Technical Abstract: We previously showed that the EP2 knockout mice were resistant to chemically-Induced skin carcinogenesis. The purpose of this study was to investigate the role of the overexpression of the EP2 receptor in mouse skin carcinogenesis. To determine the effect of overexpression of EP2, we used EP2 transgenic (TG) mice and wild type (WT) mice in a DMBA (7,12-dimethylbenz[a]anthracene)/TPA (12-0-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis protocol. EP2 TG mice developed significantly more tumors compared with WT mice. Overexpression of the EP2 receptor increased TPA-induced keratinocyte proliferation both in vivo and in vitro. In addition, the epidermis of EP2 TG mice 48 hr after topical TPA treatment was significantly thicker compared to that of WT mice. EP2 TG mice showed significantly increased cAMP levels in the epidermis after prostaglandin E2 (PGE2) treatment. The inflammatory response to TPA was increased in EP2 mice, as demonstrated by an increased number of macrophages in the dermis. Turmors and 7xTPA-treated and DMBA-TRA-treated (6 weeks) skin from EP2 mice produced more blood vessels than those of WT mice as determined by CD-31 immunostaining. Vascular endothelial growth factor (VEGF) protein expression was significantly increased in squamous cell carcinoma (SCC) samples from EP2 TG mice compared that of WT mice. There was, however, no difference in the number of apoptotic cells in tumors from WT and EP2 mice. Together, our results suggest that the overexpression of the EP2 receptor plays a significant role in the pro-tumorigenic action of PGE2 in mouse skin.