TGFbeta/TNF(alpha)-mediated Epithelial-Mesenchymal Transition Generates Breast Cancer Stem Cells With a Claudin-Low Phenotype

Cancer Res. 2011 Jul 1;71(13):4707-19. doi: 10.1158/0008-5472.CAN-10-4554. Epub 2011 May 9.

Abstract

Breast cancer recurrence is believed to be caused by a subpopulation of cancer cells that possess the stem cell attribute of treatment resistance. Recently, we and others have reported the generation of breast cancer stem cells (BCSC) by epithelial-mesenchymal transition (EMT), although the physiologic process by which these cells may arise in vivo remains unclear. We show here that exposure of tumor cells to TGFβ and TNFα induces EMT and, more importantly, generates cells with a stable BCSC phenotype which is shown by increased self-renewing capacity, greatly increased tumorigenicity, and increased resistance to oxaliplatin, etoposide, and paclitaxel. Furthermore, gene expression analyses found that the TGFβ/TNFα-derived BCSCs showed downregulated expression of genes encoding claudin 3, 4, and 7 and the luminal marker, cytokeratin 18. These changes indicate a shift to the claudin-low molecular subtype, a recently identified breast cancer subtype characterized by the expression of mesenchymal and stem cell-associated markers and correlated with a poor prognosis. Taken together, the data show that cytokine exposure can be used to generate stable BCSCs ex vivo, and suggest that these cells may provide a valuable tool in the identification of stem cell-directed biomarkers and therapies in breast cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Humans
  • Mammary Glands, Human / drug effects
  • Mammary Glands, Human / pathology
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Mice, Transgenic
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology*
  • Phenotype
  • Transforming Growth Factor alpha / pharmacology*
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Transforming Growth Factor alpha
  • Transforming Growth Factor beta