Hormonal carcinogenesis: Separation of estrogenicity from carcinogenicity

Liehr, Joachim G.; Stancel, George M.; Chorich, Lynn P.; Bousfield, George R.; Ulubelen, A A

doi:10.1016/s0009-2797(86)80064-3

Cited by 70 publications

(63 citation statements)

References 12 publications

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“…Different estrogens used in the present study differ in their estrogenic, carcinogenic, and metabolic activation potentials (14-17). ␤E2 is a good catechol progenitor and a potent estrogen; its use results in 80-100% tumor incidence in the hamster kidney (6,10,14,15). 17␣-estradiol (␣E2) is a nontumorigenic, weak estrogen with a catechol-forming potential similar to that of ␤E2 (24, 25).…”

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confidence: 99%

“…The natural female sex hormone 17␤-estradiol (␤E2) and the synthetic estrogen diethylstilbestrol induce tumors in rats, mice, and hamsters (10)(11)(12)(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)(15)(16)(17).…”

mentioning

confidence: 99%

“…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)(15)(16)(17). Therefore, it is postulated that estrogen metabolism may play a key role in hormonal carcinogenesis.…”

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confidence: 99%

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Critical role of oxidative stress in estrogen-induced carcinogenesis

Bhat

Calaf

Hei

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

121

131

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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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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Critical role of oxidative stress in estrogen-induced carcinogenesis

Bhat

Calaf

Hei

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

121

131

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“…Studies in which the development of breast and endometrial cancer was associated with estrogen therapy [2][3][4][5][6] were supported by a more recent follow-up study in which it was demonstrated that post-menopausal women have an increased risk of breast cancer when using estrogens, especially in combination with progestin [7]. In animals, too, a relationship between the administration of estrogens and the development of cancer was shown [8].The carcinogenic properties of estrogens are explained by direct stimulation of cell proliferation via estrogen receptor mediated mechanisms [9,10] and by mechanisms based on metabolic activation [11][12][13][14], leading to DNA damage such as oxidative damage [15][16][17][18] and the formation of DNA-adducts [19 -28], which can cause mutations and induce cancer [29].The latter pathways are the result of metabolic activation of estrogens by the cytochrome P-450 system leading to 2-and 4-hydroxy derivatives. The 2-hydroxy estrogens are excreted in the urine as a result of their fast transformation to water-soluble compounds [13,14].…”

mentioning

confidence: 95%

“…The carcinogenic properties of estrogens are explained by direct stimulation of cell proliferation via estrogen receptor mediated mechanisms [9,10] and by mechanisms based on metabolic activation [11][12][13][14], leading to DNA damage such as oxidative damage [15][16][17][18] and the formation of DNA-adducts [19 -28], which can cause mutations and induce cancer [29].…”

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confidence: 99%

Detection of estrogen DNA-adducts in human breast tumor tissue and healthy tissue by combined nano LC-nano ES tandem mass spectrometry

