Abstract 912: The tumor promoting activity of the prostaglandin E2 EP4 receptor in mouse skin

Chronic inflammation has recently been suggested to be involved in cancer development, and cyclooxygenase-2 (COX-2), a key mediator of the inflammatory response, is known to be upregulated in several cancers. COX-2 is responsible for the production of prostaglandins, and prostaglandin E2 (PGE2) is the major prostaglandin involved in inflammation. PGE2 binds to four receptors (EP1-EP4), and the EP4 receptor has recently been shown to be important in carcinogenesis, depending on the tissue in which it is expressed. To determine the role of EP4 in skin carcinogenesis, transgenic mice were generated that overexpress EP4 in the basal layer of the epidermis under the control of the bovine keratin 5 promoter (BK5.EP4 Tg). Using a two-stage chemical carcinogenesis protocol, the BK5.EP4 Tg mice were shown to develop both papillomas and squamous cell carcinomas earlier than wild type (WT) mice. However, a tumor observed before 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment on one BK5.EP4 Tg mouse suggested that TPA was not necessary for the promotion of the tumors. Therefore a 7,12-dimethylbenz[a]anthracene (DMBA)-only carcinogenesis protocol was performed, and by 30 weeks, the BK5.EP4 Tg mice developed more carcinomas compared to none on the WT mice. Immunohistochemistry performed on DMBA-treated mice demonstrated that the BK5.EP4 Tg epidermis began to detach 48 hours after treatment with total detachment occurring 5 days after treatment, while WT mice had only increased epidermal thickening. Caspase-3, MMP-9, and MMP-7 expression also were upregulated in the BK5.EP4 Tg mice at the same time detachment of the epidermis was occurring. Ki67 analysis showed an initial increase in proliferation in WT mice that slowly declined back to normal levels, while the BK5.EP4 Tg mice instead had a sustained increase in proliferation, which occurred during reepithelialization of the epidermis. These data suggest that overexpression of EP4 in the mouse skin can increase tumorigenesis, possibly through the wounding of the skin and the subsequent epidermal regeneration acting as a tumor promoter. Supported by CA100140. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 912. doi:10.1158/1538-7445.AM2011-912