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Osteopontin (OPN) is a secreted phosphoprotein which mediates tumorigenesis, local growth, and metastasis in a variety of cancers.It is a potential therapeutic target for the regulation of cancer metastasis.RNA aptamer technology targeting OPN may represent a clinically viable therapy.In this study, we characterize the critical sequence of an RNA aptamer, termed OPN-R3, directed against human OPN.It has a K(d) of 18 nmol/1 and binds specifically to human OPN as determined by RNA electrophoretic mobility assays.In MDA-MB231 human breast cancer cells examined under fluorescence microscopy, OPN-R3 ablates cell surface binding of OPN to its cell surface CD44 and alpha(v)beta(3) integrin receptors.Critical enzymatic components of the OPN signal transduction pathways, PI3K,JNK1/2, Src and Akt, and mediators of extracellular matrix degradation, matrix metalloproteinase 2 (MMP2) and uroplasminogen activator (uPA), are significantly decreased following exposure to OPN-R3.OPN-R3 inhibits MDAMB231 in vitro adhesion, migration, and invasion characteristics by 60, 50and 65%, respectively.In an in vivo xenograft model of breast cancer, OPN-R3 significantly decreases local progression and distant metastases.On the basis of this "proof-of-concept" study, we conclude that RNA aptamer targeting of OPN has biologically relevance for modifying tumor growth and metastasis.