Genetic factors controlling responsiveness to skin tumor promotion in mice.
Two genetic models that could explain all of the current data are depicted in Figure 4, although it should be stressed that proof of any model will require additional genetic analyses. The first model (Model A) indicates that one or more loci controlling responsiveness to TPA are also responsible for directly controlling responsiveness to other classes of skin tumor promoters such as BzPo and Chr. We have called this locus the Pms locus (for skin tumor promotion sensitivity). The differences between compounds in the magnitude of their promoting ability may reside in the inability to activate a full set or compliment of Pms loci. Genetic differences may reside in a critical Pms locus that is necessary for tumor promotion by all chemical promoters. Alternatively, the current data could be interpreted as showing that different genes responsible for high sensitivity to promotion by diverse promoting agents act on a pathway(s) common to promotion in mouse epidermis (Model B). In this case, the Pms locus would represent a common biochemical/molecular pathway where different responses mediated by different types of promoters ultimately converge and lead to the process of tumor promotion in mouse skin. Directly testing either of the above models will require analyses of progeny from appropriate segregating crosses among the various stocks and strains used in the present study. Model B could help explain several experimental observations. First, SSIn mice, while still retaining a fairly high sensitivity to skin tumor promotion with Chr relative to other inbred strains (i.e., DBA/2, C57BL/6), have lost their increased sensitivity to this anthrone derivative relative to SENCAR mice. SSIn were developed through a process of inbreeding starting with the current outbred SENCAR and employing a selection scheme using DMBA initiation and TPA promotion similar to that originally devised by Boutwell (1964). Second, C57BL/6 mice, although relatively resistant to TPA, chrysarobin and BzPo, are somewhat peculiar in their high resistance to standard promotion protocols using TPA (DiGiovanni et al., 1991). Indirectly, these observations suggest that different genes may regulate some responses to particular types of promoting agent. For example, perhaps the induction of a oxidant response by phorbol esters would represent a specific response to this class of tumor promoters. A testable prediction from these observations is that it may be possible to selectively breed for mouse lines more sensitive and/or resistant to specific classes of promoting agents.
Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Smithville 78957, USA.
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D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004198:Disease Susceptibility; D014644:Genetic Variation; D051379:Mice; D008815:Mice, Inbred Strains; D008957:Models, Genetic; D012641:Selection, Genetic; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D014945:Wound Healing / Q000187:drug effects
D002273:Carcinogens