DNA Damage Response: A Therapeutic Landscape For Breast Cancer Treatment

 Breast cancer is responsible for cancer-related death among women globally. The known causes of breast cancer include genetic predisposition, dysregulated hormonal signaling due to psychological stress, and aging and lifestyle factors, such as smoking and alcohol consumption. Due to improved treatment strategies, the overall survival is significantly increased; however, it is still significantly associated with death worldwide. Breast cancer's initiation and progression are strongly influenced by genomic instability. Defect in DNA damage response (DDR) pathways, which enable cells to survive, help in the accumulation of mutation, clonal selection, and expansion of cancer cells. Germline mutation in breast cancer susceptibility genes, BRCA1 and BRCA2, TP53, and PTEN, increases the risk of early onset of disease. During the initial and clonal selection of cancer cells, a defect in one DNA repair pathway could potentially be compensated by another pathway. Therefore, cancer cells with defective DNA repair pathways could be easily killed by targeting the compensatory pathways by inducing synthetic lethality. Evidently, cancer cells with defective DDR or decreased DNA repair capacity show synthetic lethality in monotherapy when the backup DNA repair pathway is inhibited. For instance, tumors with defective homologous recombination (HR) can be targeted by inhibitors of double-strand break repair enzymes. Here, we briefly addressed the relevant factors associated with the development of breast cancer and the role of the DDR factor in the development of breast cancer. In addition, recent treatment strategies targeting genomic instability in breast cancer will be summarized as well as how the genomic instability and defective DDR can be targeted for the treatment of breast cancer. 

Keywords: DNA damage, DNA damage response , DNA repair, PARP inhibitor, Synthetic lethality.