Unusual deregulation of cell cycle components in early and frank estrogen-induced renal neoplasias in the Syrian hamster

There is strong evidence that estrogens are involved in the etiology, promo tion and progression of a variety of cancers, including the cancers of the breast and endometrium. The Syrian hamster estrogen-induced, estrogen-depen dent renal neoplasm is a well-established animal model used to elucidate th e cellular and molecular mechanisms involved in solely estrogen-induced car cinogenic processes, G(1) cell cycle progression was studied in estrogen-in duced early renal tumor foci and in large kidney tumors of castrated male h amsters. Levels of cyclin D1, cyclin E and retinoblastoma (pRb) proteins we re higher in these renal neoplasias than in adjacent uninvolved renal tissu e and kidneys from untreated, age-matched animals, Of particular interest i s the presence of a predominant 35 kDa cyclin E protein variant form in pri mary renal tumors, In addition, amounts of the phosphorylated forms of cycl in-dependent kinases (cdk) 2 and 4 were decreased, and both RNA and protein levels of p27(kip1) (p27), a cyclin-dependent kinase inhibitor, were marke dly higher in early and frank renal tumors than in adjacent uninvolved rena l tissue and kidneys of untreated, age-matched animals. These changes in ce ll cycle components coincided with a rise in renal tumor cell proliferation . Binding of the elevated p27 protein to cyclin E, cdk2 and cdk4, however, was not impaired, suggesting that this cell cycle suppressor protein is fun ctional. In addition, cyclin D1-, cdk2-, cdk4- and cyclin E-associated kina se activities were also lower in these estrogen-induced renal neoplasms tha n in untreated, age-matched kidneys. Interestingly, when compared with untr eated kidney tissue, early and frank renal neoplasms had less of the 62 kDa native form of E2F1 and contained a 57 kDa variant form. Thus we have char acterized an unusual deregulation of the cell cycle during estrogen-induced renal tumorigenesis in Syrian hamsters which still allows for estrogen-dri ven kidney tumor cell proliferation and may contribute to the early genomic instability found.