N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation.
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.
Hulit
James
J
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Suyama
Kimita
K
Chung
Su
S
Keren
Rinat
R
Agiostratidou
Georgia
G
Shan
Weisong
W
Dong
Xinyuan
X
Williams
Terence M
TM
Lisanti
Michael P
MP
Knudsen
Karen
K
Hazan
Rachel B
RB
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D010766:Phosphorylation; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D000952:Antigens, Polyomavirus Transforming; D015820:Cadherins; D017468:Receptors, Fibroblast Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9