisms of therapeutic resistance,
tumor heterogeneity, and the role of combination therapies to overcome these challenges. Furthermore, the
importance of predictive biomarkers and personalized DDR profiling for optimizing treatment outcomes is
highlighted. We discuss clinical study of DDR-targeting agents such as PARP inhibitors (e.g., Olaparib),
mechanisms of resistance, and future directions in harnessing DDR for improved therapeutic outcomes in breast
cancer patients.