Antibodies directed to α6β4 highlight the adhesive and signaling functions of the integrin in breast cancer cell lines

Abstract

Integrin α6β4 signaling interactions have been implicated in tumor progression, and β4 expression has been linked to poor prognosis in certain breast cancer subtypes. We generated human antibodies to α6β4 to further evaluate its role in tumor cell signaling. Biochemical characterization indicated these antibodies are specific for α6β4, recognize distinct epitopes and have low nanomolar affinities for both human and murine protein. The antibodies demonstrated differing effects on α6β4-mediated cellular adhesion, highlighting the existence of different functional epitopes on α6β4. Interestingly however both antibodies blocked adhesion-independent growth in a panel of breast cancer cell lines. Antibody induced apoptosis and inhibition of phosphoinositide 3-kinase (PI3K) signaling were also observed within the context of matrix adhesion. Enhanced inhibitory effects were observed when the α6β4 antibodies were used in combination with antibodies to epidermal growth factor receptor (EGFR) or erythoblastic leukemia viral oncogene homolog 2 (ErbB2).  These findings illustrate a role for both the adhesive and signaling functions of α6β4 in breast cancer cell survival. The antibodies and data generated herein advance our understanding of α6β4 in regulating tumorigenic processes, and suggest that combination therapies involving α6β4 may be therapeutically effective in breast cancer.