Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib

PLoS One. 2014 Aug 21;9(8):e104302. doi: 10.1371/journal.pone.0104302. eCollection 2014.

Abstract

Background: Breast cancer stem cells (BCSCs) have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL), BrCA-MZ-01.

Methods: ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+) and mature cancer (ALDH-) cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE). Differentially-expressed spots were excised and proteins were gel-extracted, digested and identified using MALDI-TOF MS.

Results: 2-D DIGE identified poly(ADP-ribose) polymerase 1 (PARP1) as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor.

Conclusion: An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / enzymology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Electrophoresis, Gel, Two-Dimensional
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Neoplastic Stem Cells / enzymology*
  • Phthalazines / pharmacology*
  • Piperazines / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • Antineoplastic Agents
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases
  • olaparib

Grants and funding

This work was supported by SIRIC program (INCa-DGOS-Inserm 6038) and Sanofi-Aventis. MG was supported by a grant from “Association pour la Recherche sur le Cancer (ARC)”. SL was supported by a grant from “Fondation pour la Recherche Médicale (FRM)”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.