Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis
Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis
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DOI：
10.1038/sj.onc.1210144
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发表时间：
2007-05-01
期刊：
影响因子：
8
通讯作者：
Rogan, E.
中科院分区：
文献类型：
--
作者：
Montano, M. M.;Chaplin, L. J.;Rogan, E.
我们以前报道，抗雌激素配体雌激素受体β（ER β）转录激活主要解毒酶醌还原酶（QR）（NAD（P）H：醌氧化还原酶）。对ERb介导的抗氧化酶上调的功能作用的进一步研究表明，对雌激素诱导的氧化性DNA损伤（ODD）具有保护作用。我们现在报告在体内和体外研究表明，ER β介导的上调QR参与对雌激素诱导的乳腺肿瘤发生的保护。使用八月哥本哈根爱尔兰（ACI）模型的雌激素诱导的致癌作用，我们观察到，增加ODD和QR表达下降发生在雌激素诱导的乳腺肿瘤发生的过程中早期。他莫昔芬预防ACI乳腺肿瘤发生伴随着ODD降低和QR水平增加。这些相关的发现得到了我们的发现的支持，即QR水平的下调导致雌激素醌代谢物水平的增加和17 β-雌二醇处理的MCF 10 A非致瘤性乳腺上皮细胞的转化潜力的增强。同时表达ER β和用4-羟基他莫昔芬治疗降低了这些MCF 10A细胞的致瘤潜力。我们的结论是，QR的上调，通过诱导他莫昔芬，可以抑制雌激素诱导的ODD和乳腺细胞肿瘤的发生，代表一种可能的新机制，他莫昔芬预防乳腺癌。
We previously reported that antiestrogen-liganded estrogen receptor beta (ER beta) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:quinone oxidoreductase). Further studies on the functional role of ERb-mediated upregulation of antioxidative enzymes indicated protective effects against estrogen induced oxidative DNA damage (ODD). We now report on in vivo and in vitro studies that show that ER beta-mediated upregulation of QR are involved in the protection against estrogen-induced mammary tumorigenesis. Using the August Copenhagen Irish (ACI) model of estrogen-induced carcinogenesis, we observed that increased ODD and decreased QR expression occur early in the process of estrogen-induced mammary tumorigenesis. Prevention of ACI mammary gland tumorigenesis by tamoxifen was accompanied by decreased ODD and increased QR levels. These correlative findings were supported by our findings that down regulation of QR levels led to increased levels of estrogen quinone metabolites and enhanced transformation potential of 17 beta-estradiol treated MCF10A non-tumorigenic breast epithelial cells. Concurrent expression of ER beta and treatment with 4-hydroxytamoxifen decreased tumorigenic potential of these MCF10A cells. We conclude that upregulation of QR, through induction by tamoxifen, can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a possible novel mechanism of tamoxifen prevention against breast cancer.