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

X. Qian, A. Anzovino, S. Kim, Kimita Suyama, J. Yao, J. Hulit, G. Agiostratidou, N. Chandiramani, Hayley M. McDaid, C. Nagi, H. W. Cohen, G. R. Phillips, L. Norton, Rachel Hazan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3411-3421
Number of pages11
JournalBritish Dental Journal
Volume217
Issue number1
DOIs
StatePublished - Jul 11 2014

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Fibroblast Growth Factor Receptors
Cadherins
Stem Cells
Neoplasm Metastasis
Epithelial-Mesenchymal Transition
Extracellular Signal-Regulated MAP Kinases
Cyclin D1
Cell Proliferation
Breast Neoplasms
Proto-Oncogene Proteins c-akt
Aldehyde Dehydrogenase
Gastropoda
Snails
Breast
Up-Regulation
Epithelium
Phosphorylation
Carcinoma

Keywords

  • ErbB2
  • FGFR
  • mammospheres
  • metastasis
  • N-cadherin

ASJC Scopus subject areas

  • Dentistry(all)

Cite this

N-cadherin/FGFR promotes metastasis through epithelial-tomesenchymal transition and stem/progenitor cell-like properties. / Qian, X.; Anzovino, A.; Kim, S.; Suyama, Kimita; Yao, J.; Hulit, J.; Agiostratidou, G.; Chandiramani, N.; McDaid, Hayley M.; Nagi, C.; Cohen, H. W.; Phillips, G. R.; Norton, L.; Hazan, Rachel.

In: British Dental Journal, Vol. 217, No. 1, 11.07.2014, p. 3411-3421.

Research output: Contribution to journalArticle

Qian, X, Anzovino, A, Kim, S, Suyama, K, Yao, J, Hulit, J, Agiostratidou, G, Chandiramani, N, McDaid, HM, Nagi, C, Cohen, HW, Phillips, GR, Norton, L & Hazan, R 2014, 'N-cadherin/FGFR promotes metastasis through epithelial-tomesenchymal transition and stem/progenitor cell-like properties', British Dental Journal, vol. 217, no. 1, pp. 3411-3421. https://doi.org/10.1038/onc.2013.310
Qian, X. ; Anzovino, A. ; Kim, S. ; Suyama, Kimita ; Yao, J. ; Hulit, J. ; Agiostratidou, G. ; Chandiramani, N. ; McDaid, Hayley M. ; Nagi, C. ; Cohen, H. W. ; Phillips, G. R. ; Norton, L. ; Hazan, Rachel. / N-cadherin/FGFR promotes metastasis through epithelial-tomesenchymal transition and stem/progenitor cell-like properties. In: British Dental Journal. 2014 ; Vol. 217, No. 1. pp. 3411-3421.
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