Prostaglandin E receptor EP3 deficiency modifies tumor outcome in mouse two-stage skin carcinogenesis

We have recently shown that the prostaglandin E-2 (PGE(2)) receptor EP3 plays an important role in suppression of colon cancer cell proliferation and that its deficiency enhances late stage colon carcinogenesis. Here we examined the effects of EP3-deficiency on two-stage skin carcinogenesis. 7,12-Dimethylbenz[a]anthracene (50 mu g/200 mu l of acetone) was thus applied to the back skin of female EP3-knockout and wild-type mice at 8 weeks of age, followed by treatment with 12-O-tetradecanoylphorbol-13-acetate (5 mu g/200 mu l of acetone) twice a week for 25 weeks. First tumor appearance was observed in EP3-knockout mice at week 10, which was 3 weeks later than in EP3 wild-type mice, and multiplicity observed at week 11 was significantly lower in the EP3-knockout case. However, histological examination showed that the tumor incidence and multiplicity at week 25 were not significantly changed in knockout mice and wild-type mice (incidence, 19/19 versus 23/24; multiplicity, 3.58 +/- 0.51 versus 3.17 +/- 0.63, respectively). Interestingly, there were no squamous cell carcinomas (SCCs) in the EP3-knockout mice, while SCCs were observed in 3 out of 24 wild-type mice. Furthermore, benign keratoacanthomas only developed in EP3-knockout mice (6/19 versus 0/24, P < 0.01). The results suggest that PGE(2) receptor EP3 signaling might contribute to development of SCCs in the skin.