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Evidence that mirex promotes a unique population of epidermal cells that cannot be distinguished by their mutant Ha‐ras genotype

Mirex is a potent tumor promoter in 7,12‐dimethylbenz[a]anthracene (DMBA)–initiated female CD‐1 mouse skin. Like 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA), mirex promotes papillomas that have a Ha‐ras mutation; however, unlike TPA promotion, mirex promotion does not involve a general hyperplastic response. We used proliferating cell nuclear antigen (PCNA) and 5‐bromo‐2′‐deoxyuridine (BrdU) immunohistochemical staining to further examine the proliferative capacity of mirex. The numbers of PCNA‐ and BrdU‐positive epidermal S‐phase cells were highly concordant in all treatment groups. Unlike a single application of TPA, a single application of mirex had little or no effect on the number of S‐phase epidermal cells, and chronic application of mirex to mouse skin produced only minimal increases in S‐phase cells. Moreover, mirex did not significantly alter the growth of BALB/MK‐2 keratinocytes in media containing either 0.05 or 1.2 mM Ca++. These results suggest that mirex may have highly specific effects on the proliferation of initiated cells and support the existence of a unique mirex mechanism and/or distinct population of mirex‐promotable mutant Ha‐ras epidermal cells. To begin to address this issue of a distinct population of mirex‐promotable mutant Ha‐ras cells, we conducted a tandem experiment in which DMBA‐initiated mice were treated twice weekly with a maximal promoting dose of mirex. Then, when the number of papillomas reached a plateau, these same mice were treated twice weekly with a maximal promoting dose of TPA. Mice treated with mirex developed a maximum of 6.4 papillomas/mouse. These mice were then promoted with TPA, which produced 8.9 additional papillomas/mouse for a total of 15.3 papillomas/mouse. The maximum tumor yields from other groups of mice treated with only TPA or mirex were 9.8 and 7.3 papillomas/mouse, respectively. Therefore, under these tandem conditions, tumor yields were additive, indicating that there are at least two distinct populations of mutant Ha‐ras cells: one promoted by mirex and the other by TPA. Mol. Carcinog. 20:115–124, 1997. © 1997 Wiley‐Liss, Inc.