title: Targeting abnormal DNA repair in therapy-resistant breast cancers.
abstract: 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 (ER+) MCF7 breast cancer cells and progesterone receptor-positive (PR+) 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 IIIα, a component of the highly error-prone alternative NHEJ (ALT NHEJ) pathway, is increased. Here, we show that tamoxifen- and aromatase-resistant derivatives of MCF7 cells and ER(-)/PR(-) cells have even higher steady-state levels of DNA ligase IIIα and increased levels of PARP1, another ALT NHEJ component. This results in increased dependence upon microhomology-mediated ALT NHEJ to repair DNA double-strand breaks (DSB) and the accumulation of chromosomal deletions. Notably, therapy-resistant derivatives of MCF7 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.
authors: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors: Lisa A
authors: LA
authors: Tobin
authors: Carine
authors: C
authors: Robert
authors: Pratik
authors: P
authors: Nagaria
authors: Saranya
authors: S
authors: Chumsri
authors: William
authors: W
authors: Twaddell
authors: Olga B
authors: OB
authors: Ioffe
authors: George E
authors: GE
authors: Greco
authors: Angela H
authors: AH
authors: Brodie
authors: Alan E
authors: AE
authors: Tomkinson
authors: Feyruz V
authors: FV
authors: Rassool
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics; D059766:DNA End-Joining Repair / Q000187:drug effects / Q000235:genetics; D011088:DNA Ligases / Q000037:antagonists & inhibitors; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013629:Tamoxifen / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013629:Tamoxifen; D011088:DNA Ligases