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

Abstract

Integrin alpha6beta4 signaling interactions have been implicated in tumor progression, and beta4 expression has been linked to poor prognosis in certain breast cancer subtypes. We generated human antibodies to alpha6beta4 to further evaluate its role in tumor cell signaling. Biochemical characterization indicated these antibodies are specific for alpha6beta4, recognize distinct epitopes and have low nanomolar affinities for both human and murine protein. The antibodies demonstrated differing effects on alpha6beta4-mediated cellular adhesion, highlighting the existence of different functional epitopes on alpha6beta4. 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 alpha6beta4 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 alpha6beta4 in breast cancer cell survival. The antibodies and data generated herein advance our understanding of alpha6beta4 in regulating tumorigenic processes, and suggest that combination therapies involving alpha6beta4 may be therapeutically effective in breast cancer.

EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines

“…It www.nature.com/scientificreports/ is possible that the high level of Akt phosphorylation in A431 cells precluded detection of a subtle effect of β4 on Akt phosphorylation. In line with this reasoning, previous reports have shown that β4 does influence PI3K signaling, but that the effect of β4 on PI3K signaling is diminished by the presence of constitutively active Akt 53,54 . However, in HaCat keratinocytes that do not exhibit high constitutive levels of phosphorylated Akt and in which the EGFR is not overexpressed, an effect of β4 on the EGFR-mediated phosphorylation of Akt could not be demonstrated.…”

Immunotargeting of Integrin α6β4 for Single-Photon Emission Computed Tomography and Near-Infrared Fluorescence Imaging in a Pancreatic Cancer Model

“…In addition, the inhibition of signaling pathways to interrupt tumor growth by α 6 β 4 antibody in conjunction with growth factor receptor-targeted therapies is attracting attention. 38 Altogether, α 6 β 4 is a good target and the molecular probes that associate to this target should be attractive and promising theranostic agents.…”

α6β4 Integrin Genetic Variations (A380T and R1281W) and Breast Cancer Risk in an Argentinian Population

“…The α6β4 integrin appears to have importance in breast cancer malignancy, as well as in other epithelial carcinomas [12,13,14,16]. There is strong evidence that α6β4 expression is pathologically significant [17].…”