title: Antibodies directed to alpha6beta4 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.
authors.affiliation: Biogen Idec, San Diego, CA, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Gabarra
authors.forename: Samuel
authors.initials: S
authors.lastname: Cho
authors.forename: Miriam
authors.initials: M
authors.lastname: Ramirez
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: Chen
authors.forename: Anne
authors.initials: A
authors.lastname: Cheung
authors.forename: Xianjun
authors.initials: X
authors.lastname: Cao
authors.forename: Rachel
authors.initials: R
authors.lastname: Rennard
authors.forename: Kelsey R
authors.initials: KR
authors.lastname: Unruh
authors.forename: Christilyn P
authors.initials: CP
authors.lastname: Graff
authors.forename: Beth
authors.initials: B
authors.lastname: Browning
authors.forename: Heather A
authors.initials: HA
authors.lastname: Huet
authors.forename: Karen
authors.initials: K
authors.lastname: McLachlan
mesh_terms: D000906:Antibodies / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism* / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000906:Antibodies; D039161:Integrin alpha6beta4; D016023:Integrins; D066246:ErbB Receptors