Overexpression and amplification of c-myc in the Syrian hamster kidney during estrogen carcinogenesis: A probable critical role in neoplastic transformation

An estrogen receptor-driven, multistep process for estrogen carcinogenesis in the Syrian hamster kidney is proposed. Because in this species the repro ductive and urogenital tracts arise from the same embryonic germinal ridge, it is evident that the kidney has carried over genes that are responsive t o estrogens, Using in situ hybridization, overexpression of early estrogen- response genes, i.e., c-myc and c-fos, has been shown to be localized prefe rentially in early renal tumor foci after 3.5-4.0 months of estrogen treatm ent. This event coincides with an increased number of S-phase proliferating cell nuclear antigen-labeled cells in these tumor foci, along with a rapid rise in aneuploid frequency in the kidney. Western blot analyses of c-MYC and c-FOS protein products support the overexpression of these genes, Ampli fication of c-myc, 2.4-3.6-fold, but not of c-fos, was detected in 67% of t he primary renal tumors examined, by Southern blot analyses. Consistent chr omosomal gains, common to both diethylstilbestrol- and estradiol-induced re nal neoplasms, were observed in chromosomes 1, 2, 3, (6), 11, (13), 16, 20, and 21 (chromosome number alterations are indicated in parentheses). Using fluorescence in situ hybridization, the c-myc gene was localized to hamste r chromosome 6qb, Chromosome 6 exhibited a high frequency of trisomies and tetrasomies in the kidney after 5.0 months of estrogen treatment and in pri mary renal tumors. The data presented indicate that estrogen-induced genomi c instability may be a key element in carcinogenic processes induced by est rogens.