Epidermal expression of transforming growth factor-α in transgenic mice: Induction of spontaneous and 12-O-tetradecanoylphorbol-13-acetate-induced papillomas via a mechanism independent of Ha-ras activation or overexpression

To assess the requirements for papilloma formation in transgenic mice that over express transforming growth facto‐α (TGF‐α) in the epidermis (HK1.TGFα), we tested the sensitivity of HK1 TGFα mice to tumor promotion with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) and analyzed the resultant papillomas for synergic c‐Ha‐ras activation and overexpression. We observed that HK1.TGFα mice were highly sensitive to TPA promotion, exhibition multiple papillomas as early as the third week of treatment. After 60 wk of promotion, malignant conversion was not observed and tumors regressed upon removal of the TPA promotion stimulus. Most of the TPA‐induced papillomas did not have detectable c‐Ha‐ras mutations at codons 12, 13, or 61, but three papillomes arising after long‐term TPA promotion (5–7 mo) exhibited c‐Ha‐ras activation at codon 61 (A←T and A←G). Conversely, spontaneous papillomas arising without TPA promotion, including persisting autonomous pipiliomas, were all negative for activating c‐Ha‐ras mutations. Both spontaneous and TPA‐induced HK1.TGFα pipiliomas expressed c‐Ha‐ras message levels similarto those in normal, nontransgenic epidermis or HK1 TGFα nyperpiastic epidermis. These data demonstrate that TGF‐α overexpression can be an initiating event for TPA promotion, that papillomatogenesis in HK1.TGFα mice proceeds frequently via a pathway independent of Ha‐ras activation or overexpression, and, thus, that other events are required for autonomous growth and malignant conversion. © 1994 Wiley‐Liss, Inc.