ALTERED EXPRESSION OF EPIDERMAL GROWTH-FACTOR RECEPTOR LIGANDS IN TUMOR PROMOTER-TREATED MOUSE EPIDERMIS AND IN PRIMARY MOUSE SKIN TUMORS INDUCED BY AN INITIATION-PROMOTION PROTOCOL

Multiple epidermal growth factor receptor (EGFr) ligands have been ide ntified, including transforming growth factor a (TGF alpha), heparin-b inding epidermal growth factor (HB-EGF), amphiregulin (AR), and betace llulin (BTC). Previous work from our laboratory demonstrated that TGFa mRNA and protein are upregulated in epidermis during tumor-promoter t reatment of mouse skin and in skin tumors produced by initiation-promo tion regimens. The purpose of the study described here was to explore the role of other EGFr ligands in multistage skin carcinogenesis. A si ngle topical treatment of either 12-O-tetradecanoylphorbol-13-acetate (TPA) or chrysarobin or a single full-thickness wound induced the expr ession of HB-EGF and AR in mRNA samples isolated from whole mouse skin . However, only full-thickness wounding significantly elevated express ion of the BTC transcript. The revels of HB-EGF and AR transcripts wer e significantly elevated in skin tumors (both papillomas and squamous cell carcinomas) induced by initiation-promotion protocols. BTC transc ript levels were low and barely detectable in all skin tumors examined . The level of keratinocyte growth factor (KGF) mRNA was also examined as a possible mechanism for upregulation of EGFr ligands. Only full-t hickness wounding significantly elevated KGF transcript levels in whol e-skin RNA samples. Furthermore, no evidence for upregulation of KGF m RNA in skin tumors was obtained. The results are discussed in terms of the role of EGFr activation in skin carcinogenesis and the mechanisms for altered regulation of EGFr ligands. Mel. Carcinog. 22:73-83, 1998 . (C) 1998 Wiley-Liss, Inc.