Conversion of C57B1/6 mice from a tumor promotion-resistant to a -sensitive phenotype by enhanced ornithine decarboxylase expression

A transgenic mouse model was developed in which ornithine decarboxylase (OD C) can be overexpressed in a tissue-specific and regulated manner. Hair fol licle keratinocytes were targeted by use of a bovine keratin 6 (K6) promote r/regulatory region, and regulation was accomplished by using the tetracycl ine-regulated transactivator/tetracycline-response element system. Double-t ransgenic mice carrying both transgenes (K6/tetracycline-regulatable transa ctivator protein (tTA) and tetracycline-response element/Odc) on a C57BI/6 background had no obvious phenotypic abnormalities in the absence (Ode tran sgene-expressed) of doxycycline (a tetracycline analog) in the drinking wat er. However, induction of KG-driven tTA expression by the tumor promoter (1 2-O-tetradecanoylphorbol-13-acetate) (TPA) led to very high levels of epide rmal ODC activity and robust hyperplasia, especially involving hair follicl es. Both effects were abolished by inclusion of doxycycline in the drinking water to repress transgene expression. Finally, the number of papillomas t hat developed in a standard (7,12-dimethybenz[a]anthracene) (DMBA)/TPA prot ocol was greatly reduced in mice in which transgenic Ode expression was rep ressed by doxycycline. Our results demonstrated that the higher levels of O DC expression produced in the transgenic model in the induced versus the re pressed condition make the normally promotion-resistant C57BI/6 strain much more sensitive to the short-term and long-term (i.e., tumor-promoting) eff ects of TPA. (C) 1999 Wiley-Liss, Inc.