Therapeutic Targeting of Osteopontin in Breast Cancer Cells

Osteopontin (OPN), a cytokine like ECM associated member of Small Integrin Binding LIgand N-linked Glycoprotein (SIBLING) family of protein plays an important role in determining the metastatic potential of many cancers. The function of OPN in various pathophysiological conditions, especially in cancer indicated that the variation in posttranslational modification generate different functional forms that might alter its normal physiological functions. Recent data indicated that OPN regulates tumor growth through induction of pro-angiogenic and metastatic genes like COX-2, and VEGF expressions and activation of matrix metalloproteinase (MMP) in cancer cells. The exact role of stromaand tumor-derived OPN in regulation of tumor growth and angiogenesis in various cancers is not well understood. Therefore, it is important to delineate the mechanism by which both tumor and stroma-derived OPN control the cell migration and tumor growth. p70S6 kinase, STAT3 and VEGF are directly involved in regulation of breast tumor growth and angiogenesis. But, the mechanism by which OPN regulates p70S6 kinase and STAT3 activation and VEGF expression leading to breast cancer cell migration, tumor growth and angiogenesis are not well defined. We have recently shown that OPN induces p70S6 kinase phosphorylation in a site specific manner. Interestingly, OPN has no effect on mTOR phosphorylation, but overexpression of mTOR does not regulate OPN-induced phosphorylation of p70S6 kinase. Overexpression of mTOR/p70S6 kinase suppresses OPNinduced ICAM-1 expression, while treatment with rapamycin enhances OPN-induced ICAM-1 expression. Our recent data also indicated that OPN upregulates JAK2 dependent STAT3 activation in breast cancer cells. Wild type STAT3 enhanced whereas mutant STAT3 suppressed OPN-induced breast tumor cell migration. Cells overexpressing STAT3 upregulate whereas mutant STAT3 downregulate OPN-induced tumor growth leading to