title: The EP1 receptor for prostaglandin E2 promotes the development and progression of malignant murine skin tumors.
abstract: High levels of prostaglandin E2 (PGE2) synthesis resulting from the up-regulation of cyclooxygenase (COX)-2 has been shown to be critical for the development of non-melanoma skin tumors. This effect of PGE2 is likely mediated by one or more of its 4 G-protein coupled membrane receptors, EP1-4. A previous study showed that BK5.EP1 transgenic mice produced more carcinomas than wild type (WT) mice using initiation/promotion protocols, although the tumor response was dependent on the type of tumor promoter used. In this study, a single topical application of either 7,12-dimethylbenz[a]anthracene (DMBA) or benzo[a]pyrene (B[a]P), alone, was found to elicit squamous cell carcinomas (SCCs) in the BK5.EP1 transgenic mice, but not in WT mice. While the epidermis of both WT and transgenic mice was hyperplastic several days after DMBA, this effect regressed in the WT mice while proliferation continued in the transgenic mice. Several parameters associated with carcinogen initiation were measured and were found to be similar between genotypes, including CYP1B1 and aromatase expression, B[a]P adduct formation, Ras activity, and keratinocyte stem cell numbers. However, EP1 transgene expression elevated COX-2 levels in the epidermis and SCC could be completely prevented in DMBA-treated BK5.EP1 mice either by feeding the selective COX-2 inhibitor celecoxib in their diet or by crossing them onto a COX-2 null background. These data suggest that the tumor promoting/progressing effects of EP1 require the PGE2 synthesized by COX-2.
authors: The University of Texas MD Anderson Cancer Center, Department of Molecular Carcinogenesis, Science Park, Smithville, TX 78957, USA.
authors: Inok
authors: I
authors: Surh
authors: Joyce E
authors: JE
authors: Rundhaug
authors: Amy
authors: A
authors: Pavone
authors: Carol
authors: C
authors: Mikulec
authors: Erika
authors: E
authors: Abel
authors: Melissa
authors: M
authors: Simper
authors: Susan M
authors: SM
authors: Fischer
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism / Q000502:physiology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*
chemical_list: D002273:Carcinogens; D058306:Receptors, Prostaglandin E, EP1 Subtype; D015127:9,10-Dimethyl-1,2-benzanthracene; D051546:Cyclooxygenase 2; D015232:Dinoprostone