Estrogen Receptor-beta and Prostate Function

描述(由申请人提供) 目前认为雌激素可能对前列腺有深远的影响。 细胞生长、分化和肿瘤转化。最近我们的 实验室获得了令人兴奋的新数据，表明雌激素受体-β 内质网(ER-β)是前列腺癌发生和前列腺癌细胞的关键介质 成长。基于我们已发布和未发布的数据(在我们的 应用)我们的长期目标是确定：1)ER-β是否促进细胞 分化和/或抑制正常前列腺上皮生长和 受体表达的进行性丧失是否与恶性有关 2)ER-β在转移性前列腺癌中是否重新表达 癌细胞是癌细胞生存/或维持恶性的关键 表型和β受体的激活，通过已知的抗雌激素或 新设计的配体(汉森化合物)，导致细胞周期停滞或 与Survivin、TERT(The 端粒酶催化亚单位)，以及由cdna鉴定的其他基因。 微阵列。为解决这些长期问题，我们提出了以下具体目标 目标。目标1：鉴定新的(Hanson化合物)或已知的(他莫昔芬， ICI-182,780和雷洛昔芬)雌激素样化合物显示出明显的 配基结合、前列腺细胞生长的亚型选择性差异 对ER-β的抑制和/或转录效力。目标2：实现 确定抗雌激素对人前列腺是否有生长抑制作用 只表达ER-β的癌细胞系涉及改变的表达 Survivin、TERT、胸苷合成酶(TS)和金属硫蛋白-II(MT-II)。 此外，还将采用cDNA微阵列和ER-β反义技术 以确定在这一过程中更多的ER-β/抗雌激素调节基因。 目标3：a)进一步确定在 T+E_2诱导的异型增生及其与ICI联合治疗的逆转作用 NBL大鼠。B)确定选定的抗雌激素和/或 Hanson化合物预防T+E_2诱导的高龄大鼠异型增生 并确定化学预防是否通过改变表达的 FRA-2和GADD45以及在次级目标3a中发现的基因。来自这些网站的数据 预计研究将确定新的ER-βSERM，并提供对 ER-β选择性的结构要求。他们还将确定新的 ER-β/抗雌激素调节基因及其可能的作用 前列腺癌的发生及ER-βSERMs在前列腺癌中的应用 治疗。

DESCRIPTION (Provided by the applicant) It is currently believed that estrogens may have profound effects on prostatic cell growth, differentiation, and neoplastic transformation. Recently our laboratory has obtained exciting new data indicating estrogen receptor-beta (ER-beta) is a key mediator of prostate carcinogenesis and prostate cancer cell growth. Based on our published and unpublished data (summarized in our application) our long term goals are to determine if: 1) ER-beta promotes cell differentiation and/or inhibits growth in normal prostatic epithelium and whether progressive loss of receptor expression is causally linked to malignant transformation, and 2) if re-expression of ER-beta in metastatic prostate cancer cells is essential for cancer cell survival/or maintenance of malignant phenotypes, and activation of the beta receptor, via known antiestrogens or newly devised ligands (the Hanson compounds), leads to cell cycle arrest or cell death which is associated with downregulation of survivin, TERT (the catalytic subunit of the telomerase), and other genes identified by cDNA microarray. The following specific aims are proposed to address these long-term goals. Aim 1: To identify novel (the Hanson compounds) or known (tamoxifene, ICI-182,780, and Raloxifene) estrogen-like compounds that show pronounced subtype-selective differences in ligand binding, prostatic cell growth inhibition and/or transcriptional potency or efficacy for ER-beta. Aim 2: To determine whether the antiestrogen-induced growth inhibition in human prostate cancer cell lines, that express only ER-beta, involves altered expression of survivin, TERT, thymidylate synthase (TS) and metallothionein-II (MT-II). Additionally, cDNA microarray and ER-beta antisense technology will be employed to identify additional ER-beta/antiestrogen regulated genes in this process. Aim 3: A) To further identify genes that are upregulated during the T+E2-induced dysplasia and their reversal induced by co-treatment with ICI in the NBL rats. B) To determine the efficacy of selected antiestrogens and/or Hanson compounds in preventing dysplasia induction by T+E2 in the Noble rats and ascertain whether the chemoprevention is mediated via altered expression of Fra-2 and GADD45 as well as genes identified in Sub-aim 3a. Data from these studies are expected to identify new ER-beta SERMs and provide sights into the structural requirements of ER-beta selectivity. They will also identify new ER-beta/antiestrogen regulating genes and illuminate potential roles of ER-beta in prostate carcinogenesis and utility of ER-beta SERMs in prostate cancer treatment.