UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many kallikrein genes were found to be differentially expressed in various malignancies, and prostate specific antigen (encoded by the KLK3 gene) is the best tumour marker for prostate cancer. Prostate specific antigen has recently been shown to be an independent favourable prognostic marker for breast cancer. KLK15 is newly discovered kallikrein gene that is located adjacent to KLK3 on chromosome 19q13.4. KLK15 has 41% similarity to KLK3 and the encoded protein, hK15, can activate pro-prostate specific antigen. We studied the expression of KLK15 by real-time quantitative reverse transcriptase-polymerase chain reaction in 202 tissues from patients with breast carcinoma of various stages, grades and histological types. KLK15 expression was found to be a significant predictor of progression-free survival (hazard ratio of 0.41 and P=0.011) and overall survival (hazard ratio of 0.34 and P=0.009). When all other known confounders were controlled in the multivariate analysis, KLK15 retained its prognostic significance. Higher concentrations of KLK15 mRNA were found more frequently in node negative patients (P=0.042). No association was found between KLK15 expression and any other clinicopathological variable. Further, KLK15 is an independent prognostic factor of progression-free survival and overall survival in the subgroup of patients with lower grade and those with oestrogen receptor and progesterone receptor negative tumours in both univariate and multivariate analysis. KLK15 levels of expression were slightly higher (although not statistically significant) in the oestrogen receptor negative and progesterone receptor negative subgroups of patients. KLK15 is up-regulated by androgens in breast cancer cell lines. Time-course and blocking experiments suggest that this regulation is mediated through the androgen receptor.
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PMID:The androgen-regulated gene human kallikrein 15 (KLK15) is an independent and favourable prognostic marker for breast cancer. 1243 20

The steroid compound cyproterone acetate was identified in a high-throughput screen for glucocorticoid receptor (GR) binding compounds. Cyproterone (Schering AG) is clinically used as an antiandrogen for inoperable prostate cancer, virilizing syndromes in women, and the inhibition of sex drive in men. Despite its progestin properties, cyproterone shares a similar pharmacological profile with the antiprogestin mifepristone (RU486; Roussel Uclaf SA). The binding affinities of cyproterone and RU486 for the GR and progesterone receptor were similar (K(d), 15-70 nM). Both compounds were characterized as competitive antagonists of dexamethasone without intrinsic transactivating properties in rat hepatocytes (K(i), 10-30 nM). In osteosarcoma cells, RU486 revealed a higher potency than cyproterone acetate to prevent responses to dexamethasone-induced GR transactivation and NF kappa B transrepression. Upon administration to Sprague-Dawley rats, both compounds were found to be orally bioavailable and to inhibit transactivation of liver GR. Molecular docking of cyproterone acetate and RU486 into the homology model for the GR ligand binding domain illustrated overlapping steroid scaffolds in the binding pocket. However, in contrast to RU486, cyproterone lacks a bulky side chain at position C11 beta that has been proposed to trigger active antagonism of nuclear receptors by displacing the C-terminal helix of the ligand-binding domain, thereby affecting activation function 2. Cyproterone may therefore inhibit transactivation of the GR by a molecular mechanism recently described as passive antagonism. New therapeutic profiles may result from compounds designed to selectively stabilize the inactive and active conformations of certain nuclear receptors.
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PMID:Glucocorticoid receptor antagonism by cyproterone acetate and RU486. 1269 29

