Article | Published:

The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis

Nature Cell Biology volume 15, pages 677687 (2013) | Download Citation

Abstract

Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial–mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.

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Acknowledgements

This work was supported by NIH grant P50CA94056 to the Imaging Core of the Siteman Cancer Center at Washington University, and NIH grants GM080673 and CA143868, and Susan G. Komen for the Cure KG110889 to G.D.L. C.A.C. was supported by NIH grant F31CA165729.

Author information

Affiliations

  1. BRIGHT Institute, Washington University, St Louis, Missouri 63110, USA

    • Kun Zhang
    • , Callie A. Corsa
    • , Julie L. Prior
    • , David Piwnica-Worms
    •  & Gregory D. Longmore
  2. Department of Cell Biology and Physiology, Washington University, St Louis, Missouri 63110, USA

    • Kun Zhang
    • , Callie A. Corsa
    • , David Piwnica-Worms
    •  & Gregory D. Longmore
  3. Department of Medicine, Washington University, St Louis, Missouri 63110, USA

    • Callie A. Corsa
    •  & Gregory D. Longmore
  4. Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA

    • Suzanne M. Ponik
    •  & Patricia J. Keely
  5. Molecular Imaging Center in the Mallinckrodt Institute of Radiology, Washington University, St Louis, Missouri 63110, USA

    • Julie L. Prior
    •  & David Piwnica-Worms
  6. Laboratory for Optical and Computational Imaging, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA

    • Kevin W. Eliceiri
    •  & Patricia J. Keely

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Contributions

K.Z., C.A.C., S.M.P. and J.L.P. were involved in project planning, experimental work and data analysis. D.P-W., K.W.E., P.J.K. and G.D.L. were involved in project planning and data analysis. G.D.L. wrote the manuscript. D.P-W. and P.J.K. provided editorial assistance in the writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gregory D. Longmore.

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DOI

https://doi.org/10.1038/ncb2743

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