Natural Products as Modulators of the DNA Damage Response and Oncogenic Signaling in Breast Cancer Therapy

Breast cancer (BC) is the most frequently diagnosed malignancy and generally the leading cause of cancer-related mortality among women worldwide. Molecular targeted thera- pies, including endocrine treatment for hormone-responsive tumors, anti-HER2 agents for HER2-positive tumors and PARP inhibitors (PARPis) for homologous recombination- deficient (HRD) tumors, have significantly improved patient outcomes, but several clinical challenges are still open. The development of acquired resistance strongly limits the long- term efficacy of current treatment strategies, underscoring the necessity to identify novel therapeutic approaches for breast cancer therapy. In this review, we summarize and discuss recently investigated natural compounds with anti-breast cancer activity, ranging from polyphenols, terpenoids, alkaloids, sulfur-containing compounds and the emerging plant- derived extracellular vesicles. We focus on their ability to induce DNA damage or oxidative stress, modulating the DNA damage response (DDR) and interfering with key oncogenic signaling pathways. We also discuss the potential of these compounds to enhance the efficacy of conventional therapies, thereby offering a promising role in overcoming clinical resistance. Despite clinical relevance remains under development and further studies are required; many of the natural compounds examined here appear to effectively target DDR signaling and oncogenic pathways, supporting their potential use in breast cancer therapy.