Functional interaction between E-cadherin and αv-containing integrins in carcinoma cells

Abstract

We have demonstrated the possibility of cross-talk between E-cadherin and αv integrins in breast carcinoma cells. Using the function-blocking anti-αv monoclonal antibody 17E6, applied to monolayer cultures of breast cancer lines, it was found that treatment of cells possessing detergent-insoluble (implying attachment to the actin cytoskeleton) E-cadherin resulted in the adoption of a spheroid configuration of cell growth. This effect was dependent upon not just αv occupancy but also receptor aggregation. Thus in vitro αv-dependent adhesion suppresses E-cadherin-mediated morphological changes. To investigate whether manipulation of E-cadherin would, conversely, modulate integrin activity we introduced a dominant-negative E-cadherin construct into one of the lines, ZR75-1, giving rise to the cell line ZR-E2R1. Surface expression of endogenous E-cadherin was downregulated (by around 25%), whereas β-catenin levels were increased two- to threefold in ZR-E2R1 cells. There was also a highly significant increase in migration of ZR-E2R1 cells(relative to control cells) toward vitronectin (P < 0.001), but not toward collagen type I, fibronectin or laminin. Such increased migration could be abrogated totally by antibody blockade of αvβ5 and αvβ1 integrins. There was no detectable change in αv integrin levels. These data suggest that the introduction of a dominant-negative E-cadherin mutant into ZR75-1, in addition to a loss of cohesion, generates a signal (or signals) which increases migration towards vitronectin through increased activity of αv integrins.