Multiple promoters and differential splicing of 5' upstream exons are often found in various nuclear receptor genes including steroid receptors. Three promoters control the expression of human estrogen receptor alpha (ERalpha) isoforms: ERalpha-A, ERalpha-B, and ERalpha-C, and two promoters control the expression of human progesterone receptor (PR) isoforms: PR-A and PR-B. The expression levels of these isoforms differ with respect to each other in certain target tissues. The role of these isoforms may differ in various types of cells and tissues. The ER and PR contain CpG islands in the 5' upstream regions. One possible mechanism for changing the transcriptional status is methylation of CpG-enriched regions in these isoforms. We have investigated the expression and methylation status of the three different ERalpha promoters and the two different PR gene promoters by using methylation specific PCR (MSP) and direct DNA sequencing in several endometrial and prostate cancer cell lines and tissues. The results of these experiments suggest that ERalpha-A, ERalpha-B, and PR-A were expressed and ERalpha-C and PR-B were inactivated in endometrial cancers. To the contrary, ERalpha-A and ERalpha-B were inactivated and ERalpha-C, PR-A and PR-B were expressed in all prostate cancer. Treatment with demethylating agent (5-aza-2'-deoxycytidine) restored these gene expressions, suggesting that inactivation of this gene is through methylation. Our MSP and direct DNA sequencing showed that ERalpha-A, ERalpha-B, and PR-A genes were unmethylated and ERalpha-C and PR-B were methylated in endometrial cancers although ERalpha-A and ERalpha-B were methylated and ERalpha-C, PRA and PRB were unmethylated in prostate cancers. These reports clearly demonstrate that selective hypermethylation can selectively silence multiple promoters of steroid receptors in carcinogenesis.
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PMID:Hypermethylation can selectively silence multiple promoters of steroid receptors in cancers. 1277 Jul 52

BACKGROUND: Steroid hormone receptors (SHRs) are members of the superfamily of ligand-activated transcription factors that regulate many biological processes. Co-regulators act as bridging molecules between the SHR and general transcription factors to enhance transactivation of target genes. Previous studies demonstrated that Stat3 is constitutively activated in prostate cancer and can enhance prostate specific antigen (PSA) expression and promote androgen independent growth. In this study, we investigate whether Stat3 can enhance steroid hormone receptors activation. METHODS: CV-1 cells in which plasmids expressing androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR) or estrogen receptor (ER) were cotransfected with a constitutively active STAT3 mutant. RESULTS: Stat3 stimulates the transcriptional activity of all four SHR tested, AR, GR, PR and ER, in a hormone-dependent manner. Stat3 acts in a synergistic fashion with other coactivators such as SRC-1, pCAF, CBP, and TIF-2 on the transcriptional activity of these SHR. In addition, Stat3 significantly enhanced the sensitivity of androgen receptor in response to androgen. STAT3 did not affect the specificity of AR for other steroid hormones other than androgen or binding of AR to other hormone responsive elements. CONCLUSIONS: These findings suggest that Stat3 can enhance the transactivation of AR, GR, PR and ER, and activated Stat3 could have a role in the development or progression of a hypersensitive AR.
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PMID:Stat3 enhances transactivation of steroid hormone receptors. 1290 56

The androgen receptor (AR) binds to and activates transcription of target genes in response to androgens. In an attempt to isolate cofactors capable of influencing AR transcriptional activity, we used an immunoprecipitation method and identified a 44-kDa protein, designated p44, as a new AR-interacting protein. p44 interacts with AR in the nucleus and with an androgen-regulated homeobox protein (NKX3.1) in the cytoplasm of LNCaP cells. Transient-transfection assays revealed that p44 enhances AR-, glucocorticoid receptor-, and progesterone receptor-dependent transcription but not estrogen receptor- or thyroid hormone receptor-dependent transcription. p44 was recruited onto the promoter of the prostate-specific antigen gene in the presence of the androgen in LNCaP cells. p44 exists as a multiprotein complex in the nuclei of HeLa cells. This complex, but not p44 alone, enhances AR-driven transcription in vitro in a cell-free transcriptional system and contains the protein arginine methyltransferase 5, which acts synergistically with p44 to enhance AR-driven gene expression in a methyltransferase-independent manner. Our data suggest a novel mechanism by which the protein arginine methyltransferase is involved in the control of AR-driven transcription. p44 expression is dramatically enhanced in prostate cancer tissue compared with adjacent benign prostate tissue.
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PMID:Purification and identification of a novel complex which is involved in androgen receptor-dependent transcription. 1297 18

