Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extramammary Paget's disease (EMPD) is an uncommon neoplasm of the skin that shows differentiation to an apocrine sweat gland. Although we previously showed that erbB-2 overexpression may play a part in the progression of EMPD, molecular genetic defects underlying the development of EMPD are poorly understood. In the study described here, we examined androgen receptor expression and gene alterations in 30 cases of EMPD without internal malignancy. Immunohistochemistry revealed that 24 of 30 (80%) cases of EMPD variably expressed nuclear androgen receptor. Semi-quantitation of receptor content by scoring immunostained sections showed no difference between in situ (n = 17) and invasive (n = 13) EMPD tumors. Androgen receptor expression was also observed in four of six lymph node metastases. In these lymph nodes, expression of androgen receptor mRNA was confirmed by reverse transcriptase-polymerase chain reaction. Direct sequencing of exon 2 through exon 8, which encodes DNA- and hormone-binding domains of the androgen receptor gene, revealed no mutation in any of the 10 advanced stage tumors. Neither amplification nor deletion of the androgen receptor gene locus was detected by dual color fluorescence in situ hybridization analysis in 14 tumors. The present findings showing frequent expression of structurally unaltered androgen receptor in an advanced stage of EMPD may provide a rational basis for hormone therapy, which is widely used in the treatment of metastatic prostate cancer and androgen receptor-positive breast cancer recurrence.
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PMID:Expression of structurally unaltered androgen receptor in extramammary Paget's disease. 1100 14

Androgen receptor (AR), a key nuclear transcription factor in the prostate gland, is expressed in all histological types and stages of prostate cancer. The AR regulates proliferation of prostate cancer cells by stimulation of cyclin-dependent kinases. However, in some prostate tumors AR stimulates expression of cell cycle inhibitors, thus leading to down-regulation of cellular proliferation. Androgens, by activation of the AR, control differentiation of prostate cells and synthesis of neutral lipids. There are several mechanisms by which prostate cancer cells adapt to an environment with low androgen supply during endocrine therapy. The AR expression and activity increase in several cell lines that are used as an in vitro model for monitoring changes during long-term androgen ablation. Mutant ARs are of importance for monitoring the natural course of the disease and for determining the response to anti-androgens in metastatic lesions from prostatic carcinoma. In addition, AR activity is up-regulated by various stimulators of intracellular protein kinases. Current research efforts are focused on elucidation of function of AR coregulatory proteins, coactivators and corepressors. Their inappropriate expression and/or function might critically influence cellular events in advanced carcinoma of the prostate. It is hoped that information on these coregulatory proteins will serve as a basis for a more efficient pharmacological inhibition of the AR in advanced carcinoma of the prostate.
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PMID:Androgen receptor--an update of mechanisms of action in prostate cancer. 1101 57

Androgen ablation is standard therapy for advanced prostate carcinoma. It can be administered either as a monotherapy or as a combined androgen blockade. In the present study we have investigated molecular mechanisms which are responsible for the development of resistance to therapy in advanced prostate cancer. For this purpose, we have cultured LNCaP cells in steroid-depleted medium for 1 year. The newly generated subline LNCaP-abl was characterized. In early passages (<75) LNCaP-abl cells showed a biphasic hypersensitive response to androgenic stimulation. Passages later than 75 are inhibited by androgen. Proliferation of LNCaP-abl cells was stimulated by the pure nonsteroidal antiandrogen bicalutamide (Casodex). To improve our understanding of changes which occur during intermittent androgen ablation, we have generated the sublines LNCaP-R (reversal; cultured with fetal calf serum) and LNCaP-RA (reversal and androgen; cultured with fetal calf serum and androgen) from LNCaP-abl cells. In both cell lines an increase of the basal proliferation rate was observed. Androgen receptor expression in LNCaP-abl cells was 4-fold higher than that in parental LNCaP cells (4.7 vs. 1.2 fmol/microg protein). Androgen receptor content in LNCaP-R cells was 1.8 fmol/microg protein and in LNCaP-RA cells 1.0 fmol/microg protein. The basal androgen receptor activity was 30-fold higher in LNCaP-abl cells compared to that in parental LNCaP cells. This basal activity was reduced in LNCaP-RA cells. Both androgen and the nonsteroidal androgen receptor antagonist hydroxyflutamide induced a 2- to 4-fold higher activation of androgen receptor in LNCaP-abl than in LNCaP cells. There was a switch from an antagonist to an agonist of the nonsteroidal antiandrogen bicalutamide (Casodex) in LNCaP-abl cells. Antagonistic properties of this androgen receptor blocker were again observed in both sublines (LNCaP-R and LNCaP-RA) derived from LNCaP-abl cells. In concordance with proliferation data in vitro, growth of LNCaP-abl cells in nude mice was stimulated by bicalutamide. In contrast, supplementation of androgen led to inhibition of proliferation of these cells. The present study provides new information that is useful for a better understanding of therapy-refractory prostate cancer. It is also important for the development of new therapy strategies for advanced carcinoma of the prostate.
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PMID:Antagonist/agonist balance of the nonsteroidal antiandrogen bicalutamide (Casodex) in a new prostate cancer model. 1102 27

