Mirex is a chlorinated pesticide and represents a potent prototypical skin tumor promoter that: i) functions through an unidentified mechanism distinct from other skin tumor promoters; ii) appears to promote a unique population of epidermal or epidermal appendage cells that are different than those promoted by phorbol ester, however, this population cannot be distinguished by its mutant Ha-ras genotype; iii) is 4-5 times more potent in female mice; and iv) clonally expands a population of mutant Ha-ras cells that appears to be dependent upon estrogen. Topical estrogen treatment itself has a profound effect on the hair follicle cycle by blocking the transition of the telogen follicle to an anagen follicle, presumably through its direct effect or through its modulation of dermally- or dermal papilla-derived factors that influence proliferations and/or differentiation of the putative bulge stem cell/transient amplifying (TA) cell. Members of the FGF family are known potent modulators of hair follicle as well as epidermal growth and differentiation. We hypothesize that estrogen directly or indirectly through the FGF family influences the differentiation of the putative stem cell/TA cell resulting in a phenotype that is sensitive to mirex promotion.
The specific aims of this proposal are to; i) conclusively demonstrate the estrogen- and estrogen receptor-dependent nature of mirex promotion; ii) localize the expression of the estrogen receptor in skin and the cycling hair follicle and determine if estrogen modulates the expression of FGF members and their receptors; iii) identify the cutaneous origin and phenotype of the mirex promoted papillomas with respect of the estrogen receptor, and FGFs, their cognate receptors and iv) demonstrate a functional interaction between mirex and estrogen/estrogen-modulated FGF in keratinocytes. Further study of this novel tumor promoter will yield a fundamental understanding of how mirex, an environmental chlorinated pesticide, interfaces with estrogen, to function as a potent tumor promoter in skin. The proposed studies will also contribute to our understanding of the role of estrogen and FGF in the regulation hair follicle growth, development and differentiation; epithelial/mesenchymal interactions; and factors that influence the differentiation of putative epidermal stem cells/TA cells to a tumor promoter specific phenotype. An understanding of the mechanism of mirex promotion will be important in the identification of other members of this class and ultimately to the rational risk assessment of nongenotoxic carcinogens.