Embrechts

Lemière

Dongen

et al. 2003

J. Am. Soc. Mass Spectrom.

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For the first time estrogen DNA-adducts were identified in DNA human breast tumor tissue using nano-LC coupled to nano-Electrospray Tandem Mass Spectrometry. Normal breast tissue was analyzed analogously. The data obtained in the five breast tumor and five adjacent normal tissue samples were compared qualitatively, but no straightforward difference was observed. Prior to LC-MS analysis the DNA was enzymatically hydrolyzed to a nucleoside pool. The DNA-hydrolysates were directly injected onto a column switching system developed for on-line sample clean-up and subsequent analysis of the DNA-adducts. In four patients using Premarin, DNA-adducts of 4-hydroxy-equilenin (4OHEN) were detected. All except three samples contained DNA-adducts from 4-hydroxy-estradiol or 4-hydroxy-estrone. Also DNA isolated from eight alcohol fixed and paraffin embedded breast tumor tissue showed the presence of different estrogen DNA-adducts. Worthwhile mentioning is the presence of adducts responding to m/z 570 Ͼ m/z 454 transition. This is a well-known SRM-transition indicative for the presence of the 2'-deoxyguanosine (dGuo) adduct of Benzo H ormone treatment is widespread for women of all ages. In the United States, for instance, 30% of post-menopausal women use hormone eeplacement therapy (HRT) [1], e.g., Premarin. Studies in which the development of breast and endometrial cancer was associated with estrogen therapy [2][3][4][5][6] were supported by a more recent follow-up study in which it was demonstrated that post-menopausal women have an increased risk of breast cancer when using estrogens, especially in combination with progestin [7]. In animals, too, a relationship between the administration of estrogens and the development of cancer was shown [8].The carcinogenic properties of estrogens are explained by direct stimulation of cell proliferation via estrogen receptor mediated mechanisms [9,10] and by mechanisms based on metabolic activation [11][12][13][14], leading to DNA damage such as oxidative damage [15][16][17][18] and the formation of DNA-adducts [19 -28], which can cause mutations and induce cancer [29].The latter pathways are the result of metabolic activation of estrogens by the cytochrome P-450 system leading to 2-and 4-hydroxy derivatives. The 2-hydroxy estrogens are excreted in the urine as a result of their fast transformation to water-soluble compounds [13,14]. The 4-hydroxy form, however, has a longer half-life

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Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: Involvement of metabolic activation and cytochrome P450

Patel

Bhat

2004

J Biochem & Molecular Tox

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Different estrogens vary in their carcinogenic potential despite having similar hormonal potencies; however, mechanisms of estrogen-induced carcinogenesis remain to be fully elucidated. It has been hypothesized that generation of reactive estrogen-quinones and oxidative stress, both of which result from metabolic activation of estrogens, play an essential role in estrogen-induced carcinogenesis. This hypothesis was tested using the estrogen-receptor (ER)-alpha-positive hamster kidney tumor (H301) and the human breast cancer (MCF-7) cell lines. Estrogens with differing carcinogenic potentials were compared in terms of their capacities to induce 8-iso-prostaglandin F(2alpha) (8- iso-PGF(2alpha)), a marker of oxidative stress. Tumor cells were treated with either 17beta-estradiol (E2), a carcinogenic estrogen or 17-alpha-ethinylestradiol (EE), a weakly-carcinogenic estrogen. Tumor cells were also treated with alpha-naphthoflavone, a cytochrome P450 inhibitor, or a combination of alpha-naphthoflavone and E2 to study the effect of metabolic activation of E2 on E2-induced oxidative stress. H301 cells treated with E2 displayed time- and dose-dependent increases in 8-iso-PGF(2alpha), compared to controls; treatment with 10 nM E2 resulted in a maximal 4-fold induction following 48 h of treatment. In contrast, H301 cells treated with EE did not display an increase in 8-iso-PGF(2alpha) compared with controls. In H301 cells cotreated with alpha-naphthoflavone and E2, alpha-naphthoflavone inhibited the E2-induced increase in 8-iso-PGF(2alpha). These data indicate that a carcinogenic estrogen shows strong oxidant potential, whereas a weakly-carcinogenic estrogen shows poor oxidant potential. Furthermore, inhibiting metabolic activation of a carcinogenic estrogen blocks its oxidant potential. Our data support the hypothesis that metabolic activation and subsequent generation of oxidative stress may play critical roles in estrogen-induced carcinogenesis.

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Hormonal carcinogenesis: Separation of estrogenicity from carcinogenicity

Cited by 70 publications

References 12 publications

Critical role of oxidative stress in estrogen-induced carcinogenesis

Critical role of oxidative stress in estrogen-induced carcinogenesis

Detection of estrogen DNA-adducts in human breast tumor tissue and healthy tissue by combined nano LC-nano ES tandem mass spectrometry

Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: Involvement of metabolic activation and cytochrome P450

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