ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition

Maria Saveria Gilardini Montani, Andrea Prodosmo, Venturina Stagni, Dania Merli, Laura Monteonofrio, Veronica Gatti, Maria Pia Gentileschi, Daniela Barilà, Silvia Soddu

Research output: Contribution to journalArticle

Abstract

Background: Mutations in the DNA damage response (DDR) factors, breast cancer 1 (BRCA1) and BRCA2, sensitize tumor cells to poly(ADP-ribose) polymerase (PARP) inhibitors. The ataxia telangiectasia mutated (ATM) kinase is a key DDR protein whose heterozygous germline mutation is a moderate-risk factor for developing breast cancer. In this study, we examined whether ATM inactivation in breast cancer cell lines confers sensitivity to PARP inhibitors. Methods. Wild-type BRCA1/2 breast cancer cells (i.e., MCF-7 and ZR-75-1 lines) were genetically manipulated to downregulate ATM expression then assayed for cytostaticity/cytotoxicity upon treatment with PARP inhibitors, olaparib and iniparib. Results: When ATM-depleted cells and their relative controls were treated with olaparib (a competitive PARP-1/2 inhibitor) and iniparib (a molecule originally described as a covalent PARP-1 inhibitor) a different response to the two compounds was observed. ATM-depletion sensitized both MCF-7 and ZR-75-1 cells to olaparib-treatment, as assessed by short and long survival assays and cell cycle profiles. In contrast, iniparib induced only a mild, ATM-dependent cytostatic effect in MCF-7 cells whereas ZR-75-1 cells were sensitive to this drug, independently of ATM inactivation. These latest results might be explained by recent observations indicating that iniparib acts with mechanisms other than PARP inhibition. Conclusions: These data indicate that ATM-depletion can sensitize breast cancer cells to PARP inhibition, suggesting a potential in the treatment of breast cancers low in ATM protein expression/activity, such as those arising in mutant ATM heterozygous carriers.

Original languageEnglish
Article number95
JournalJournal of Experimental and Clinical Cancer Research
Volume32
Issue number1
DOIs
Publication statusPublished - Nov 19 2013

Keywords

  • ATM
  • Breast cancer
  • Iniparib
  • Olaparib
  • PARP inhibitors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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