Androgen receptor (AR) may communicate with the general transcription machinery on the core promoter to exert its function as a transcriptional modulator. Our previous report demonstrated that the AR interacted with transcription factor IIH (TFIIH) under physiological conditions and that overexpression of Cdk-activating kinase, the kinase moiety of TFIIH, enhanced AR-mediated transcription in prostate cancer cells. In an effort to further dissect the mechanisms implicated in AR transactivation, we report here that AR interacts with PITALRE, a kinase subunit of positive elongation factor b (P-TEFb). Cotransfection of the plasmid encoding the mutant PITALRE (mtPITALRE), defective in its RNA polymerase II COOH-terminal domain (CTD)-kinase activity, resulted in preferential inhibition of AR-mediated transactivation. Indeed, AR transactivation in PC-3 cells was preferentially inhibited at the low concentration of 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB), a CTD kinase inhibitor. These results suggest that CTD phosphorylation may play an important role in AR-mediated transcription. Furthermore, a nuclear run-on transcription assay of the prostate-specific antigen gene, an androgen-inducible gene, showed that transcription efficiency of the distal region of the gene was enhanced upon androgen induction. Taken together, our reports suggest that AR interacts with TFIIH and P-TEFb and enhances the elongation stage of transcription.
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PMID:Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation. 1126 37

Androgen receptor (AR) belongs to the steroid hormone nuclear receptor superfamily. It functions as an androgen-dependent transcriptional factor that regulates genes for cell proliferation and differentiation. Caveolin is a principal component of caveolae membranes serving as a scaffold protein of many signal transduction pathways. Recent results correlate caveolin-1 expression with androgen sensitivity in murine prostate cancer. Furthermore, immunohistochemical staining of patient specimens suggests that caveolin expression may be an independent predictor of progression of prostate cancer. In this study, we investigate the potential interactions between AR signaling and caveolin-1 and demonstrate that overexpression of caveolin-1 potentiates ligand-dependent AR activation. Conversely, down-regulation of caveolin-1 expression by a caveolin-1 antisense expression construct can down-regulate ligand-dependent AR activation. Association between these two molecules is also demonstrated by co-localization of AR with caveolin-rich, low-density membrane fractions isolated by an equilibrium sucrose gradient centrifugation method. Co-immunoprecipitation and glutathione S-transferase fusion protein pull-down experiments demonstrate that interaction between AR and caveolin-1 is an androgen-dependent process, offering further evidence for a physiological role of this interaction. Using a mammalian two-hybrid assay system, we determine that the NH(2) terminus region of caveolin-1 is responsible for the interaction with both the NH(2)-terminal domain and the ligand-binding domain of AR.
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PMID:Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. 1127 9

Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 +/- 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 +/- 0.08). Cellular proliferation measured using Ki-67 revealed <1% immunostained cells on day 6. Androgen receptor immunostained cells increased to 63% on day 6 and 84% on day 32 although immunostaining remained weak. Cellular proliferation was undetectable beyond day 6 after castration until multiple foci of 5 to 20 proliferating cells became apparent on day 120. These foci expressed increased levels of prostate-specific antigen, an androgen receptor-regulated gene product. In tumors recurrent 150 days after castration androgen receptor-immunostaining intensity was similar to CWR22 tumors from intact mice although the percentage of cells immunostained was more variable. The appearance of proliferating tumor cells that expressed androgen receptor and prostate-specific antigen 120 days after castration suggests that these cells represent the origin of recurrent tumors.
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PMID:Androgen receptor expression and cellular proliferation during transition from androgen-dependent to recurrent growth after castration in the CWR22 prostate cancer xenograft. 1178 15

