Use of RNA interference to inhibit integrin (alpha6beta4)-mediated invasion and migration of breast carcinoma cells.
The application of small interfering RNA (siRNA) oligonucleotides to silence gene expression has profound implications for the intervention of human diseases including cancer. Using this technique, we explored the possibility that the alpha6beta4 integrin, a laminin adhesion receptor with a recognized role in the invasive phenotype of many carcinomas, represents a potential therapeutic target to inhibit the migration and invasion of carcinoma cells. We found that siRNA oligonucleotides targeted to either subunit of the alpha6beta4 integrin reduced cell surface expression of this integrin and resulted in decreased invasion of MDA-MB-231 breast carcinoma cells. Interestingly, reduced alpha6beta4 expression also promoted decreased migration on non-laminin substrata indicating that this integrin can function in a ligand-independent manner. In addition, the absence of beta4 expression in these cells augmented the formation of alpha6beta1 heterodimers and increased adhesion to laminin-1. Taken together, these results substantiate the importance of the alpha6beta4 integrin in invasion and migration that has been demonstrated previously by expression of the beta4 subunit in beta4-deficient cell lines and by function blocking antibodies. Furthermore, these data suggest that the utilization of siRNA oligonucleotides to reduce the expression of the alpha6beta4 integrin may be a useful approach to prevent carcinoma cell progression.
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Elizabeth A
EA
Lipscomb
Aisling S
AS
Dugan
Isaac
I
Rabinovitz
Arthur M
AM
Mercurio
D019921:Biotinylation; D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D019281:Dimerization; D005260:Female; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D039161:Integrin alpha6beta4 / Q000037:antagonists & inhibitors*; D007797:Laminin / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D039161:Integrin alpha6beta4; D007797:Laminin; D034741:RNA, Small Interfering; C121346:laminin 1