Abstract 2462: Overexpression of prostaglandin E2 EP4 receptor enhances mouse skin tumorigenesis

Abstract

Abstract 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 skin under the control of the bovine keratin 5 promoter (BK5.EP4). Using a two-stage chemical carcinogenesis protocol, the BK5.EP4 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 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 mice again developed more carcinomas compared to none on the WT mice. Immunohistochemistry performed on DMBA-treated mice demonstrated that the BK5.EP4 epidermis began to detach 48 hours after treatment with total detachment occurring 5 days after treatment, while WT mice had only increased epidermal thickening. By 7 to 10 days after DMBA treatment, patches were observed on the BK5.EP4 skin where it appeared the hair and epidermis were detaching, which were not seen on the WT mice. MMP-9, MMP-7, and E-cadherin expression also were upregulated in the BK5.EP4 mice at the same time detachment of the epidermis was occurring. However, no differences in proliferation, stem cell numbers, or CYP1A1 and CYP1B1 expression have been observed. These data suggest that overexpression of EP4 in the mouse skin can increase tumorigenesis, possibly through the wounding of the skin and the subsequent inflammation and epidermal regeneration acting as a tumor promoter. Supported by CA100140. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2462.