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.
