N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties. Academic Article uri icon

Overview

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.

publication date

  • August 26, 2013

Research

keywords

  • Breast Neoplasms
  • Cadherins
  • Epithelial-Mesenchymal Transition
  • Extracellular Signal-Regulated MAP Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptors, Fibroblast Growth Factor

Identity

PubMed Central ID

  • PMC4051865

Scopus Document Identifier

  • 84903616764

Digital Object Identifier (DOI)

  • 10.1038/onc.2013.310

PubMed ID

  • 23975425

Additional Document Info

volume

  • 33

issue

  • 26