N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation

James Hulit, Kimita Suyama, Su Chung, Rinat Keren, Georgia Agiostratidou, Weisong Shan, Xinyuan Dong, Terence M. Williams, Michael P. Lisanti, Karen Knudsen, Rachel B. Hazan

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143 Scopus citations

Abstract

N-cadherin is up-regulated in aggressive breast carcinomas, but its mechanism of action in vivo remains unknown. Transgenic mice coexpressing N-cadherin and polyomavirus middle T antigen (PyVmT) in the mammary epithelium displayed increased pulmonary metastasis, with no differences in tumor onset or growth relative to control PyVmT mice. PyVmT-N-cadherin tumors contained higher levels of phosphorylated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) than PyVmT controls, and phosphorylated ERK staining was further increased in pulmonary metastases. Tumor cell isolates from PyVmT-N-cadherin mice exhibited enhanced ERK activation, motility, invasion, and matrix metalloproteinase-9 (MMP-9) expression relative to PyVmT controls. MAPK/ERK kinase 1 inhibition in PyVmT-N-cadherin cells reduced MMP-9 production and invasion but not motility. Furthermore, inactivation of fibroblast growth factor receptor in PyVmT-N-cadherin cells reduced motility, invasion, and ERK activation but had no effect on PyVmT cells. Thus, de novo expression of N-cadherin in mammary ducts enhances metastasis of breast tumors via enhanced ERK signaling.

Original languageEnglish (US)
Pages (from-to)3106-3116
Number of pages11
JournalCancer Research
Volume67
Issue number7
DOIs
StatePublished - Apr 1 2007

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hulit, J., Suyama, K., Chung, S., Keren, R., Agiostratidou, G., Shan, W., Dong, X., Williams, T. M., Lisanti, M. P., Knudsen, K., & Hazan, R. B. (2007). N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Research, 67(7), 3106-3116. https://doi.org/10.1158/0008-5472.CAN-06-3401