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Toxicologic Pathology
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Journal Article

TGF{alpha} is Dispensable for Skin Tumorigenesis in Tg.AC Mice

Michael C. Humble

Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27514

Carl J. Szczesniak

Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Noreen C. Luetteke

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27514

Judson W. Spalding

Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Ronald E. Cannon

Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Laura A. Hansen

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892

David C. Lee

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27514

Raymond W. Tennant

Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Alterations in growth factor signaling pathways frequently accompany the development and maintenance of epithelial neoplasia. Transforming growth factor a (TGF{alpha}) and its epidermal growth factor receptor have been thought to play an especially important role in epithelial neoplasia. In this study, mice were derived genetically deficient (null) in functional TGF{alpha} expression and carrying the Tg.AC/v-Ha-ras transgene. The goals were to determine if (a) papillomagenesis was dependent on TGF{alpha} and (b) progression to malignancy was dependent on TGF{alpha} expression. Groups of male and female mice heterozygous or homozygous for the TGF{alpha} null allele and hemizygous for the Tg.AC transgene were treated twice weekly for 10 or 15 wk with doses of 12-O-tetradecanoylphorbol-13-acetate (TPA) known to produce papillomas in Tg.AC mice. Papillomas were readily induced in both male and female TGF{alpha} null mice. Malignant progression of papillomas was observed in all TGF{alpha} null treatment groups. Additionally, we examined the response of TGF{alpha} null mice to full thickness dorsal wounds, a stimulus known to promote papillomagenesis in Tg.AC mice. As in the TPA study, papillomas were induced in both male and female TGF{alpha} null mice. These studies indicate that TGF{alpha} is not required for the induction and maintenance of papillomas nor is it essential for the malignant conversion of papillomas in Tg.AC mice.

Key Words: Transgenic mice • v-Ha-ras • TPA • wounding • epidermal growth factor receptor (EGFR) • oncogene

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Toxicologic Pathology, Vol. 26, No. 4, 562-569 (1998)
DOI: 10.1177/019262339802600413
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