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N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties

Oncogene volume 33, pages 3411–3421 (2014)Cite this article

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Abstract

N-cadherin and HER2/neu were found to be co-expressed in invasive breast carcinomas. To test the contribution of N-cadherin and HER2 in mammary tumor metastasis, we targeted N-cadherin expression in the mammary epithelium of the MMTV-Neu mouse. In the context of ErbB2/Neu, N-cadherin stimulated carcinoma cell invasion, proliferation and metastasis. N-cadherin caused fibroblast growth factor receptor (FGFR) upmodulation, resulting in epithelial-to-mesenchymal transition (EMT) and stem/progenitor like properties, involving Snail and Slug upregulation, mammosphere formation and aldehyde dehydrogenase activity. N-cadherin potentiation of the FGFR stimulated extracellular signal regulated kinase (ERK) and protein kinase B (AKT) phosphorylation resulting in differential effects on metastasis. Although ERK inhibition suppressed cyclin D1 expression, cell proliferation and stem/progenitor cell properties, it did not affect invasion or EMT. Conversely, AKT inhibition suppressed invasion through Akt 2 attenuation, and EMT through Snail inhibition, but had no effect on cyclin D1 expression, cell proliferation or mammosphere formation. These findings suggest N-cadherin/FGFR has a pivotal role in promoting metastasis through differential regulation of ERK and AKT, and underscore the potential for targeting the FGFR in advanced ErbB2-amplified breast tumors.

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Acknowledgements

We thank Dr Jeffrey Segall for providing the wild-type MMTV-ErbB2 mouse. We thank Dr Peng Guo for expert assistance in confocal imaging and the imaging facility at Albert Einstein College of Medicine. This work was supported by grants from the Breast Cancer Research Foundation (RB Hazan and Larry Norton) and the National Cancer Institute grant (1R01 CA135061-01A1; RB Hazan). This publication was also supported in part by the CTSA Grant UL1RR025750, KL2RR025749 and TL1RR025748 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH roadmap for Medical Research.

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Author notes

  1. X Qian and A Anzovino: Xia Qian and Amy Anzovino are equal first authors.

Authors and Affiliations

  1. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA

    X Qian, A Anzovino, S Kim, K Suyama, J Yao, G Agiostratidou, N Chandiramani & R B Hazan

  2. Manchester Breast Centre and Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

    J Hulit

  3. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    H M McDaid

  4. Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA

    C Nagi

  5. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

    H W Cohen

  6. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    G R Phillips

  7. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    L Norton

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Correspondence to R B Hazan.

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Qian, X., Anzovino, A., Kim, S. et al. N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties. Oncogene 33, 3411–3421 (2014). https://doi.org/10.1038/onc.2013.310

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