Targeting abnormal DNA repair in therapy-resistant breast cancers

Lisa A. Tobin, Carine Robert, Pratik Nagaria, Saranya Chumsri, William Twaddell, Olga B. Ioffe, George E. Greco, Angela H. Brodie, Alan E. Tomkinson, Feyruz V. Rassool

Research output: Contribution to journalArticle

51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)96-107
Number of pages12
JournalMolecular Cancer Research
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2012

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ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Tobin, L. A., Robert, C., Nagaria, P., Chumsri, S., Twaddell, W., Ioffe, O. B., Greco, G. E., Brodie, A. H., Tomkinson, A. E., & Rassool, F. V. (2012). Targeting abnormal DNA repair in therapy-resistant breast cancers. Molecular Cancer Research, 10(1), 96-107. https://doi.org/10.1158/1541-7786.MCR-11-0255