Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness

Expert Opin Ther Targets. 2014 Feb;18(2):121-35. doi: 10.1517/14728222.2014.860447. Epub 2013 Dec 11.


Introduction: Cyclooxygenase-2 (COX-2) is overexpressed in several malignancies and is implicated in breast cancer progression.

Objectives: We investigated whether changes in COX-2 expression may affect epithelial-to-mesenchymal transition (EMT) and then invasive potential of human breast cancer cells, in relationship with hypoxia. COX-2-null MCF-7 human breast cancer cells, MCF-7 cells transiently expressing COX-2 and COX-2-expressing MDA-MB-231 cells were employed.

Results: COX-2 overexpression resulted in downregulation of E-cadherin and β-catenin, upregulation of vimentin, N-cadherin and SNAI1, suggesting EMT occurrence. COX-2-overexpressing MCF-7 cells were also characterized by increased invasiveness and release of matrix-metalloproteinase-9. The above-mentioned characteristics, homologous to those detected in highly invasive MDA-MB-231 cells, were reverted by treatment of COX-2-overexpressing MCF-7 cells with celecoxib, a COX-2-specific inhibitor, partly through the inhibition of COX-2-related intracellular generation of reactive oxygen species. Hypoxia further exacerbated COX-2 expression, EMT changes and invasive ability in both COX-2-overexpressing MCF-7 cells and MDA-MB-231 cells. Finally, immunohistochemistry performed on samples from normal and neoplastic human breast tissues revealed that COX-2-positive malignant cells were also positive for EMT-related antigens, hypoxia-inducible factor (HIF)-2α and the oxidative stress marker heme oxygenase.

Conclusions: These findings support the existence of a direct link between COX-2 overexpression, EMT and invasiveness in human breast cancer cells, emphasizing the role of hypoxic microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Breast Neoplasms / metabolism*
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • DNA, Complementary / genetics
  • Dinoprostone / metabolism
  • Epithelial-Mesenchymal Transition*
  • Female
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Hypoxia / metabolism
  • MCF-7 Cells
  • Neoplasm Invasiveness
  • Reactive Oxygen Species / metabolism
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Cadherins
  • DNA, Complementary
  • Reactive Oxygen Species
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • endothelial PAS domain-containing protein 1
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Dinoprostone