The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone

Turan, Valerie K.; Sánchez, Rosa I.; Li, J J; Li, S A; Reuhl, Kenneth R.; Thomas, Paul E.; Conney, Allan H.; Gallo, Michael A.; Kauffman, Frederick C.; Mesía-Vela, Sonia

doi:10.1677/joe.1.05802

Cited by 58 publications

(51 citation statements)

References 33 publications

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“…A 50% incidence of mammary tumors in animals treated with E 2 (3mg) occurred at 16 weeks, whereas a 50% incidence in rats treated with the low dose of E 2 (1 mg) was noted at about 36 weeks. This dose dependency of the incidence of palpable mammary tumors is comparable to that reported earlier for ACI rats implanted with cholesterol pellets containing 1 or 3 mg E 2 (Turan, et al,2004). With the exeception of one rat treated with the high dose of E 2 and fed the clofibrate-containing diet, there were no detectable palpable mammary tumors before 15 weeks.…”

Section: Experiments 1-supporting

confidence: 87%

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Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats

et al. 2008

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Administration of 0.4% clofibrate in the diet stimulated estradiol (E 2 )-induced mammary carcinogenesis in the August-Copenhagen Irish (ACI) rat without having an effect on serum levels of E 2 . This treatment stimulated by several-fold the NAD(P)H-dependent oxidative metabolism of E 2 and oleyl-CoA-dependent esterification of E 2 to 17β-oleyl-estradiol by liver microsomes. Glucuronidation of E 2 by microsomal glucuronosyltransferase was increased moderately. In contrast, the activity of NAD(P)H quinone reductase 1 (NQO1), a representative monofunctional phase 2 enzyme, was significantly decreased in liver cytosol of rats fed clofibrate. Decreases in hepatic NQO1 in livers of animals fed clofibrate were noted before the appearance of mammary tumors. E 2 was delivered in cholesterol pellets implanted in 7 to 8 week old female ACI rats. The animals received AIN-76A diet containing 0.4% clofibrate for 6, 12 or 28 weeks. Control animals received AIN-76A diet. Dietary clofibrate increased the number and size of palpable mammary tumors but did not alter the histopathology of the E 2 -induced mammary adenocarcinomas. Collectively, these results suggest that the stimulatory effect of clofibrate on hepatic esterification of E 2 with fatty acids coupled with the inhibition of protective phase 2 enzymes, may in part, enhance E 2 -dependent mammary carcinogenesis in the ACI rat model.

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Section: Experiments 1-supporting

confidence: 87%

“…26, 239-253. The failure of E2 to stimulate uterine growth in female ACI rats was expectet (e.g., Turan et al (2004); ).…”

Section: Tissue Wet Weights and Serum E 2 Levelsmentioning

confidence: 99%

Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats

et al. 2008

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“…However, El-Bayoumy and colleagues (32) reported that cholesterol epoxides and estrone-3,-4-quinone lack tumorigenic activity in the rat mammary gland. Treatment of pellets containing 2-OHE 2 , 4-OHE 2 , 16a-OHE 2 , or 4-OHE 1 failed to induce any significant mammary tumorigenesis compared with E 2 in the ACI rats (33). Therefore, the direct involvement of 4-OHE 2 or other metabolites of E 2 in the mammary carcinogenesis remains controversial.…”

Section: Discussionmentioning

confidence: 99%

4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of IκB Kinase: Potential Role of Reactive Oxygen Species

Park

Kim

et al. 2009

Cancer Research

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Estrogen is converted by cytochrome P450 1B1 to 4-hydroxyestradiol (4-OHE 2 ), a putative carcinogenic metabolite of estrogen. This catechol estrogen metabolite is oxidized further to produce a reactive quinone via semiquinone. Redox cycling between 4-OHE 2 and its quinoid generates reactive oxygen species (ROS). ROS not only causes oxidative DNA damage but also promotes neoplastic transformation of initiated cells. In the present study, 4-OHE 2 induced anchorageindependent colony formation in human mammary epithelial cells (MCF-10A). MCF-10A cells treated with 4-OHE 2 exhibited increased accumulation of intracellular ROS. The antioxidant N-acetyl-L-cysteine inhibited the neoplastic transformation induced by 4-OHE 2 . ROS overproduced by 4-OHE 2 increased the nuclear translocation of nuclear factor-KB (NF-KB) and its DNA binding through induction of IKB kinase A (IKKA) and IKKB activities. The inhibition of the IKK activities with Bay 11-7082 significantly reduced the anchorage-independent growth induced by 4-OHE 2 . The 4-OHE 2 -induced activation of extracellular signal-regulated kinase and Akt resulted in enhanced IKK activities and phosphorylation of IKBA, thereby inducing NF-KB activation and anchorage-independent growth of MCF-10A cells. In conclusion, ROS, concomitantly overproduced during redox cycling of 4-OHE 2 , activates IKK signaling, which may contribute to neoplastic transformation

