Phytoestrogen and Antioxidant Regulation of Prostate Cancer

描述（由申请人提供）：消费者使用膳食补充剂预防和治疗前列腺癌。最近，动物前列腺癌模型已经允许测试这些补充剂的安全性和有效性。我们已经建立了小鼠前列腺（TRAMP）转基因腺癌小鼠、雌激素受体缺陷（ER α KO和ER β KO）小鼠和表达TRAMP转基因的ER缺陷小鼠的集落。因此，一个系统的方法是现在可能的分子机制，通过植物影响肿瘤的发病率和进展的鉴定。来自我们模型的令人兴奋的数据清楚地表明，ER α KO小鼠对前列腺的PDC（低分化癌）具有高度保护作用，而ER β KO小鼠对PDC高度易感。除了雌激素信号传导，另外两种信号传导途径也被认为在介导前列腺癌的发生和进展中很重要：DNA甲基化和抗氧化剂信号传导。我们的总体假设是，植物雌激素对ER α和ERP的差异调节，本质上是作为天然的SERM，将有效地预防和治疗人类前列腺癌。我们的目标是描述关键前列腺肿瘤生物标志物对植物药的反应，并为这些反应提供新的分子机制。目标：我们将使用TRAMP小鼠模型，在ER WT或ER-阴性/ TRAMP小鼠中使用两种剂量，用2种高优先级植物药（菠菜和绿色茶;及其生物活性标记物/组分）进行体内癌症预防试验，以研究ER α和ER β蛋白在前列腺肿瘤发生中的体内作用及其对PDC发展的影响。目的Ib：我们将证实我们以前的发现，即在TRAMP小鼠中，前列腺PDC的发展是由ER α促进的，而ER β使用ER α和ER β特异性配体来阻止。目标二：我们将分析相同的2种优先植物药及其生物活性标记物加染料木黄酮对人和小鼠培养的前列腺肿瘤细胞中选定的细胞内DNA甲基化、雌激素和抗氧化途径的诱导作用的分子机制。最后，目标3：我们将在目标#1的小鼠组织中体内证实所选植物及其生物活性标记物在调节对致癌作用重要的细胞途径中的作用，包括所选细胞内DNA甲基化、雌激素和抗氧化剂途径。我们也将使用已经收集的染料木黄酮治疗的组织样本，因为染料木黄酮的PDC和我们的发现，它对WDC（分化良好的癌）的影响的报告。这些研究将为前列腺肿瘤生物学提供基本的见解，并评估这些植物在改变人类前列腺肿瘤发病率和进展中的作用。

DESCRIPTION (provided by applicant): Dietary supplements are used by consumers to prevent and to treat prostate cancer. Recently, an animal prostate cancer model has allowed the safety and efficacy of these supplements to be tested. We have established colonies of TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, estrogen receptor-deficient (ERalphaKO and ERbetaKO) mice, and ER-deficient mice expressing the TRAMP transgene. Thus, a systematic approach is now possible for the identification of molecular mechanisms through which botanicals affect tumor incidence and progression. Exciting data from our model clearly show that ERalphaKO mice are highly protected against PDC (poorly differentiated carcinoma) of the prostate and ERbetaKO mice are highly susceptible to PDC. In addition to estrogen-signaling, two more signaling pathways are also believed important in mediating the initiation and progression of prostate cancer: DNA methylation and antioxidant- signaling. Our overall hypothesis is that differential regulation of ERalpha and ERP by plant phytoestrogens, acting essentially as natural SERMs, will be effective in human prostate cancer prevention and treatment. Our goals are to characterize responses of key prostate tumor biomarkers to botanicals and to provide novel molecular mechanisms for these responses. Aim la: We will use the TRAMP mouse model to perform in vivo cancer prevention trials with 2 high priority botanicals (spinach and green tea; and their bioactive markers/components) using two doses in ER WT or ER-minus / TRAMP mice to investigate the in vivo roles of ERalpha and ERbeta proteins in prostate tumorigenesis and their impact on the development of PDC. Aim Ib: We will confirm our previous findings that in TRAMP mice the development of PDC of the prostate is promoted by ERalpha and prevented by ERbeta using ERalpha and ERbeta specific ligands. Aim 2: We will profile the molecular mechanisms by which the same 2 priority botanicals and their bioactive markers plus genistein induce the effect on selected intracellular DNA methylation, estrogenic and antioxidant pathways in both human and mice cultured prostate tumor cells. Finally, in Aim 3: We will confirm in vivo in mouse tissues from Aim #1, the role of selected botanicals and their bioactive markers in regulation of cellular pathways of importance to carcinogenesis, including selected intracellular DNA methylation, estrogenic and antioxidant pathways. We will also use already collected genistein-treated tissue samples because of genistein's reported effect on PDC and our finding of its effect on WDC (well differentiated carcinoma). These studies will provide fundamental insights into prostate tumor biology, and assess the role of these botanicals in modifying the incidence and progression of prostate tumors in humans.