The 2-series of prostaglandin E (PGE(2)) is regarded as a pro-cancer prostanoid, whereas the 1-series (PGE(1)) and the 3-series ( PGE(3)) are considered to act as anti-cancer prostanoids. In the present study, we provide possible reasons why PGE(1) and PGE(3), but not PGE(2), exert anti-cancer effects by focusing on each diverged E-type prostanoid (EP)(4) receptor-mediated signaling pathway. PGE(1), PGE(2) and PGE(3) function as full agonists in terms of Gas-and Gai-protein-mediated signaling. However, PGE(1) and PGE(3) function as partial agonists of T-cell factor (TCF)/beta-catenin (beta-cat)-mediated activity, the well-known cancer-related signaling pathway. Furthermore, pretreatment with PGE(1) or PGE(3) almost completely reduces PGE(2)-induced TCF/beta-cat activity. These results provide a plausible reason why PGE(1) and PGE(3) function as anti-cancer prostanoids as a result of novel biased activity for EP4 receptors.