Activated epidermal growth factor (EGF) receptor in ovarian cancer cells disrupts the function of integrins: Role in cancer cell morphology, adhesion and migration

Elevated expression or activity of the epidermal growth factor (EGF) receptor is common in ovarian cancer and is associated with poor patient prognosis. A naturally occurring EGF receptor mutation termed variant III (EGFRvIII) has been detected in ovarian cancer. This mutant receptor does not bind EGF; however it is constitutively active as detected by receptor dimerization, autophosphorylation and stimulation of signal transduction cascades. In order to identify the consequences of EGFRvIII expression in ovarian cancer cells, we introduced EGFRvIII into the epithelial ovarian cancer cell line OVCA 433. The EGFRvIII-transfected cells displayed functional changes, including decreased integrin alpha2 and beta4 expression. The modulation of integrin alpha2 and beta4 expression corresponded to marked changes in cell spreading, focal adhesions and hemidesmosome assembly. Moreover, we confirmed that activated EGFR transiently modulates integrin alpha2 expression and induces integrin alpha2 internalization, targeting caveolae/raft-mediated endocytosis rather than clathrin-mediated endocytosis in OVCA 433 cells. Together, these findings suggest that EGF receptor acting contributes to more aggressive disease, in part through modulated integrin alpha2 and integrin beta4, which are involved in adhesive processes in both early and late stages of ovarian cancer metastasis.