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WNT10B/β‐catenin signalling induces HMGA2 and proliferation in metastatic triple‐negative breast cancer

Peter Wend, Stephanie Runke, Korinna Wend, Brenda Anchondo, Maria Yesayan, Meghan Jardon, Natalie Hardie, Christoph Loddenkemper, Ilya Ulasov, Maciej S. Lesniak, Rebecca Wolsky, Laurent A. Bentolila, Stephen G. Grant, David Elashoff, Stephan Lehr, Jean J. Latimer, Shikha Bose, Husain Sattar, Susan A. Krum, Gustavo A. Miranda‐Carboni

Author Affiliations

  1. Peter Wend1,
  2. Stephanie Runke1,
  3. Korinna Wend2,
  4. Brenda Anchondo1,
  5. Maria Yesayan1,
  6. Meghan Jardon1,
  7. Natalie Hardie1,
  8. Christoph Loddenkemper3,
  9. Ilya Ulasov4,
  10. Maciej S. Lesniak4,
  11. Rebecca Wolsky5,
  12. Laurent A. Bentolila6,
  13. Stephen G. Grant7,
  14. David Elashoff8,
  15. Stephan Lehr9,
  16. Jean J. Latimer7,
  17. Shikha Bose10,11,
  18. Husain Sattar5,
  19. Susan A. Krum2 and
  20. Gustavo A. Miranda‐Carboni (gmiranda{at}mednet.ucla.edu) *,1
  1. 1Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
  2. 2UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  3. 3Institute of Pathology, Charité University Medicine/UKBF, Berlin, Germany
  4. 4Department of Brain Tumor Biology, The University of Chicago, Chicago, IL, USA
  5. 5Department of Pathology, The University of Chicago, Chicago, IL, USA
  6. 6California NanoSystems Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA
  7. 7Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale‐Davie, FL, USA
  8. 8Department of Biostatistics, UCLA School of Public Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  9. 9Baxter Innovations GmbH, Vienna, Austria
  10. 10Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  11. 11Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
  1. *Tel: +1 310 794 1216; Fax: +1 310‐206‐6531
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Abstract

Wnt/β‐catenin signalling has been suggested to be active in basal‐like breast cancer. However, in highly aggressive metastatic triple‐negative breast cancers (TNBC) the role of β‐catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β‐catenin in human TNBC and predicts survival‐outcome of patients with both TNBC and basal‐like tumours. We provide evidence that transgenic murine Wnt10b‐driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical β‐catenin signalling leading to up‐regulation of HMGA2. Treatment of mouse and human triple‐negative tumour cells with two Wnt/β‐catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse‐free‐survival and metastasis in TNBC patients.

  • Received February 22, 2012.
  • Revision received November 13, 2012.
  • Accepted November 14, 2012.
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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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