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“…12 However, conflicting findings against the carcinogenic activity of catechol estrogens and their intermediates have been reported. Turan et al 13 demonstrated the lack of mammary gland carcinogenicity for 2-and 4-OHE 2 and 4-OHE 1 in the estrogen-sensitive female ACI rat. El-Bayoumy et al…”

mentioning

confidence: 99%

Effects of a catechol‐O‐methyltransferase inhibitor on catechol estrogen‐induced cellular transformation, chromosome aberrations and apoptosis in Syrian hamster embryo cells

Hirose¹,

Tsutsui²,

Ohno³

et al. 2007

Intl Journal of Cancer

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To examine a possible mechanism of endogenous estrogen-induced carcinogenesis, we studied the effect of the catechol-O-methyltransferase (COMT) inhibitor Ro 41-0960 on cell transforming and clastogenic activities of 2 catechol estrogens 2-and 4-hydroxyestrone (2-or 4-OHE 1 ) using Syrian hamster embryo (SHE) cells. COMT activity was assayed by determining the methylation of 2-or 4-OHE 1 using gas chromatography. The production of 2-methoxyestrone in cultures treated with 2-OHE 1 was approximately 2-fold that of 4-methoxyestrone in cultures treated with 4-OHE 1 . 4-OHE 1 induced morphological transformation at a higher frequency than 2-OHE 1 did and the frequencies of cell transformation and chromosome aberrations were not significantly changed in cells treated with 4-OHE 1 in the presence of Ro 41-0960. In contrast, the frequencies of cell transformation and chromosome aberrations were markedly increased in cells treated with 2-OHE 1 along with Ro 41-0960 when compared to cells treated with 2-OHE 1 alone. In addition, both catechol estrogens induced P53 protein expression and apoptosis. The frequencies of apoptotic cells induced by the catechol estrogens were modified by the COMT inhibition in a manner similar to those observed with the chromosome aberrations assay and the cell transformation assay, indicating that each effect by the catechol estrogens at the three measured endpoints might be caused by a mechanism similar to the others. Our findings indicate that COMT activity has an influence on cell transforming activity and its related genetic effects of catechol estrogens in SHE cells, which implies that an individual activity of COMT may be one of the etiological factors in endogenous estrogen-induced carcinogenesis. ' 2007 Wiley-Liss, Inc.Key words: catechol estrogen; cellular transformation; chromosome aberrations; apoptosis; catechol-O-methyltransferase Estrogens are carcinogenic in humans and rodents, 1 but the mechanisms by which these hormones induce cancer are not fully elucidated. Accumulating evidence has suggested that epigenetic mechanisms of estrogens, related to stimulation of cell proliferation, mediated through the estrogen receptor are necessary, but not sufficient, to explain the carcinogenic activity of estrogens in vivo and in vitro under certain experimental conditions, because some estrogens are not carcinogenic.2,3 Estrogen-induced genetic alterations are other possible mechanisms for estrogen-induced carcinogenesis. [3][4][5] Endogenous estrogens may be an etiological factor in the causation of certain types of human cancers, including breast, endometrium, ovary, prostate, and possibly, brain cancers. 6 The endogenous estrogens 17b-estradiol (E 2 ) and estrone (E 1 ) undergo oxidative metabolism, resulting in the production of 16a-hydroxyestrone and catechol estrogens [2-or 4-hydroxyestradiol (2-or 4-OHE 2 ) and 2-or 4-hydroxyestrone (2-or 4-OHE 1 )]. 6 The catechol estrogens may be intermediates in estrogen-induced carcinogenesis. Administration of 4-OHE 1 or 4-OHE 2 at high nonphys...

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The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone

Cited by 58 publications

References 33 publications

Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats

Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats

4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of IκB Kinase: Potential Role of Reactive Oxygen Species

Effects of a catechol‐O‐methyltransferase inhibitor on catechol estrogen‐induced cellular transformation, chromosome aberrations and apoptosis in Syrian hamster embryo cells

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