12-O-tetradecanoylphorbol-13-acetate promotion of transgenic mouse epidermis coexpressing transforming growth factor-α and v-fos: acceleration of autonomous papilloma formation and malignant conversion via c-Ha-ras activation

✍ Scribed by Xiao-Jing Wang; Kristin M. Liefer; David A. Greenhalgh; Dennis R. Roop

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 588 KB
• Volume: 26
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/(sici)1098-2744(199912)26:4<305::aid-mc9>3.0.co;2-b

✦ Synopsis

To study oncoprotein cooperation in vivo, transgenic mice were established that coexpressed human transforming growth factor-a (TGFa) and v-fos exclusively in the epidermis by means of a human keratin 1 (HK1)-based vector. HK1.fos/a mice exhibited aberrant epidermal proliferation and differentiation and formed spontaneous papillomas that achieved tumor autonomy but did not convert to malignancy. To determine the sensitivity to a chemical promotion stimulus, HK1.fos/a mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). Previously, after 7 mo TPA promotion of HK1.TGFa mice that express moderate levels of TGFa elicited papillomas that remained regression-prone and benign for up to 2 yr. In HK1.fos mice, 6 mo TPA elicited papillomas that required spontaneous c-Ha-ras activation and converted to malignancy after 14±16 mo. We now show that in HK1.fos/a transgenic genotypes, TPA promotion accelerated papillomatogenesis, with the earliest papilloma appearance at 2 mo after initiation of TPA promotion. These papillomas started to convert to malignancy by 10 mo. Analysis of HK1.fos/a papillomas and carcinomas revealed that the endogenous c-Ha-ras gene possessed mutations at codons 12, 13, and 61 at the papilloma stage, but no mutations of the p53 tumor suppressor gene were detected. These data indicate that coexpression of fos and TGFa increased epidermal sensitivity to TPA promotion, which accelerated malignant conversion. However, in this transgenic model conversion always required additional genetic events, e.g., activation of the endogenous c-Ha-ras gene.