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

Journal of Experimental & Clinical Cancer Research

Silvia Soddu²  Daniela Baril๠ Maria Pia Gentileschi²  Veronica Gatti²  Laura Monteonofrio²  Dania Merli³  Venturina Stagni¹  Andrea Prodosmo²  Maria Saveria Gilardini Montani³ 

[1] Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica, 00133 Rome, Italy;Experimental Oncology, Regina Elena National Cancer Institute, Via Elio Chianesi, 53-00144 Rome, Italy;Department of Ecological and Biological Sciences, Tuscia University, Largo dell’Università, 01100 Viterbo, Italy

关键词: Iniparib;    Olaparib;    PARP inhibitors;    ATM;    Breast cancer;   

Others  :  814135
DOI  :  10.1186/1756-9966-32-95

 received in 2013-08-29, accepted in 2013-11-14,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Gilardini Montani et al.; licensee BioMed Central Ltd.

【 图 表 】

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