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N-Cadherin Signaling Potentiates Mammary Tumor Metastasis via Enhanced Extracellular Signal-Regulated Kinase Activation

¹ Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; ² Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; ³ Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and ⁴ Lankenau Institute for Medical Research, Wynnewood, Pennsylvania

Requests for reprints: Rachel B. Hazan, Department of Pathology, Albert Einstein College of Medicine, F529S, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: 718-430-3349; E-mail: rhazan{at}aecom.yu.edu.

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. [Cancer Res 2007;67(7):3106–16]

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