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

By R. Hazan, G. Phillips, R. Qiao, Larry Norton, S. Aaronson. Journal of Cell Biology, 2000

948 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d1dcd1e0e4746a26bfc195658629eda08d2629e8

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Citations in the corpus

Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression (2007, background): “…E- and N-cadherin in untreated PMC42-LA cells is different from previous studies of other breast cancer cell lines, in which N-cadherin was selectively expressed by E-cadherin–negative invasive human breast carcinoma cell lines and predicted invasiveness (Nieman et al., 1999; Hazan et al., 2000).”
DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells (2005, background): “N-cadherin has previously been shown to promote cell migration and tumour progression and to accumulate in E-cadherin-negative tumour cells (Hazan et al., 2000; Tomita et al., 2000).”
Putting tumours in context (2001, background): “Loss of E-cadherin can be accompanied by increased expression of alternate cadherin isoforms that promote inappropriate survival signals and enhance the malignant phenotyp”
The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis (2008, neutral): “dtd" [ ]> MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that are important in many biological processe”
The cadherin-catenin adhesion system in signaling and cancer. (2002, background): “N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression.”
P120 Catenin Regulates the Actin Cytoskeleton via Rho Family Gtpases (2000, background): “In this respect, it is pertinent that expression of N-cadherin in breast epithelial cells promotes cell migration (Nieman et al., 1999; Hazan et al., 2000).”
Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. (2002, result): “suggests a new role for this mesenchymal, pro-migratory cadherin in gastric cancer progression, as recently reported by Yanagimoto et al(42) Similar findings were published for melanoma, breast, and prostate cancer cells before.(15,17,18,33) This abnormal expression in tumors has never been linked t”
EMT, the cytoskeleton, and cancer cell invasion (2009, background): “As a result, sustained MAPK pathway activation and increased cell motility and MMP secretion promote invasiveness of N-cadherin-expressing cells [96–98].”
Role of tissue stroma in cancer cell invasion (2003, background): “NCadherin is receiving increasing attention, not only in cancer [121] but also in the formation of axon trajectories in the nervous system [256,257].”
The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways (2022, methodology): “Invasion assays were carried out as previously described with Boyden chambers (25).”
Cell adhesion and signalling by cadherins and Ig-CAMs in cancer (2004, background): “N-cadherin has been shown to promote cell motility and migration — an opposite effect to that of E-cadheri”
Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. (2006, positive): “It has also been postulated that expression of N-cadherin in tumor cells acts as a targeting mechanism for endothelial and stromal tissue during metastasis (Hazan et al. 2000; De Wever et al. 2004; Qi et al. 2005).”