Many epithelial tumors highly express the cyclooxygenase-2 (COX-2) enzyme which contributes to tumorigenic and metastatic potential.Preclinical and clinical studies indicate that administration of selective COX-2 inhibitors has protective activity in both cancer prevention and treatment settings.Recent concerns regarding the risk of cardiovascular events resulting from long term use of COX-2 inhibitors, has prompted the examination of other approaches to target the COX-2 pathway.The principal COX-2 product in tumors is prostaglandin E2 (PGE2).Cellular effects of PGE2 are mediated through a family of four G-protein-coupled receptors designated EP 1, EP2, EP3 and EP4.Each receptor is coupled to different intracellular signaling pathways and mediate different cellular responses.Using a murine model of metastatic breast cancer, we examined the effect of targeting two of these receptors, EP 1 and EP4, on tumor growth properties and metastatic potential.Using either a pharmacologic or genetic approach, we have now shown that inhibition of EP4 inhibits tumor metastasis to the same degree as achieved with a COX-2 inhibitor.This beneficial effect is dependent on functioning host Natural Killer cells.In contrast, gene-silencing or pharmacologic antagonism of EP1 actually enhances metastatic ability.Thus, two EP receptors play antagonistic roles in tumor behavior.The EP4 receptor promotes metastasis, whereas EP 1 functions as a metastasis suppressor.These studies indicate that downstream targeting of certain EP receptors should be considered as a potential therapeutic approach to prevent tumor progression.