The overall goal of this proposal is to determine the role of the glucocorticoid receptor in mouse skin carcinogenesis. Preliminary studies have demonstrated a loss of cytoplasmic glucocorticoid receptors in carcinogenesis. To evaluate the significance of these observations, a four-part approach will be taken. First, in order to construct a more complete molecular model of multistage carcinogenesis in epithelial malignancies, tumors from initial studies will be examined for alterations in glucocorticoid receptor expression and correlated with markers of tumor progression and changes observed in other carcinogenic mechanisms under study in this program project. Second, nuclear translocation and association with the fos/jun oncoproteins will be investigated as mechanisms of glucocorticoid receptor loss. Third, to determine if glucocorticoid receptor loss if tumorigenic, down regulation of glucocorticoid receptor expression will be induced using antisense suppression, and functional loss will be mimicked using RU 486, a pharmacologic antagonist. Fourth, changes in glucocorticoid receptor mRNA during phorbol ester promotion in epidermis will be evaluated to determine how pre-translational changes relate to glucocorticoid receptor loss. The results of this research will allow an evaluation of the glucocorticoid receptor as a potential tumor suppressor gene. An improved understanding of the role of glucocorticoid receptor loss in carcinogenesis may ultimately lead to improved clinical intervention strategies.
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