Abstract
The up‐regulation of the inducible form of cyclooxygenase (COX‐2), a central enzyme in the prostaglandin (PG) biosynthetic pathway, occurs in many epithelial tumors and has been associated with tumor cell proliferation and angiogenesis. To better understand the role of COX‐2 in skin tumor development, we generated transgenic mice that overexpress COX‐2 under the control of the keratin 14 promoter. We previously reported (Cancer Res. 62: 2516, 2002) that these mice, referred to as keratin 14 (K14).COX2 mice, were unexpectedly very resistant to 12‐O‐tetradecanoylphorbol 13‐acetate (TPA) tumor promotion. The current studies were undertaken to determine the mechanism of this resistance and determine if it was restricted to TPA promotion. Transgenic and wild‐type mice were subjected to a complete carcinogenesis protocol using 7,12‐dimethylbenz[a]anthracene (DMBA) only, as well as a two‐stage protocol using DMBA plus an unrelated tumor promoter, anthralin. In addition, the responses of transgenic and wild‐type mice to TPA in terms of induction of proliferation and various down‐stream mediators were examined. The TPA resistance phenotype correlated with a reduced ability to induce ornithine decarboxylase, interleukin‐1α, and tumor necrosis factor‐α and a reduced proliferation response. This resistance phenotype appears to be restricted to phorbol ester promotion because K14.COX2 mice developed six times more tumors than wild‐type mice when anthralin was used as the tumor promoter. Additionally, K14.COX2 mice treated only with DMBA developed approximately 3.5 times more tumors than wild‐type mice, suggesting that PGs have intrinsic tumor promoting activity. We conclude that the role of PGs in skin tumorigenesis is context dependent. © 2007 Wiley‐Liss, Inc.