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 Based on our published and unpublished data (summarized in our application) our long term goals are to determine if: 1) ER-beta promotes cell differentiation and/or inhibits growth in normal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.

R01DK061084

2001-09-30

2006-08-31