Background: Osteopontin (OPN) is a secreted glycoprotein that mediates cell–matrix interactions and cellular signaling by binding with integrin (primarily AvB3) and CD44 receptors. OPN regulates cell adhesion, chemotaxis, macrophage-directed IL-10 suppression, stressdependent angiogenesis, apoptosis prevention, and anchorage-independent growth of tumor cells. However, the molecular mechanisms that define the role of OPN in tumor progression and metastasis are incompletely understood. Methods: In this study, we use a system of 4T1 and 4T07 murine mammary epithelial tumor cell lines that are divergent in both metastatic phenotype and OPN expression. 4T1 expresses OPN and hematogeneously metastasizes, whereas 4T07 does not express OPN and is highly tumorigenic but fails to metastasize. Results: Our results demonstrate that OPN regulates Stat1 protein degradation through the ubiquitin–proteasome pathway to alter interferon-;–dependent growth inhibition and p21 expression. We identify Stat-interacting LIM protein as the critical Stat ubiquitin E3 ligase in this setting. Conclusions: OPN regulates Stat1-dependent functions, such as growth inhibition and p21 expression, in the murine mammary epithelial cells lines 4T1 and 4T07. This relationship between OPN and Stat1 in the context of tumor biology has not been previously examined.