ATM-depletion in breast cancer cells confers sensitivity to PARP inhibitionReportar como inadecuado




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Journal of Experimental and Clinical Cancer Research

, 32:95

First Online: 19 November 2013Received: 29 August 2013Accepted: 14 November 2013DOI: 10.1186-1756-9966-32-95

Cite this article as: Gilardini Montani, M.S., Prodosmo, A., Stagni, V. et al. J Exp Clin Cancer Res 2013 32: 95. doi:10.1186-1756-9966-32-95

Abstract

BackgroundMutations in the DNA damage response DDR factors, breast cancer 1 BRCA1 and BRCA2, sensitize tumor cells to polyADP-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.

MethodsWild-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.

ResultsWhen 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.

ConclusionsThese 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.

KeywordsBreast cancer ATM PARP inhibitors Olaparib Iniparib AbbreviationsATMAtaxia telangiectasia mutated

BRCA1-2Breast cancer 1-2

DDRDNA damage response

IRIonizing radiation

PARPPolyADP-ribose polymerase

PBSPhosphate buffered saline

SDStandard deviation

shRNAShort hairpin RNA.

Electronic supplementary materialThe online version of this article doi:10.1186-1756-9966-32-95 contains supplementary material, which is available to authorized users.

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Autor: Maria Saveria Gilardini Montani - Andrea Prodosmo - Venturina Stagni - Dania Merli - Laura Monteonofrio - Veronica Gatti -

Fuente: https://link.springer.com/







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