title: Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness.
abstract: BACKGROUND
  Cyclooxygenase-2 (COX-2) is overexpressed in several malignancies and is implicated in breast cancer progression.
  
  
  OBJECTIVE
  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.
authors: University of Torino, Department of Clinical and Biological Sciences , C.so Raffaello, 30 - 10125 Torino , Italy +39 0116707756 ; +39 0116707753 ; claudia.bocca@unito.it.
authors: Claudia
authors: C
authors: Bocca
authors: Monica
authors: M
authors: Ievolella
authors: Riccardo
authors: R
authors: Autelli
authors: Manuela
authors: M
authors: Motta
authors: Luciano
authors: L
authors: Mosso
authors: Bruno
authors: B
authors: Torchio
authors: Francesca
authors: F
authors: Bozzo
authors: Stefania
authors: S
authors: Cannito
authors: Claudia
authors: C
authors: Paternostro
authors: Sebastiano
authors: S
authors: Colombatto
authors: Maurizio
authors: M
authors: Parola
authors: Antonella
authors: A
authors: Miglietta
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D051546:Cyclooxygenase 2; D018076:DNA, Complementary; D015232:Dinoprostone; D051547:Heme Oxygenase-1; D017382:Reactive Oxygen Species; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C000604407:SNAI1 protein, human; C496541:HMOX1 protein, human; C496540:PTGS2 protein, human