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Breast Cancer Research and Treatment

, Volume 138, Issue 1, pp 47–57 | Cite as

Loss of E-cadherin is not a necessity for epithelial to mesenchymal transition in human breast cancer

  • Antoinette Hollestelle
  • Justine K. Peeters
  • Marcel Smid
  • Mieke Timmermans
  • Leon C. Verhoog
  • Pieter J. Westenend
  • Anouk A. J. Heine
  • Alan Chan
  • Anieta M. Sieuwerts
  • Erik A. C. Wiemer
  • Jan G. M. Klijn
  • Peter J. van der Spek
  • John A. Foekens
  • Mieke Schutte
  • Michael A. den Bakker
  • John W. M. Martens
Preclinical Study

Abstract

Epithelial to mesenchymal transition (EMT) is typically defined by the acquisition of a spindle cell morphology in combination with loss of E-cadherin and upregulation of mesenchymal markers. However, by studying E-cadherin inactivation in 38 human breast cancer cell lines, we noted that not all cell lines that had undergone EMT had concomitantly lost E-cadherin expression. We further investigated this discrepancy functionally and in clinical breast cancer specimens. Interestingly, reconstitution of wild-type E-cadherin cDNA in a E-cadherin negative cell line that had undergone EMT (MDA-MB-231) did not revert the spindle morphology back to an epithelial morphology. Neither were changes observed in the expression of several markers known to be involved in the EMT process. Similarly, upregulation of E-cadherin via global DNA demethylation in eleven cell lines that had undergone EMT did not induce a change in cell morphology, nor did it alter the expression of EMT markers in these cells. Next, we extracted genes differentially expressed between cell lines that had undergone EMT versus cell lines that had not undergone EMT. Caveolin-1 was identified to be an excellent marker for EMT, irrespective of E-cadherin status (specificity and sensitivity of 100 %). Consistent with our observations in the breast cancer cell lines, expression of Caveolin-1 identified a subset of basal breast cancers, particularly of metaplastic pathology, and only 50 % of these lacked E-cadherin expression. The discrepancy between E-cadherin loss and EMT was thus reproduced in clinical samples. Together, these results indicate that in human breast cancer loss of E-cadherin is not causal for EMT and even not a necessity.

Keywords

E-cadherin EMT Spindle cell morphology Basal subtype Metaplastic breast cancer Caveolin-1 

Notes

Acknowledgments

We appreciate the assistance of members of the pathology immunohistochemistry labs. We thank Prof. Wolter Oosterhuis for insightful discussions. This work was supported by the Dutch Cancer Society, Erasmus MC Mrace and Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Antoinette Hollestelle
    • 1
    • 3
    • 8
  • Justine K. Peeters
    • 2
  • Marcel Smid
    • 1
    • 3
  • Mieke Timmermans
    • 1
    • 3
  • Leon C. Verhoog
    • 4
  • Pieter J. Westenend
    • 5
  • Anouk A. J. Heine
    • 1
    • 3
  • Alan Chan
    • 6
    • 7
  • Anieta M. Sieuwerts
    • 1
    • 3
  • Erik A. C. Wiemer
    • 1
  • Jan G. M. Klijn
    • 1
  • Peter J. van der Spek
    • 2
  • John A. Foekens
    • 1
    • 3
  • Mieke Schutte
    • 1
  • Michael A. den Bakker
    • 4
  • John W. M. Martens
    • 1
    • 3
  1. 1.Department of Medical Oncology, Josephine Nefkens InstituteErasmus University Medical Center-Daniel den Hoed Cancer CenterRotterdamThe Netherlands
  2. 2.Department of BioinformaticsErasmus University Medical CenterRotterdamThe Netherlands
  3. 3.Cancer Genomics CentreRotterdamThe Netherlands
  4. 4.Department of Pathology, Josephine Nefkens InstituteErasmus University Medical CenterRotterdamThe Netherlands
  5. 5.Laboratory for PathologyDordrechtThe Netherlands
  6. 6.PamGene International B.V.s-HertogenboschThe Netherlands
  7. 7.PercurosLeidenThe Netherlands
  8. 8.Department of Medical Oncology, Josephine Nefkens InstituteErasmus University Medical CenterRotterdamThe Netherlands

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