Mechanisms of estrogen-induced tumorigenesis in the target organ are not well understood. It has been suggested that oxidative stress resulting from metabolic activation of carcinogenic estrogens plays a critical role in estrogen-induced carcinogenesis. We tested this hypothesis by using an estrogen-induced hamster renal tumor model, a well established animal model of hormonal carcinogenesis. Hamsters were implanted with 17␤-estradiol (␤E2), 17␣-estradiol (␣E2), 17␣-ethinylestradiol (␣EE), menadione, a combination of ␣E2 and ␣EE, or a combination of ␣EE and menadione for 7 months. The group treated with ␤E2 developed target organ specific kidney tumors. The kidneys of hamsters treated with ␣E2, ␣EE, or menadione alone did not show any gross evidence of tumor. Kidneys of hamsters treated with a combination of ␣E2 and ␣EE showed early signs of proliferation in the interstitial cells. Kidneys of hamsters treated with a combination of menadione and ␣EE showed foci of tumor with congested tubules and atrophic glomeruli. ␤E2-treated tumor-bearing kidneys showed >2-fold increase in 8-iso-prostaglandin F 2␣ (8-iso-PGF2␣) levels compared with untreated controls. Kidneys of hamsters treated with a combination of menadione and ␣EE showed increased 8-iso-PGF2␣ levels compared with untreated controls, whereas no increase in 8-iso-PGF2␣ was detected in kidneys of ␣EE-treated group. A chemical known to produce oxidative stress or a potent estrogen with poor ability to produce oxidative stress, were nontumorigenic in hamsters, when given as single agents, but induced renal tumors, when given together. Thus, these data provide evidence that oxidant stress plays a crucial role in estrogen-induced carcinogenesis.tumor ͉ hormonal carcinogenesis ͉ menadione ͉ prostaglandin ͉ metabolic activation S ex hormones are implicated in the development of a variety of human cancers (1-4). Estrogen administration to postmenopausal women is associated with an increased risk of endometrial and breast cancer (1-4). An increasing evidence of elevated breast cancer risk with increases in total lifetime exposure of women to estrogens has been presented (1-3). Recently, the clinical trial of estrogen plus progestin treatment therapy was stopped because of an increased risk of breast cancer (5). Knowledge of how estrogens induce proliferation and tumorigenesis in their target organ is not well defined (6-9). The mechanism of tumor induction by estrogens is being investigated in rodent models of hormonal carcinogenesis. The natural female sex hormone 17␤-estradiol (␤E2) and the synthetic estrogen diethylstilbestrol induce tumors in rats, mice, and hamsters (10-13). It must be noted that in rodent models, different estrogens tested have not shown similar carcinogenic potential despite their similar hormonal potencies (6, 14, 15). However, carcinogenic and noncarcinogenic estrogens differ in their metabolic activation profiles (14-17). Therefore, it is postulated that estrogen metabolism may play a key role in hormonal carcinogenesis.Estrogens can be met...

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