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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of the genomic organization of the corresponding gene has enabled us to study androgen receptors in subjects with the clinical manifestation of androgen insensitivity and in a human prostate carcinoma cell line (LNCaP). Using PCR amplification, subcloning and sequencing of exons 2-8, we identified a G----T mutation in the androgen receptor gene of a subject with the complete form of androgen insensitivity, which inactivates the splice donor site at the exon 4/intron 4 boundary. This mutation causes the activation of a cryptic splice donor site in exon 4, which results in the deletion of 41 amino acids from the steroid binding domain. In two other independently arising cases we identified two different nucleotide alterations in codon 686 (GAC; aspartic acid) located in exon 4. One mutation (G----C) results in an aspartic acid----histidine substitution (with negligible androgen binding), whereas the other mutation (G----A) leads to an aspartic acid----asparagine substitution (normal androgen binding, but a rapidly dissociating androgen receptor complex). Sequence analysis of the androgen receptor in human LNCaP-cells (lymph node carcinoma of the prostate) revealed a point mutation (A----G) in codon 868 in exon 8 resulting in the substitution of threonine by alanine. This mutation is the cause of the altered steroid binding specificity of the LNCaP-cell androgen receptor. The functional consequences of the observed mutations with respect to protein expression, specific ligand binding and transcriptional activation, were established after transient expression of the mutant receptors in COS and HeLa cells. These findings illustrate that functional errors in the human androgen receptor have an enormous impact on phenotype and fertility.
J Steroid Biochem Mol Biol 1991
PMID:Androgen receptor abnormalities. 195 38

The xenograft line, UCRU-PR-2, has been characterized further. Established from a primary human undifferentiated small cell carcinoma of the prostate, it has been maintained as a stable xenograft line in nude mice and is currently in passage 9. The tumor has maintained the features of small cell undifferentiated carcinoma but shows epithelial as well as neuroendocrine characteristics. In this paper, we describe synthesis and secretion of peptide hormones, ACTH, beta-endorphin and somatostatin in vivo and ACTH and beta-endorphin in vitro by the tumor, UCRU-PR-2. This suggests that the gene for proopiomelanocortin is expressed and that processing of the molecule occurs. This line may yield insights into the histogenesis of the subtypes of prostate cancer, and also aid studies of regulation of ectopic hormone production.
Mol Cell Endocrinol 1988 Feb
PMID:Ectopic hormone production by a prostatic small cell carcinoma xenograft line. 283 15

The metabolism of androgens in prostatic carcinoma has not been sufficiently studied so far, mainly because of the difficulty in obtaining human tissue specimens. The availability of LNCaP (lymph node carcinoma of the prostate) cells which retain most of the characteristics of the original carcinoma (dependence on androgens, presence of androgen receptors, production of acid phosphatase, etc.) has allowed the present in vitro study designed to characterize the metabolic pathways through which testosterone (T) is metabolized in malignant cells. LNCaP cells have been incubated in the presence of different labelled androgenic precursors to quantitate the formation of the respective metabolites, as indicators of the specific activities of the enzymes involved in such conversions; whenever possible, the kinetic constants (Km and Vmax) of the enzymes have also been calculated. It has been observed that, when [14C] T is used as substrate, the cells form both dihydrotestosterone (DHT) and androst-4-en-3,17 dione (delta 4) with the prevalence of the latter. When [14C] delta 4 is the substrate, T and 5 alpha-androstan-3,17-dione (5 alpha-A) are found with 5 alpha-A representing the major product. In addition, the cells form diols and 5 alpha-A from [14C]DHT as well as androsterone (A) and DHT from [14C]5 alpha-A; there is a prevalence of diols in the former case, and of A in the latter one. The yields of the different metabolites recovered after 2 h of incubation of the cells with the appropriate labelled substrates are therefore in descending order of magnitude: 5 alpha-A > A > diols > delta 4 > DHT > T. These results are also confirmed by the analysis of the rate of production of the different steroids. Taken together the present results suggest that: (a) qualitatively LNCaP cells possess all the major key enzymes involved in androgen processing; (b) the metabolism of androgens in this cell line resembles quantitatively that found in prostatic cancer tissue; all the metabolic steps which contribute to DHT degradation exceed the ones leading to its accumulation; (c) 5 alpha-reductase shows a significantly higher affinity for delta 4 than for T; (d) LNCaP cells may represent a suitable in vitro model for the study of factors controlling the formation and the degradation of androgens in prostatic carcinoma, thus permitting a better understanding of the metabolic processes involved in prostatic benign or malignant (carcinoma) transformation.
J Steroid Biochem Mol Biol 1994 Oct
PMID:Androgen metabolism in the human prostatic cancer cell line LNCaP. 794 55

