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Breast Cancer Research and Treatment

, Volume 134, Issue 2, pp 649–659 | Cite as

Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells

  • Hsiao-Ching Chuang
  • Naval Kapuriya
  • Samuel K. Kulp
  • Ching-Shih Chen
  • Charles L. ShapiroEmail author
Preclinical study

Abstract

Despite recent advances in the clinical evaluation of various poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer (TNBC) patients, data defining potential anti-tumor mechanisms beyond PARP inhibition for these agents are lacking. To address this issue, we investigated the effects of four different PARP inhibitors (AG-014699, AZD-2281, ABT-888, and BSI-201) in three genetically distinct TNBC cell lines (MDA-MB-468, MDA-MB-231, and Cal-51). Assays of cell viability and colony formation and flow cytometric analysis were used to determine effects on cell growth and cell cycle progression. PARP-dependent and -independent signaling mechanisms of each PARP inhibitor were investigated by western blotting and shRNA approaches. Potential synergistic interactions between PARP inhibitors and cisplatin in suppressing TNBC cell viability were assessed. These PARP inhibitors exhibited differential anti-tumor activities, with the relative potencies of AG-014699 > AZD-2281 > ABT-888 > BSI-201. The higher potencies of AG-014699 and AZD-2281 were associated with their effects on G2/M arrest and DNA damage as manifested by γ-H2AX formation and, for AG-014699, its unique ability to suppress Stat3 phosphorylation. Abilities of individual PARP inhibitors to sensitize TNBC cells to cisplatin varied to a great extent in a cell context- and cell line-specific manner. Differential activation of signaling pathways suggests that the PARP inhibitors currently in clinical trials have different anti-tumor mechanisms beyond PARP inhibition and these PARP-independent mechanisms warrant further investigation.

Keywords

Poly(ADP-ribose) polymerase PARP inhibitors Triple-negative breast cancer 

Abbreviations

ER

Estrogen receptor

ERKs

Extracellular signal related kinases

PAR

Poly(ADP-ribose)

PARP

Poly(ADP-ribose) polymerase

pCR

Pathological complete response

PHLPP

PH domain leucine-rich repeat phosphatase

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

TNBC

Triple-negative breast cancer

Notes

Acknowledgments

This study was supported by the Stefanie Spielman Fund for Breast Cancer Research and the Lucius A. Wing Endowed Chair Fund of The Ohio State University College of Medicine.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10549_2012_2106_MOESM1_ESM.doc (360 kb)
Supplementary material 1 (DOC 360 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Hsiao-Ching Chuang
    • 1
  • Naval Kapuriya
    • 1
  • Samuel K. Kulp
    • 1
  • Ching-Shih Chen
    • 1
  • Charles L. Shapiro
    • 2
    Email author
  1. 1.Division of Medicinal Chemistry, College of PharmacyThe Ohio State University (OSU)ColumbusUSA
  2. 2.Division of Medical Oncology, Wexner Medical Center and the Breast ProgramOSU Comprehensive Cancer CenterColumbusUSA

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