Role of WWOX and ERK in Controlling Cancer Cell Migration

Malignant breast cancer MDA-MB-231 cells are highly metastatic and their cell-cell contact is fairly loose. Accordingly, they migrate individually. Upon stably expressing with ERK, the MDA-MB-231 cells lost individual migration and underwent migration in a collective manner. No apparent loss of speed was observed due to ectopic ERK. Suppression of ERK phosphorylation by U0126 abolished ERK-induced collective migration. Similarly, dominant negative ERK with K72R mutation failed to induce collective migration, indicating that ERK phosphorylation is needed for its induction of collective migration. MDA-MB-231 is a WWOX-negative cell line due to epigenetic modification in the promoter. Ectopic ERK induced the expression of endogenous WWOX. Stimulation of cells with antibody against Ser14 phosphorylation in WWOX abolished the ERK-induced collective migration. In parallel, transiently overexpressed WWOX increased cell-to-cell adhesion and their collective migration. These observations suggest that ERK-induced c...