Here, we demonstrate that engagement of the extracellular matrix protein vitronectin (VN), via the integrin and urokinase/plasminogen activator urokinase receptors (uPARs), leads to activation of SRC and mitogen-activated protein (MAP) kinase (MAPK) signaling and ultimately enhanced FRA-1 phosphorylation and the induction of breast cancer invasion. Here, VTN is linked to breast carcinoma.