Targeted expression of bcl-2 to murine basal epidermal keratinocytes results in paradoxical retardation of ultraviolet- and chemical-induced tumorigenesis

The antiapoptotic protein bcl-2 is found up-regulated in a number of malign ant and premalignant skin conditions of keratinocyte origin, but in normal skin, it is expressed at low levels only in interfollicular epidermis. To i nvestigate whether unregulated bcl-2 expression could affect the incidence of epidermal tumors, we have generated a mouse line that or er-expresses hu man bcl-2 in the basal layer of epidermis under the control of the human ke ratin 14 promoter. These mice were subjected to both UVB photocarcinogenesi s and classical two-stage chemical carcinogenesis. Although transgenic Bcl- 2 in these mice reduces the formation of sunburn cells after short-term UVB irradiation, chronically UVB irradiated K14/bcl-2 mice were protected agai nst tumor development, because transgenic mice developed tumors much later and at a significantly lower frequency than controls. Immunohistochemical a nalyses of the UVB-induced tumors revealed no significant differences in th e degree of inflammatory cell infiltrates. When either K14/bcl-2 mice or F- 1 progeny of matings with mice expressing an activated Na-ras oncogene (K14 /bcl-2/ras) were treated with 9,10-dimethyl-1,2-benzanthracene/phorbol 12-m yristate 13-acetate, the latency of first papilloma appearance was the same in transgenic mice and controls, but further papillomas developed more slo wly in the mutant mice. Moreover, the K14/bcl-2/ras mice de,eloped far fewe r albeit larger tumors/mouse than did the ras/+ controls. The rate of conve rsion to malignant carcinomas, the carcinoma grade, and the frequency of ly mph node metastases were not significantly different between mutants and co ntrols. We conclude that despite its antiapoptotic Function, bcl-2, overexp ressed in basal epidermal keratinocytes, exerts a paradoxical retardation o n the development of skin tumors induced by chemical carcinogens and partic ularly by UVB.