Slug/β-catenin-dependent proinflammatory phenotype in hypoxic breast cancer stem cells

Am J Pathol. 2013 Nov;183(5):1688-1697. doi: 10.1016/j.ajpath.2013.07.020. Epub 2013 Sep 12.

Abstract

Cancer stem cell survival relies on the activation of inflammatory pathways, which is speculatively triggered by cell autonomous mechanisms or by microenvironmental stimuli. Here, we observed that hypoxic bone marrow stroma-derived transforming growth factor-β 1 promotes the growth of human breast cancer stem cells as mammospheres. The ensuing Slug-dependent serine 139 phosphorylation of the DNA damage sensor H2AX in breast cancer stem cells induces tumor necrosis factor-α and IL-8 mRNAs, whose stability is enhanced by cytoplasmic β-catenin. β-Catenin also up-regulates and binds miR-221, reducing the stability of the miR-221 targets Rad51 and ERα mRNAs. Our data show that the Slug/β-catenin-dependent activation of DNA damage signaling triggered by the hypoxic microenvironment sustains the proinflammatory phenotype of breast cancer stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autocrine Communication / drug effects
  • Autocrine Communication / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / genetics
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA Damage / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histones / metabolism
  • Humans
  • Inflammation / genetics
  • Inflammation / pathology*
  • MCF-7 Cells
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology
  • Models, Biological
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Serine / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Snail Family Transcription Factors
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta1 / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism
  • beta Catenin / metabolism*

Substances

  • Cytokines
  • H2AX protein, human
  • Histones
  • RNA, Messenger
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • beta Catenin
  • Serine
  • Rad51 Recombinase