Prior meetings of the International Conference on Neoadjuvant Hormonal Therapy in Prostate Cancer identified areas of concern in the pathologic analysis of post-treatment specimens. In response, a pathology subcommittee was formed to address the questions that had been raised. Recommendations are made here concerning pretreatment biopsy review and reporting, handling and reporting of radical prostatectomy specimens, Gleason scoring of treated cancer, grading of therapy effect, role of immunohistochemistry procedures, and the significance of high-grade prostatic intraepithelial neoplasia. Neoadjuvant trials with both surgery and radiation therapy were considered in drawing up these recommendations.
Mol Urol 1999
PMID:Pathologic Handling and Reporting of Prostate Tissue Specimens in Patients Receiving Neoadjuvant Hormonal Therapy: Report of the Pathology Committee. 1085 23

The US T(2b) study of 3 months of neoadjuvant hormonal therapy (NHT) showed a reduction in the likelihood of positive margins from 48% (control group) to 18% in the treated patients. Follow-up at 42 months shows that the cumulative relapse rate (prostate specific antigen) for 129 patients having NHT was not statistically different from that of the 126 control patients. Because the T(2b) study has been criticized for lacking central pathology review, we present a review of a series involving only one surgeon (MS) and one pathologist (FC) of NHT plus prostatectomy (109 patients) v prostatectomy alone (145 patients) with 24 months' follow-up. Positive margins were decreased from 38% in the untreated to 28% in the treated group, the only statistically significant difference in the results. Biochemical recurrence (PSA >0.2 ng/mL) was higher in the treated group, reflecting selection of more aggressive tumors for NHT, but the difference was not statistically significantly. The incidence of extracapsular extension, seminal vesicle invasion, and lymph node metastasis was similar in the two groups. The largest nonrandomized experience with NHT shows a decrease in the incidence of positive surgical margins when used in high-risk patients with clinically localized carcinoma of the prostate. However, it does not have an impact on disease-free survival at a mean 24-month follow-up.
Mol Urol 1999
PMID:Neoadjuvant Hormonal Therapy Prior to Radical Prostatectomy. 1085 24

The action of androgens is essential for the development of benign prostatic hyperplasia and carcinoma of the prostate. The androgen receptor is a ligand-dependent nuclear transcription factor. The transcriptional activation domain of the androgen receptor gene contains a polymorphic CAG repeat sequence. A shorter CAG repeat sequence within the normal range has been reported to be associated with increased risk of prostate cancer and symptomatic benign prostatic hyperplasia. Here, we examine the in vitro transcriptional activity of the androgen receptor (AR) with different numbers of CAG repeats within the normal range in a number of different cell lines of prostatic (LNCaP, PC3) and non-prostatic (COS-1, MCF7) origin. We utilize a luciferase reporter driven by the rat probasin promoter (-286/+28) containing two androgen receptor binding sites. Transcriptional activation of the androgen responsive reporter was observed to be greater with the AR containing 15 vs 31 CAG repeats in COS-1 cells (123.2+/-16.6 vs 78.2+/-10.9, P value 0.01) and the well differentiated prostate cancer cell line LNCaP (103.4+/-17.7 vs 81.4+/-7.7, P value 0.045). No difference was observed in the poorly differentiated prostate cancer cell line, PC3 (106.9+/-21.9 vs 109. 6+/-21.4, P>0.5) or the breast cancer cell line MCF7 (120.4+/-39.4 vs 103.1+/-23.1, P value >0.5). Dose-response experiments with varying quantities of ligand (0.01, 0.1, 1 and 10 nM dihydrotestosterone) or AR cDNA did not demonstrate significant differences in transactivation of the androgen responsive reporter in PC3 cells by the different AR constructs. This suggests that the lack of influence of CAG number in this prostatic cell line is not related to dose of ligand or quantity of androgen receptor. Western immunoblot analysis of androgen receptor protein in transiently transfected COS-1 cells did not demonstrate a difference in the expression of the androgen receptor protein with different numbers of CAG repeats following incubation in the presence or absence of androgen. Gel shift assay did not demonstrate increased DNA binding by androgen receptor with a shorter CAG repeat sequence. These experiments using a relatively androgen- and prostate-specific reporter provide evidence for an inverse relationship between androgen receptor transcriptional activity and the number of CAG repeats in the transcriptional activation domain. The effect of CAG repeat number was cell specific suggesting the involvement of accessory factors expressed differentially between different cell lines.
J Mol Endocrinol 2000 Aug
PMID:Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. 1091 21