Androgen receptor (AR) is required for sexual differentiation and is implicated in the development of prostate cancer. Here we describe distinct functions for cofactor proteins and gene regulatory elements in the assembly of AR-mediated transcription complexes. The formation of an activation complex involves AR, coactivators, and RNA polymerase II recruitment to both the enhancer and promoter, whereas the formation of a repression complex involves factors bound only at the promoter and not the enhancer. These results suggest a model for the functional coordination between the promoter and enhancer in which communication between these elements is established through shared coactivators in the AR transcription complex.
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PMID:Formation of the androgen receptor transcription complex. 1193 67

Androgen receptor (AR) has long been hypothesized to play an important role in prostate cancer etiology. Two trinucleotide repeat polymorphisms (CAG and GGC repeats in exon 1 of the AR gene) have been investigated as risk factors for prostate cancer in several studies. However, the results are inconclusive, probably because of the variations of study designs, characteristics of study samples, and choices of analytical methods. In this study, we evaluated evidence for linkage and association between the two AR repeats and prostate cancer by using the following comprehensive approaches: (1) a combination of linkage and association studies, (2) a test for linkage by parametric analysis and the male-limited X-linked transmission/disequilibrium test (XLRC-TDT), (3) a test for association by using both population-based and family-based tests, and (4) a study of both hereditary and sporadic cases. A positive but weak linkage score (HLOD=0.49, P=0.12) was identified in the AR region by parametric analysis; however, stronger evidence for linkage in the region, especially at the GGC locus, was observed in the subset of families whose proband had < or = 16 GGC repeats (HLOD=0.70, P=0.07) or by using XLRC-TDT ( z'=2.65, P=0.008). Significantly increased frequencies of the < or = 16 GGC repeat alleles in 159 independent hereditary cases (71%) and 245 sporadic cases (68%) cases compared with 211 controls (59%) suggested that GGC repeats were associated with prostate cancer ( P=0.02). Evidence for the association between the < or = 16 GGC repeats and prostate cancer risk was stronger with XLRC-TDT ( z'=2.66, P=0.007). No evidence for association between the CAG repeats and prostate cancer risk was observed. The consistent results from both linkage and association studies strongly implicate the GGC repeats in the AR as a prostate cancer susceptibility gene. Further studies on this polymorphism in other independent data sets and functional analysis of the GGC repeat length on AR activity are warranted.
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PMID:Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk. 1193 17

Androgen receptor (AR) is a member of the steroid hormone receptor family of molecules. AR primarily is responsible for mediating the physiologic effects of androgens by binding to specific DNA sequences that influence transcription of androgen-responsive genes. The three-dimensional structure of the AR ligand-binding domain has shown it is similar to other steroid hormone receptors and that ligand binding alters the protein conformation to allow binding of coactivator molecules that amplify the hormone signal and mediate transcriptional initiation. However, AR also undergoes intramolecular interactions that regulate its interactions with coactivators and influence its activity. A large number of naturally occurring mutations of the human AR gene have provided important information about AR molecular structure and intermolecular interactions. AR is also a critical mediator of prostate cancer promotion, conferring growth signals to prostate cancer cells throughout the natural history of the disease. Late-stage prostate cancer, unresponsive to hormonal deprivation, sustains AR signaling through a diverse array of molecular strategies. Variations in the AR gene may also confer genetic predisposition to prostate cancer development and severity. Further understanding of AR action and new strategies to interfere with AR signaling hold promise for improving prostate cancer therapy.
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PMID:Molecular biology of the androgen receptor. 1208 31

Androgen receptor (AR) is a hormone-regulated transcription factor that mediates a wide array of biological processes including sexual differentiation, spermatogenesis, and prostate cancer progression. The transcriptional activity of AR and other members of the nuclear receptor superfamily are modulated by coregulatory proteins. In this study, we have investigated the regulation of AR transcriptional activity by the silencing mediator for retinoid and thyroid hormone receptors (SMRT). We found that AR possesses an intrinsic transcriptional repression activity, and AR interacts directly with SMRT. One interacting surface on AR is mapped to the ligand-binding domain, and the presence of a DNA binding/hinge region enhances this interaction. The binding surface on SMRT is mapped to the C-terminal ID2 region, and mutation in the ID2 corepressor motif inhibits the interaction. Overexpression of SMRT inhibits dihydrotestosterone-dependent transactivation by AR and further suppresses the antiandrogen flutamide-mediated inhibition of AR activity. We provide evidence to suggest that the mechanisms of SMRT-mediated inhibition of AR activity involves inhibition of AR N/C interaction and competition with the p160 coactivator. Our data establish a significant role of SMRT in modulating AR transcriptional activity.
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PMID:Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT. 1244 55


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