Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models.
Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models.
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发表时间：
2001-10
期刊：
影响因子：
11.2
通讯作者：
K. Bhat;D. Lantvit;K. Christov;R. Mehta;R. Moon;J. Pezzuto
中科院分区：
文献类型：
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作者：
K. Bhat;D. Lantvit;K. Christov;R. Mehta;R. Moon;J. Pezzuto
反式 3,4',5-三羟基芪（白藜芦醇）是一种存在于葡萄和葡萄酒等葡萄产品中的植物抗毒素，已被确定为化学预防剂。 Recent studies performed with MCF-7 human breast cancer cells have demonstrated superestrogenic effects with resveratrol.相反，使用雌激素受体转染细胞系进行的研究表明，白藜芦醇充当混合激动剂/拮抗剂。本研究的主要目的是表征白藜芦醇在各种体外和体内乳腺模型中的雌激素调节作用。因此，使用 MCF-7、T47D、LY2 和 S30 乳腺癌细胞系评估了白藜芦醇单独使用以及与 17β-雌二醇 (E2) 组合的效果。通过转染报告基因系统的细胞，研究雌激素反应元件荧光素酶的激活，并使用蛋白质印迹分析监测E2反应性孕酮受体（PR）和presnelin 2蛋白的表达。此外，利用置于器官培养物中的 BALB/c 小鼠的乳腺评估了白藜芦醇对肿瘤前病变形成（由 7,12-二甲基苯并（a）蒽诱导）和 PR 表达（有或没有 E2）的影响。最后，po的效果。在雌性 Sprague Dawley 大鼠中研究了给予白藜芦醇对 N-甲基-N-亚硝基脲诱发的乳腺肿瘤的影响。结果，在MCF-7细胞的瞬时转染研究中，白藜芦醇表现出较弱的雌激素反应，但当白藜芦醇与E2（1 nM）组合时，观察到明显的剂量依赖性拮抗作用。 S30 细胞也观察到类似的混合雌激素/抗雌激素作用，而白藜芦醇在 T47D 和 LY2 细胞中充当纯雌激素拮抗剂。此外，在MCF-7细胞中，白藜芦醇诱导PR蛋白表达，但当白藜芦醇与E2联合时，PR表达被抑制。对于 T47D 细胞，白藜芦醇显着下调稳态和 E2 诱导的 PR 蛋白水平。对于 LY2 和 S30 细胞，白藜芦醇下调 presnelin 2 蛋白表达。使用小鼠乳腺器官培养模型，单独施用白藜芦醇可诱导 PR，但在 E2 (1 nM) 存在时表达受到抑制。此外，当通过灌胃法给雌性斯普拉道利大鼠施用时，白藜芦醇可抑制这些乳腺中由 7,12-二甲基苯并（a）蒽诱导的雌激素依赖性癌前导管病变的形成（IC50 = 3.2 µM），并减少 N-甲基-N-亚硝基脲诱导的乳腺肿瘤发生。因此，在缺乏E2的情况下，白藜芦醇在一些乳腺癌细胞系中发挥混合雌激素激动剂/拮抗剂活性，但在存在E2的情况下，白藜芦醇起到抗雌激素的作用。在啮齿动物模型中，致癌物引起的癌前病变和乳腺肿瘤受到抑制。这些数据表明，如果将白藜芦醇用作乳腺癌的化学预防剂，可能会产生有益的作用。
Trans-3,4',5-trihydroxystilbene (resveratrol), a phytoalexin present in grapes and grape products such as wine, has been identified as a chemopreventive agent. Recent studies performed with MCF-7 human breast cancer cells have demonstrated superestrogenic effects with resveratrol. In contrast, studies performed using estrogen receptor-transfected cell lines have shown that resveratrol acts as a mixed agonist/antagonist. The major objective of this study was to characterize the estrogen-modulatory effects of resveratrol in a variety of in vitro and in vivo mammary models. Thus, the effect of resveratrol alone and in combination with 17beta-estradiol (E2) was assessed with MCF-7, T47D, LY2, and S30 mammary cancer cell lines. With cells transfected with reporter gene systems, the activation of estrogen response element-luciferase was studied, and using Western blot analysis, the expression of E2-responsive progesterone receptor (PR) and presnelin 2 protein was monitored. Furthermore, the effect of resveratrol on formation of preneoplastic lesions (induced by 7,12-dimethylbenz(a)anthracene) and PR expression (with or without E2) was evaluated with mammary glands of BALB/c mice placed in organ culture. Finally, the effect of p.o. administered resveratrol on N-methyl-N-nitrosourea-induced mammary tumors was studied in female Sprague Dawley rats. As a result, in transient transfection studies with MCF-7 cells, resveratrol showed a weak estrogenic response, but when resveratrol was combined with E2 (1 nM), a clear dose-dependent antagonism was observed. Similar mixed estrogenic/antiestrogenic effects were noted with S30 cells, whereas resveratrol functioned as a pure estrogen antagonist with T47D and LY2 cells. Furthermore, in MCF-7 cells, resveratrol induced PR protein expression, but when resveratrol was combined with E2, expression of PR was suppressed. With T47D cells, resveratrol significantly down-regulated steady-state and E2-induced protein levels of PR. With LY2 and S30 cells, resveratrol down-regulated presnelin 2 protein expression. Using the mouse mammary organ culture model, resveratrol induced PR when administered alone, but expression was suppressed in the presence of E2 (1 nM). Furthermore, resveratrol inhibited the formation of estrogen-dependent preneoplastic ductal lesions induced by 7,12-dimethylbenz(a)anthracene in these mammary glands (IC50 = 3.2 microM) and reduced N-methyl-N-nitrosourea-induced mammary tumorigenesis when administered to female Sprague Dawley rats by gavage. Therefore, in the absence of E2, resveratrol exerts mixed estrogen agonist/antagonist activities in some mammary cancer cell lines, but in the presence of E2, resveratrol functions as an antiestrogen. In rodent models, carcinogen-induced preneoplastic lesions and mammary tumors are inhibited. These data suggest that resveratrol may have beneficial effects if used as a chemopreventive agent for breast cancer.