Most current therapies against human carcinoma of the prostate are palliative rather than curative. Thus, there is a pressing need for new therapies directed against this common tumor, based on knowledge of the basic biology of the prostate, rather than by extrapolation of treatments from other tumor types. This review presents the various levels of prostate targeting which could be and have been applied, at the attachment, expression and therapeutic gene levels to eliminate prostate carcinoma cells in extraprostatic sites. To achieve optimal and safe targeting, a combination approach will be necessary, as there are few genes whose expression can provide absolute prostate specificity.
Curr Opin Mol Ther 2000 Aug
PMID:Targeting therapeutic gene expression to human prostate cancers. 1124 69

mRNA differential display-PCR analysis was used to perform a systematic screening of Somatostatin (SS)-regulated genes in the human prostatic carcinoma cell line LNCaP (Lymph Node Carcinoma of the Prostate). A 170 bp fragment was shown to be up-regulated by SS. Sequence analysis of this fragment revealed its homology with the human Topoisomerase II Alpha gene. Up-regulation of Topoisomerase II Alpha was confirmed by Northern blot hybridisation and was induced by the same dose of SS (1 nM) earlier demonstrated to inhibit LNCaP cell growth. Furthermore, SS possible effects on timing, as well as concentration of Topoisomerase II Alpha along the different phases of the cell cycle were investigated. To this purpose changes in the enzyme protein concentration in response to SS were assessed in synchronised LNCaP cells. The hormone was shown to exert a perturbing effect on both parameters considered, possibly related to its inhibitory action on LNCaP cell replication.
Mol Cell Endocrinol 2001 May 15
PMID:Somatostatin up-regulates topoisomerase II alpha expression and affects LNCaP cell cycle. 1136 49

DNA hypermethylation of CpG-rich promoter sequences is associated with tumor suppressor gene inactivation in many human cancers, notably in carcinoma of the prostate and the urinary bladder. Recently, the mouse homologue of the tumor necrosis factor receptor superfamily 6 (TNFRSF6) gene was reported to be inactivated by DNA methylation in various cell types. The Fas (CD95, Apo-1) protein encoded by the TNFRSF6 gene is an important mediator of apoptosis, which also is downregulated in different types of human carcinoma. We therefore investigated the methylation of the TNFRSF6 promoter in prostatic and bladder carcinomas and cell lines. In a restriction enzyme polymerase chain reaction assay, four of 32 prostatic carcinomas and three of 15 advanced bladder carcinomas showed evidence of hypermethylation at the rel/nuclear factor kappaB (NFkappaB) binding sites essential for promoter activity. The DU145 cell line derived from a metastasis of a prostate carcinoma also displayed hypermethylation in this assay, which was confirmed by bisulfite sequencing. Treatment of DU145 cells with the methylation inhibitor deoxyazacytidine slightly increased Fas protein expression, as detected by flow cytometry analysis. In vitro methylation of the TNFRSF6 promoter at the rel/NFkappaB sites completely abolished its activity. Thus, although the TNFRSF6 gene can be inactivated efficiently by DNA methylation, hypermethylation occurs neither frequently nor extensively in human carcinomas and appears to play a limited role in downregulation of Fas expression.
Mol Carcinog 2001 Sep
PMID:Hypermethylation of the tumor necrosis factor receptor superfamily 6 (APT1, Fas, CD95/Apo-1) gene promoter at rel/nuclear factor kappaB sites in prostatic carcinoma. 1156 74

Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the western countries. Withdrawal of androgens or the peripheral blockage of androgen action remain the critical therapeutic options for the treatment of advanced prostate cancer. However, after initial regression, most of the prostate cancers become androgen-independent and progress further, with eventual fatal outcome. Understanding the mechanisms of transition to androgen independence and tumor progression in prostate cancer is critical to finding new ways to treat aged patients that are ineligible for conventional chemotherapy. A large number of different molecular mechanisms might be responsible for the transition to androgen-independence. Many of these involve the androgen receptor (AR) and its signalling pathways, but they might also include genetic changes that affect several genes, which results in the activation of oncogenes or the inactivation of tumor suppressor genes. Here, we discuss the most recent and relevant findings on androgen resistance in prostate cancer in order provide a comprehensive interpretation of the clinical behaviour of tumors at molecular levels.
J Steroid Biochem Mol Biol 2002 Jul
PMID:Transition to androgen-independence in prostate cancer. 1216 31


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