Prevention of estrogen carcinogenesis in the hamster kidney by ethinylestradiol: some unique properties of a synthetic estrogen.
Ethinylestradiol (EE) has evident paradoxical effects on cancer risk for human breast and hepatic cancer which parallel in some respects its effects on estrogen-induced neoplasms in the hamster kidney and liver. EE has been shown to be only weakly carcinogenic in the hamster kidney, but the most potent carcinogenic estrogen in the hamster liver following prolonged treatment. Unexpectedly, when EE and potent carcinogenic estrogens, such as diethylstilbestrol (DES), 17beta-estradiol (E2) and Moxestrol (MOX), are administered concomitantly, estrogen-induced carcinogenesis in the kidney is completely prevented. In studying this novel finding, we found that, compared with E2 exposure alone, EE at 0.05 and 1.0 nM significantly (P < 0.001) inhibited the rise in proliferation of cultured primary hamster proximal renal tubular (PRT) cells in the presence of E2 (1.0 nM). Consistent with these findings, combined EE + DES treatment for 5.0 months reduced hamster kidney c-myc, c-fos and c-jun RNA expression to 43, 37 and 52%, respectively, compared with levels observed after DES treatment alone. Interestingly, TAM + DES treatment for the same period also resulted in the same low level of RNA expression of these proto-oncogenes. c-MYC, c-FOS and c-JUN protein products were comparably reduced after either EE + DES or TAM + DES treatment. It appears that c-fos expression and c-FOS protein levels in the hamster kidney were more responsive to TAM inhibition. These data demonstrate that EE possesses unique anti-tumorigenic properties in vivo in the hamster kidney. Additionally, the observed anti-estrogen-like effect of EE on cell proliferation of cultured PRT cells suggests that EE may interfere critically with estrogen receptor (ER)-mediated mitogenic pathway(s) affected by potent carcinogenic estrogens, thus preventing subsequent gene dysregulation and, hence, tumor development. Based on competition studies, the differential binding of EE to hamster kidney ER relative to that of the other estrogens (E2, DES, MOX) appears not to contribute to the prevention of estrogen carcinogenesis at this organ site by EE.
Li
J J
JJ
Kansas Cancer Institute, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7312, USA. jli1@kumc.edu
Hou
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X
Bentel
J
J
Yazlovitskaya
E M
EM
Li
S A
SA
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004054:Diethylstilbestrol / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000633:toxicity*; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006965:Hyperplasia; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D008647:Mesocricetus; D011519:Proto-Oncogenes; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D004967:Estrogens; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004997:Ethinyl Estradiol; D004054:Diethylstilbestrol