Differential Expression of Skin Cancer and Hair-Follicle Cycle Regulated Genes in Tumor Susceptible K14-Agouti Mice

The mouse agouti protein is transiently expressed in the skin and signals through the melanocortin 1 receptor to switch pigment production of hair-follicle melanocytes from black to yellow. Ubiquitous over-expression of agouti protein in mice carrying the spontaneous dominant mutations Ay and Avy causes a pleiotropic syndrome characterized by solid yellow hair color, obesity, diabetes, and increased susceptibility to carcinogenesis in a wide variety of tissues, including the skin. Over-expression of agouti in the skin of keratin 14 (K14)- Agouti transgenic mice promotes skin carcinogenesis, even in the absence of obesity and diabetes. In this study cDNA microarray and qRT-PCR analyses are used to identify molecular changes in the skin of K14-Agouti mice associated with the promotion stage of carcinogenesis. Histological analysis of the skin revealed that there were no differences in gross morphology or in timing of hair- follicle stages between transgenic and control mice. However, cDNA microarray analysis identified 181 genes with significantly altered expression levels in the skin of transgenic mice. Additionally, qRT-PCR analysis demonstrated that the levels and temporal patterns of expression of 10 genes previously associated with skin and/or other epithelial cancers were significantly altered in the skin of K14- Agouti transgenic mice. Agouti-induced over-expression of these proto- oncogenes in the skin of K14-Agouti mice is proposed to be associated with the increased susceptibility to skin carcinogenesis. A hypothetical model is presented to explain the mechanism of action of the agouti protein as a tumor promoter in skin carcinogenesis. Additionally, strategies for future follow-on experiments to further investigate the role of agouti in tumor promotion and to test aspects of the proposed hypothetical model are discussed.