The present review gives a survey on the differential expression of estrogen receptors alpha and beta (ERalpha, ERbeta) and the progesterone receptor (PR) in human prostate tissue and discusses their potential implications for normal and abnormal prostatic growth. The differentiation compartment of the prostatic epithelium (secretory luminal cells) expresses high levels of ERbeta, while the ERalpha is restricted to the proliferation compartment (basal cells). In high-grade prostatic intraepithelial neoplasia (HGPIN), ERalpha gene expression extends to luminal cells and thus may mediate cancerogenic effects of estrogens on the dysplastic epithelium. Conversely, the ERbeta is downregulated in HGPIN indicating that the chemopreventive effects of phytoestrogens mediated by the ERbeta are partially lost. Irrespective of grades and stages, prostate cancer retains high levels of the ERbeta, which is partially lost in androgen-insensitive stages of the disease. In contrast with breast cancer, the presence of the ERalpha and the progesterone receptor (PR) is a late event in prostate cancer progression. At least 30% of metastatic and androgen-insensitive tumors express high levels of the PR indicating that these tumors harbor a functional ERalpha. The antiestrogen raloxifene has growth-inhibitory effects on androgen-insensitive prostate cancer cells in vitro and induces apoptotic cell death in a dose-dependent fashion. These data provide a rationale for clinical trials to study the efficiency of antiestrogens in the medical treatment of advanced prostate cancer.
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PMID:[New insights into the role of estogens and their receptors in prostate cancer]. 1466 87

Previous studies showed that progesterone receptor (PR), one of the hormone receptor superfamily, was only connected with the sex-correlated cancers such as breast cancer, endometrial cancer, prostate cancer, etc. This article deals with the PR gene in leukemia. We investigated the methylation status and the expression of the two different PR isoforms, PRA and PRB, in three leukemia cancer cell lines using methylation-specific polymerase chain reaction (MSP-PCR) and reverse transcription-PCR. The correlation of PR methylation and expression together with DNA methyltransferase (DNMT1) was further studied. We found that DNMT1 is required to maintain CpG methylation and aberrant gene silencing of PR gene in human leukemia cancer cells. The activity of 5-aza-2'-deoxycytidine in demethylation and gene reactivation may be through depleting cellular DNMT1 levels. In addition, extensive methylation of PRA and PRB was also observed in leukemia samples. Our results suggest that PR CpG island aberrant hypermethylation could be one molecular and genetic alteration in leukemia.
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PMID:Progesterone receptor gene inactivation and CpG island hypermethylation in human leukemia cancer cells. 1517 46

The traditional role of the Cdc25 family of dual-specificity phosphatases is to activate cyclin-dependent kinases (CDKs) to enable progression through the cell cycle. This chapter reports that in addition to its cell cycle role, Cdc25B functions as a novel steroid receptor coactivator (SRC). When overexpressed in transgenic mammary glands, Cdc25B can up-regulate the expression of two estrogen receptor (ER)-target genes: cyclin D1 and Lactoferrin. In addition, when coexpressed with ER, Cdc25B can coactivate an ER-dependent reporter in the presence of estradiol. The coactivation of Cdc25B can be extended to the glucocorticoid receptor (GR), progesterone receptor (PR), and androgen receptor (AR). Because of the respective importance of ER and AR in breast and prostate cancer, this chapter focuses on the coactivation of both receptors by Cdc25B. We demonstrate that Cdc25B can interact directly with these nuclear receptors, recruit and enhance the activity of histone acetyltransferases (HATs), and potentiate cell-free transcription independent of its cell cycle regulatory function. Furthermore, because Cdc25B is up-regulated in highgrade and poorly differentiated prostate tumors, which are likely transiting from the hormone-dependent to hormone-independent state, we hypothesize that the coactivation of AR by Cdc25B may induce genes responsible for this progression. Taken together, it is highly conceivable that Cdc25B can promote neoplasia by its two disparate functions of (1) coactivation to induce higher levels of expression of steroid receptor target genes and (2) its role of activating CDKs to deregulate progression of the cell cycle, DNA replication, and mitosis.
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PMID:Cdc25B as a steroid receptor coactivator. 1519 57

