Exogenous Expression of N-Cadherin in Breast Cancer Cells Induces Cell Migration, Invasion, and Metastasis

Abstract

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.

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

“…It has been suggested that increased expression of mesenchymal cadherins such as N-cadherin and cadherin 11 increases the motility and invasiveness of epithelial cells (Hazan et al, 2000;Feltes et al, 2002). Here, TMPRRS4-overexpressing SW480 cells displayed membrane ruffling and lamellipodia formation.…”

Snail2, a mediator of epithelial-mesenchymal transitions, expressed in progenitor cells of the developing endocrine pancreas

“…N-Cadherin is expressed in migratory cells which are undergoing EMT, and has been shown to increase cell motility even in the presence of E-Cadherin (Hazan et al, 2000;Nieman et al, 1999). During EMT the expression of Ecadherin defervesces and the expression of N-cadherin increases (Nakajima et al, 2004).…”

Overexpression of homeobox geneHOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells

“…39 Further, exogenous expression of N-cadherin in breast cancer cells enhances motile, invasive and metastatic ability. 40 Human squamous carcinoma cells that express N-cadherin along with a decreased expression of E-and P-cadherin disrupt cell-cell adhesion and induce a scattered fibroblastic phenotype. 41 Taken together, the loss of E-cadherin and induction of N-cadherin by HOXD3-overexpression are likely to contribute to the invasive and metastatic phenotype.…”