Carcinogenesis, Vol. 21, No. 12, 2167-2173,
December 2000
© 2000 Oxford University Press
CANCER BIOLOGY |
Unusual deregulation of cell cycle components in early and frank estrogen-induced renal neoplasias in the Syrian hamster
Hormonal Carcinogenesis Laboratory, Division of Etiology and Prevention of Hormonal Cancers, Kansas Cancer Institute, and Departments of Pharmacology, Toxicology, and Therapeutics, and Preventive Medicine, University of Kansas Medical Center, Kansas City, KS 66160-7412, USA
1 Present address: Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
2 Present address: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
3 Present address: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160-7350, USA
There is strong evidence that estrogens are involved in the etiology, promotion and progression of a variety of cancers, including the cancers of the breast and endometrium. The Syrian hamster estrogen-induced, estrogen-dependent renal neoplasm is a well-established animal model used to elucidate the cellular and molecular mechanisms involved in solely estrogen-induced carcinogenic processes. G1 cell cycle progression was studied in estrogen-induced early renal tumor foci and in large kidney tumors of castrated male hamsters. Levels of cyclin D1, cyclin E and retinoblastoma (pRb) proteins were higher in these renal neoplasias than in adjacent uninvolved renal tissue and kidneys from untreated, age-matched animals. Of particular interest is the presence of a predominant 35 kDa cyclin E protein variant form in primary renal tumors. In addition, amounts of the phosphorylated forms of cyclin-dependent kinases (cdk) 2 and 4 were decreased, and both RNA and protein levels of p27kip1 (p27), a cyclin-dependent kinase inhibitor, were markedly higher in early and frank renal tumors than in adjacent uninvolved renal tissue and kidneys of untreated, age-matched animals. These changes in cell 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 functional. In addition, cyclin D1-, cdk2-, cdk4- and cyclin E-associated kinase activities were also lower in these estrogen-induced renal neoplasms than in untreated, age-matched kidneys. Interestingly, when compared with untreated 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 characterized an unusual deregulation of the cell cycle during estrogen-induced renal tumorigenesis in Syrian hamsters which still allows for estrogen-driven kidney tumor cell proliferation and may contribute to the early genomic instability found.
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