N-cadherin engagement provides a dominant stop signal for the migration of MDA-MB-468 breast carcinoma cells

The development of a primary tumor as such is not the main cause of death, but is rather the spreading of metastases, which causes over 90% of deaths in cancer patients. This largely depends on the ability of tumor cells to migrate away from the tumor and relocate at other areas of the body. Cell migration is known to be regulated by various extracellular signal substances such as neurotransmitters. However, before single tumor cells can start to invade into distant tissue, they have to dissociate from the primary tumor. This requires the disruption of cell-cell contacts, which are provided by a plethora of adhesion molecules like the family of cadherins. Using our well, established three-dimensional collagen-based cell migration assay, we show that engagement of N-cadherin results in a significant decrease of the spontaneous and the norepinephrine-induced migration of MDA-MB-468 breast carcinoma cells, which was due to an increase in the average break length. Moreover, this N-cadherin driven influence on the migratory activity is intracellularly integrated via multiple signaling pathways. Our results show that the impact of N-cadherin on the locomotion of MDA cells involves the activation of the adenylyl cyclase and the phosphatidylinositol-3-kinase (PI3K), but is independent of the protein kinase C (PKC) alpha. In summary, we provide evidence that the engagement of N-cadherin provides a stop signal for breast carcinoma cell migration, and accordingly the use of anti-N-cadherin antibodies or soluble ligands might be a tool to inhibit metastasis formation in E-cadherin negative but N-cadherin positive tumors.