DNA Damage and Cellular Stress Responses Targeting Abnormal DNARepair in Therapy-Resistant Breast Cancers

Although hereditary breast cancers have defects in the DNA damage response that result in genomic instability, DNA repair abnormalities in sporadic breast cancers have not been extensively characterized. Recently, we showed that, relative to nontumorigenic breast epithelial MCF10A cells, estrogen receptor–positive (ERþ) MCF7 breast cancer cells and progesterone receptor–positive (PRþ) MCF7 breast cancer cells have reduced steady-state levels of DNA ligase IV, a component of the major DNA–protein kinase (PK)-dependent nonhomologous end joining (NHEJ) pathway, whereas the steady-state level of DNA ligase IIIa, a component of the highly error-prone alternative NHEJ (ALT NHEJ) pathway, is increased. Here, we show that tamoxifenand aromatase-resistant derivatives of MCF7 cells and ER /PR cells have even higher steady-state levels of DNA ligase IIIa and increased levels of PARP1, another ALT NHEJ component. This results in increased dependence upon microhomologymediated ALTNHEJ to repairDNAdouble-strand breaks (DSB) and the accumulation of chromosomal deletions. Notably, therapy-resistant derivatives ofMCF7 cells and ER /PR cells exhibited significantly increased sensitivity to a combination of PARP and DNA ligase III inhibitors that increased the number of DSBs. Biopsies from ER /PR tumors had elevated levels of ALT NHEJ and reduced levels of DNA–PK-dependent NHEJ factors. Thus, our results show that ALT NHEJ is a novel therapeutic target in breast cancers that are resistant to frontline therapies and suggest that changes in NHEJ protein levels may serve as biomarkers to identify tumors that are candidates for this therapeutic approach. Mol Cancer Res; 10(1); 96–107. 2011 AACR.