Peroxisome proliferator activated receptor-α/hypoxia inducible factor-1α interplay sustains carbonic anhydrase IX and apoliprotein E expression in breast cancer stem cells

PLoS One. 2013;8(1):e54968. doi: 10.1371/journal.pone.0054968. Epub 2013 Jan 25.

Abstract

Aims: Cancer stem cell biology is tightly connected to the regulation of the pro-inflammatory cytokine network. The concept of cancer stem cells "inflammatory addiction" leads to envisage the potential role of anti-inflammatory molecules as new anti-cancer targets. Here we report on the relationship between nuclear receptors activity and the modulation of the pro-inflammatory phenotype in breast cancer stem cells.

Methods: Breast cancer stem cells were expanded as mammospheres from normal and tumor human breast tissues and from tumorigenic (MCF7) and non tumorigenic (MCF10) human breast cell lines. Mammospheres were exposed to the supernatant of breast tumor and normal mammary gland tissue fibroblasts.

Results: In mammospheres exposed to the breast tumor fibroblasts supernatant, autocrine tumor necrosis factor-α signalling engenders the functional interplay between peroxisome proliferator activated receptor-α and hypoxia inducible factor-1α (PPARα/HIF1α). The two proteins promote mammospheres formation and enhance each other expression via miRNA130b/miRNA17-5p-dependent mechanism which is antagonized by PPARγ. Further, the PPARα/HIF1α interplay regulates the expression of the pro-inflammatory cytokine interleukin-6, the hypoxia survival factor carbonic anhydrase IX and the plasma lipid carrier apolipoprotein E.

Conclusion: Our data demonstrate the importance of exploring the role of nuclear receptors (PPARα/PPARγ) in the regulation of pro-inflammatory pathways, with the aim to thwart breast cancer stem cells functioning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Autocrine Communication
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Carbonic Anhydrases / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Culture Media, Conditioned / pharmacology
  • Female
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Models, Biological
  • Neoplastic Stem Cells / metabolism*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Protein Binding
  • Spheroids, Cellular
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Apolipoproteins E
  • Culture Media, Conditioned
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MIRN130 microRNA, human
  • MIRN17 microRNA, human
  • MicroRNAs
  • PPAR alpha
  • PPAR gamma
  • Tumor Necrosis Factor-alpha
  • Carbonic Anhydrases

Grants and funding

This work has been supported by grant Project of National Interest (PRIN) of Ministry of Education (Italy), code project: 2008KTRN38 and title project: “Clinical, diagnostic and therapeutic implications of studies on breast cancer stem cells”, Cornelia and Roberts Pallotti legacy to MB and MT and by Fundamental Oriented Research of TG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.