Green tea polyphenols, especially the catechin, (-)-epigallocatechin gallate (EGCG), have been proposed as a cancer chemopreventative based on a variety of laboratory studies. For clear assessment of the possible physiological effects of green tea consumption, we injected pure green tea catechins ip into rats and studied their acute effects on endocrine systems. We found that EGCG, but not related catechins, significantly reduced food intake; body weight; blood levels of testosterone, estradiol, leptin, insulin, insulin-like growth factor I, LH, glucose, cholesterol, and triglyceride; as well as growth of the prostate, uterus, and ovary. Similar effects were observed in lean and obese male Zucker rats, suggesting that the effect of EGCG was independent of an intact leptin receptor. EGCG may interact specifically with a component of a leptin-independent appetite control pathway. Endocrine changes induced by parenteral administration of EGCG may relate to the observed growth inhibition and regression of human prostate and breast tumors in athymic mice treated with EGCG as well as play a role in the mechanism by which EGCG inhibits cancer initiation and promotion in various animal models of cancer.

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The cDNA for a member of the nuclear receptor family was cloned and named ubiquitous receptor (UR), since UR protein and mRNA are detected in many cell types. Rat UR/human retinoid X receptor a (hRXRa) heterodimers bound preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence AGGTCA and 4-nt spacing (DR-4). Coexpression of UR in COS-1 cells inhibited the stimulation of chloramphenicol acetyltransferase (CAT) reporter gene expression by hRXRa and human retinoic acid, receptor a in the presence of all-transretinoic acid when DR-4 (but not DR-5) was present upstream of the promoter of a CAT reporter gene (DR-4-CAT). UR expression also inhibited the activation of a DR-4-CAT reporter gene by hRXRa and 9-cis-retinoic acid or by thyroid hormone receptor a in the, presence of thyroid hormone. However, in the absence of 9-cis-retinoic acid, UR in combination with hRXRa stimulted DR-4-CAT expression. Coex (4,5). The nature of the DNA flanking these half-sites also is important in determining the specificity of a response element (6). Homodimers of the thyroid hormone/retinoid receptor family are also able to modulate transcriptional activity in different ways than their heterodimeric forms (7). The effect of these homo-and heterodimeric receptors on transcriptional activity also depends on their occupancy by specific ligands (8). The complexity of this network of interacting factors is increasing with the discovery of new members of this superfamily of nuclear receptors, many of which are called orphan receptors, since they lack known ligands. An interplay of receptors, ligands, response elements, and yet-to-be-discovered factors may ultimately control the activity of these transcriptional factors and ensure the appropriate cellular responses during development and in the adult.We report here our discovery of a member of the nuclear receptor family of transcription factors that we have named ubiquitous receptor (UR),t because of its wide tissue distribution. UR is not an isoform of any known receptor and interacts with the response elements and network of receptors in the thyroid receptor (TR)/retinoic acid receptor (RAR) subfamily.

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When the human prostate cancer cell line, LNCaP 104-S, the growth of which is stimulated by physiological levels of androgen, is cultured in androgen-depleted medium for >100 and androgen-independent LNCaP 104-R2t sublines were isolated as described (6). The characteristics of these cells in vitro were confirmed before injection into nude mice. Briefly, proliferation of LNCaP 104-S cells increased 10-to 13-fold in medium containing charcoal-treated fetal bovine serum (FBS) and 0.1 nM synthetic androgen R1881, compared with cells cultured in medium containing charcoal-treated FBS without added androgen. LNCaP 104-R2 cells grew in medium supplemented with charcoal-treated FBS without additional androgen. Their proliferation was not stimulated but was repressed by 0.1 nM R1881. LNCaP 104-S cells were maintained in DMEM (GIBCO) supplemented with 1 nM S5t-dihydrotestosterone and 10% FBS (Summit Biotechnology, Ft. Collins, CO), and LNCaP 104-R2 cells were maintained in DMEM supplemented with 10% FBS treated with charcoal to remove steroid (6). PC-3 and MCF-7 cell lines were obtained from the American Type Culture Collection (Rockville, MD) and were maintained in DMEM supplemented with 10% FBS.Animals. BALB/c athymic (nude) male (LNCaP, PC-3 cell lines) and female (MCF-7 cell line) mice (Taconic, Germantown, NY), 5 to 7 weeks old, were used. Mice were housed in a pathogen-free environment, four to five mice per cage. Cages (filter top), bedding, and water were autoclaved before use. Feed was irradiated Pico Lab Mouse Chow 20 5058 (Purina).Abbreviations: AR, androgen receptor; FBS, fetal bovine serum; PSA, prostate-specific antigen; TP, testosterone propionate.

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The rat prostate is a complex ductal system with branches and subbranches extending from one end to another. Owing to the relative distance of various regions of the duct from the urethra, the entire length of the ductal system can be arbitrarily divided into three segments, i.e., the proximal, intermediate, and distal segments. The present study was carried out to assess the regional variation in cellular activities in this ductal system. Ventral prostates from adult Sprague-Dawley rats were dissected so that an individual ductal system was mechanically isolated and longitudinally sectioned to reveal various segments. Epithelial cells lining distal segments were tall-columnar type and were actively engaging in mitotic activity. Cells in intermediate segments were also tall-columnar type. However, they were mitotically quiescent, but able to produce secretory proteins. Evidence of programmed cell death was not observed in either of these two segments. Cells in proximal segments, on the other hand, were low-columnar or cuboidal in shape and were stained heavily for cathepsin D, a marker associated with late manifestation of cell death. Following castration in adult rats, there was a reversal in the site of programmed death in cells lining the ductal system. By Day 4 post-castration, distal segments contained many epithelial cells with intense cytoplasmic staining for cathepsin D while proximal segments showed a reduction in number of positively stained cells. By Day 7 post-castration, cells in proximal segments, though atrophied, were devoid of staining for cathepsin D.(ABSTRACT TRUNCATED AT 250 WORDS)