This proposed program project contains three highly relevant and interrelated projects by a number of independent investigators at the Science Park - Research Division (S.P.R.D.) of the University of Texas M.D. Anderson Cancer Center. The primary objective of this program project is to establish the importance, in an integrated manner, of specific genes, gene products and genetic changes during multistage carcinogenesis using the mouse skin model. The overall approach will allow us to determine the sequential occurrence of these alterations, how these interrelate to each other during the induction of cancer and the functional significance of these changes during the carcinogenic process. Specific goals of the program project are as follows: i) to determine the role of two cellular receptors i.e., the epidermal growth factor receptor (EGFr) and the glucocorticoid receptor (GcR) during multistage skin carcinogenesis (Projects 2 and 3); ii) to determine the role of both a positive [transforming growth factor alpha (TGFalpha)] and negative (TGFbeta) growth factor during multistage skin carcinogenesis (Project 3); iii) to determine the role of specific chromosomal changes during the tumor progression stage of multistage skin carcinogenesis (Project 1); and iv) to establish and correlate phenotypic changes (histological, biochemical, and molecular) in premalignant skin lesions with genetic events linked to tumor progression (Projects 1, 2 and 3). The overall hypotheses to be tested in this program project are i) that changes in the expression (mRNA, protein) or function of specific genes and gene products, including: TGFalpha, TGFbeta, EGRr, GcR, Ha-ras, c-Fos, and PKC are either causal or permissive for specific stages of multistage carcinogenesis in the skin, and ii) that certain phenotypic changes in premalignant skin lesions can be directly linked to specific genetic events (i.e., chromosomal changes) which are causal for their progression to malignant skin lesions.
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