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 一个实验室获得了令人兴奋的新数据，表明雌激素受体β ER-β是前列腺癌发生和前列腺癌细胞增殖的关键介质， 增长根据我们已发表和未发表的数据（总结在我们的 我们的长期目标是确定：1）ER-β促进细胞增殖， 分化和/或抑制正常前列腺上皮的生长， 受体表达的进行性缺失是否与恶性肿瘤的发生有因果关系， 转化，和2）如果ER-β在转移性前列腺中再表达， 癌细胞对于癌细胞存活/或维持恶性 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 细胞死亡，这与生存素，端粒酶逆转录酶（ 端粒酶的催化亚基），以及通过cDNA鉴定的其他基因 微阵列为解决这些长期问题，提出了以下具体目标 目标.目的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，其表现出显著的 配体结合、前列腺细胞生长的亚型选择性差异 抑制和/或转录效力或功效。目标2： 确定抗雌激素诱导的人前列腺生长抑制是否 仅表达ER-β的癌细胞系，涉及ER-β的表达改变， 存活素、TERT、胸苷酸合成酶（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额外的ER-β/抗雌激素调节基因。 目标3：A）进一步鉴定在生长过程中上调的基因 T+E2诱导的异型增生及其与ICI联合治疗诱导的逆转 NBL老鼠B）为了确定所选抗雌激素和/或抗雌激素药物的功效， Hanson化合物预防T+E2诱导的Noble大鼠发育异常 并确定化学预防是否是通过改变 Fra-2和GADD 45以及子目标3a中鉴定的基因。数据从这些 研究预计将确定新的ER-β SERM，并提供对 ER-β选择性的结构要求。他们还将确定新的 ER-β/抗雌激素调节基因和阐明ER-β的潜在作用 ER-β SERM在前列腺癌发生中的作用和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 Based on our published and unpublished data (summarized in our application) our long term goals are to determine if: 1) ER-beta promotes cell differentiation and/or inhibits growth in normal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.