E- and N-cadherin are calcium-dependent cell adhesion molecules that mediate cell–cell adhesion and also modulate cell migration and tumor invasiveness. The loss of E-cadherin–mediated adhesion has been shown to play an important role in the transition of epithelial tumors from a benign to an invasive state. However, recent evidence indicates that another member of the cadherin family, N-cadherin, is expressed in highly invasive tumor cell lines that lacked E-cadherin expression. These findings have raised the possibility that N-cadherin contributes to the invasive phenotype. To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin–expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis. Transfected cells expressed both E- and N-cadherin and exhibited homotypic cell adhesion from both molecules. In vitro, N-cadherin–expressing cells migrated more efficiently, showed an increased invasion of Matrigel, and adhered more efficiently to monolayers of endothelial cells. All cells produced low levels of the matrix metalloproteinase MMP-9, which was dramatically upregulated by treatment with FGF-2 only in N-cadherin–expressing cells. Migration and invasion of Matrigel were also greatly enhanced by this treatment. When injected into the mammary fat pad of nude mice, N-cadherin–expressing cells, but not control MCF-7 cells, metastasized widely to the liver, pancreas, salivary gland, omentum, lung, lymph nodes, and lumbar spinal muscle. The expression of both E- and N-cadherin was maintained both in the primary tumors and metastatic lesions. These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin. The increase in MMP-9 production by N-cadherin–expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin–expressing cells.
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21 February 2000
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February 21 2000
Exogenous Expression of N-Cadherin in Breast Cancer Cells Induces Cell Migration, Invasion, and Metastasis
In Special Collection:
JCB65: Cell Adhesion and Migration
Rachel B. Hazan,
Rachel B. Hazan
aThe Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029
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Greg R. Phillips,
Greg R. Phillips
aThe Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029
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Rui Fang Qiao,
Rui Fang Qiao
aThe Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029
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Larry Norton,
Larry Norton
bDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021
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Stuart A. Aaronson
Stuart A. Aaronson
aThe Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029
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Rachel B. Hazan
aThe Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029
Greg R. Phillips
aThe Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029
Rui Fang Qiao
aThe Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029
Larry Norton
bDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021
Stuart A. Aaronson
aThe Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029
Abbreviations used in this paper: ECM, extracellular matrix; H&E, hematoxylin-eosin staining; MMP, matrix metalloproteinase; uPA, urokinase plasminogen activator.
Received:
October 19 1999
Revision Requested:
January 11 2000
Accepted:
January 14 2000
Online ISSN: 1540-8140
Print ISSN: 0021-9525
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Cell Biol (2000) 148 (4): 779–790.
Article history
Received:
October 19 1999
Revision Requested:
January 11 2000
Accepted:
January 14 2000
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Citation
Rachel B. Hazan, Greg R. Phillips, Rui Fang Qiao, Larry Norton, Stuart A. Aaronson; Exogenous Expression of N-Cadherin in Breast Cancer Cells Induces Cell Migration, Invasion, and Metastasis. J Cell Biol 21 February 2000; 148 (4): 779–790. doi: https://doi.org/10.1083/jcb.148.4.779
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