Carcinogenesis of the prostate involves androgen influences, and associations between genetic polymorphisms of androgen receptor and metabolizing enzymes and prostate cancer risk have been reported. Roles for non-androgenic hormones are not well defined, but they also may have an impact judging from epidemiological and animal experimental alphalambda zeta of data. The purpose of the study was to determine whether hormone-related polymorphisms are associated with prostate cancer risk. A case-control study was performed with 147 Japanese prostate cancer patients and 266 urological controls. Polymorphisms of target genes [cytochrome P450 (CYP) 1B1, Leu432Val; debrisoquine hydroxylase, (CYP2D6)*4; aromatase (CYP19), Arg264Cys; estrogen receptor (ER)alpha-Xx (Xba I) and Pp (Pvu II); ERbeta-Rr (Rsa I); progesterone receptor (PR) Alu in intron 7] were examined by PCR-based methods. The capital and small letters signify the absence and presence of restriction sites, respectively. Odds ratios (OR) were adjusted for age using multiple logistic regression analysis with SPSS Medical Pack. Among the seven examined genetic polymorphisms, significant associations between CYP1B1 Leu432Val (OR 4.80; 95% confidence interval (CI), 1.21-19.05) and Alu in intron 7 of PR (OR 4.17; 95%CI, 1.26-13.85) were found. As for combined effects, the CYP1B1 polymorphisms (Leu/Val+Val/Val) together with heterozygosity for Alu in the PR were more frequent among prostate cancer patients (1.45%) than controls (0.41%), although without significance (OR, 3.99; 95%CI, 0.36-44.8). The combination of ERalpha (P/p+p/p) polymorphisms with heterozygosity for Alu in the PR demonstrated an OR of 4.56 (95%CI, 1.01-20.6). This pilot study showed that CYP1B1 and PR polymorphisms, alone or in combination, might be associated with prostate cancer risk. They might, therefore, have potential as a tool for identifying high-risk individuals.
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PMID:Genetic polymorphisms of hormone-related genes and prostate cancer risk in the Japanese population. 1533 Jan 95

'Classical' genomic progesterone receptors appear relatively late in phylogenesis, i.e. it is only in birds and mammals that they are detectable. In the different species, they mediate manifold effects regarding the differentiation of target organ functions, mainly in the reproductive system. Surprisingly, we know little about the physiology, endocrinology, and pharmacology of progesterone and progestins in male gender or men respectively, despite the fact that, as to progesterone secretion and serum progesterone levels, there are no great quantitative differences between men and women (at least outside the luteal phase). In a prospective cohort study of 1026 men with and without cardiovascular disease, we were not able to demonstrate any age-dependent change in serum progesterone concentrations. Progesterone influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. Other progesterone effects in men include those on the central nervous system (CNS) (mainly mediated by 5alpha-reduced progesterone metabolites as so-called neurosteroids), including blocking of gonadotropin secretion, sleep improvement, and effects on tumors in the CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system, kidney function, adipose tissue, behavior, and respiratory system. A progestin may stimulate weight gain and appetite in men as well as in women. The detection of progesterone receptor isoforms would have a highly diagnostic value in prostate pathology (benign prostatic hypertrophy and prostate cancer). The modulation of progesterone effects on typical male targets is connected with a great pharmacodynamic variability. The reason for this is that, in men, some important effects of progesterone are mediated non-genomically through different molecular biological modes of action. Therefore, the precise therapeutic manipulation of progesterone actions in the male requires completely new endocrine-pharmacological approaches.
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PMID:Progesterone: the forgotten hormone in men? 1566 43

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