ESTROGEN-INDUCED PROTOONCOGENE AND SUPPRESSOR GENE-EXPRESSION IN THE HAMSTER-KIDNEY - SIGNIFICANCE FOR ESTROGEN CARCINOGENESIS

Chronic administration of estrogen to male Syrian hamsters for 7.0 to 9.0 months induces a high frequency of estrogen-dependent renal cancer s. We have proposed a sequential multistage scheme involving tubular c ell damage, regenerative cell proliferation, aneuploidy, chromosomal i mbalance, genetic instability, gene alteration, and amplification as e ssential steps for estrogen carcinogenesis in this model, A systematic study was undertaken to assess the expression of nuclear proto-oncoge nes, c-myc, c-fos, and c-jun, and suppressor genes, p53 and WT-1, by N orthern blot analysis to further support this scheme, Hamster kidney R NA, taken at monthly intervals (1.0 to 6.0 months) from diethylstilbes trol (DES)-treated castrated male hamsters and corresponding age-match ed untreated controls was used in these studies, as well as primary es trogen-induced renal tumor RNA, for reference, Although no significant changes in the expression of these proto-oncogenes were detected in t he first 4 months of estrogen treatment relative to age-matched contro ls, 2.1-kb c-myc expression was elevated 2.8- and 4.1-fold at 5.0 and 6.0 months, respectively. Moreover, the expression of 2,2-kb c-fos tra nscript rose 4.6- and 4.8-fold; and 3.2- and 2.7-kb c-jun expression i ncreased 2.8- and 5.1-fold at these same respective estrogen treatment time intervals. Tumor suppressor gene expression, p53 and WT-1, was a lso evaluated in similar estrogen-exposed hamsters. Although no signif icant changes were found in hamster kidney p53 expression in the first 5.0 months of DES treatment, it rose 1.8-fold at 6.0 months of estrog en treatment and more than 2.0-fold in the primary renal tumor. In con trast, no detectable changes in WT-1 expression were found during the first 6.0 months of DES treatment, However, a dramatic 7.0-fold increa se in WT-1 expression was observed in the primary renal tumor. It is e vident that two WT-I transcripts reside in the hamster kidney; a lower molecular weight transcript was found in the normal adult kidney, and a higher molecular weight 3.2-kb transcript was observed in the renal tumor, similar to that seen in the newborn mouse kidney, In summary, the estrogen-induced inappropriate gene expression, including p53, rep orted herein, is consistent with the view that the elevations seen in gene expression contribute to proliferative advantages of certain prox imal tubular interstitial cells necessary for estrogen-driven tumor fo rmation in the hamster.