The effect of PPARgamma ligands on UV- or chemically-induced carcinogenesis in mouse skin.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor. There have been suggestions that PPARgamma ligands may have utility in preventing tumor development in rodent mammary glands and colon. The recent finding that mice lacking one allele of the PPARgamma gene were significantly more susceptible to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis compared to wild-type mice highlights mouse skin as another potential organ in which PPARgamma ligands may be effective as chemopreventive agents. In this study, we assessed the effect of two PPARgamma ligands (rosiglitazone and troglitazone) on UV and DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis, two of the most commonly used mouse skin carcinogenesis models. Unexpectedly, neither rosiglitazone (dietary 200 ppm) nor troglitazone (topical 100 microg) significantly inhibited UV-induced skin tumor development in SKH-1 hairless mice. Likewise, dietary rosiglitazone did not statistically significantly inhibit DMBA/TPA-induced skin tumor development. Interestingly, dietary troglitazone significantly inhibited basal level keratinocyte proliferation as shown by 5-bromo-2'-deoxyuridine (BrdU) labeling, but it had no effect on TPA-induced epidermal cell proliferation. Northern blot analysis showed that PPARgamma expression was extremely low in normal mouse epidermis and was virtually undetectable in skin tumors. Collectively, our data suggest that PPARgamma ligands may not be useful in the prevention of chemically or UV-induced skin tumors. 2005 Wiley-Liss, Inc.