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)

Androgen receptor (AR) activity is required for prostate growth, differentiation, and secretion. Deregulation of AR activity results in inappropriate mitogenic signaling and is thought to contribute both to the initiation and progression of prostate cancers. Cyclin D1 functions as a strong AR corepressor by directly interacting with and inhibiting receptor activity. However, the extent to which cyclin D1 functions to inhibit AR activity under conditions associated with cancer progression has not been determined. We now demonstrate that cyclin D1 action is conserved in multiple tumor cell backgrounds, inhibiting AR-dependent gene activation in breast, bladder, and androgen-independent prostatic adenocarcinoma cell lines. In androgen-dependent prostatic adenocarcinomas, cyclin D1 effectively muted androgen-stimulated target gene expression in a manner analogous to dominant negative ARs. The ability of cyclin D1 to inhibit AR activity was conserved with regard to target promoter, repressing transactivation from mouse mammary tumor virus, probasin, and prostate-specific antigen promoters. Inappropriate, nonligand AR activation, postulated to act through regulation of receptor phosphorylation, was also sensitive to cyclin D1 regulation. Moreover, we show that several phosphorylation site mutants of the AR were equally inhibited by cyclin D1 as compared with the wild-type receptor. Given these data establishing the potency of cyclin D1-mediated repression, we evaluated the ability of cyclin D1 to inhibit tumor-derived AR alleles and polymorphisms associated with tumor progression and increased prostate cancer risk. We demonstrate that the AR alleles and polymorphisms tested respond completely to cyclin D1 corepressor activity. In addition, activation of a common tumor-derived AR allele by 17 beta-estradiol and progesterone was inhibited through ectopic expression of cyclin D1. Taken together, these data establish the potency of cyclin D1 as an AR corepressor and provide support for additional studies examining the efficacy of developing novel prostate cancer therapies for both androgen-dependent and -independent tumors.
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PMID:Specificity of cyclin D1 for androgen receptor regulation. 1294 14

Androgen receptor (AR) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgen-responsive elements (AREs) on the target genes. Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen-independent prostate cancer. The levels of interleukin-4 (IL-4) are significantly elevated in sera of patients with hormone refractory prostate cancer. The potential role of IL-4 on the activation of AR was investigated in prostate cancer cells. IL-4 enhances AR-mediated prostate-specific antigen (PSA) expression and ARE-containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells. The AR can also be sensitized by IL-4 and activated by significantly lower levels of androgen (10 pM of R1881) in prostate cancer cells. IL-4 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells. Blocking of the Akt pathway by an Akt-specific inhibitor LY294002 abrogates IL-4-induced PSA expression and AR signaling. These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells.
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PMID:Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway. 1297 Jul 46

Androgen receptor (AR) is expressed in nearly all prostate cancers, including treatment-refractory disease. The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years. The AR is now known to participate in tumor progression through 3 mechanisms: expression (activation and upregulation of receptor activity), point mutations, and ligand-independent activation. With regard to the latter mechanism, interleukin-6 (IL-6) is among the most important nonsteroidal regulators of AR activity. In the absence of androgen, IL-6 causes activation of AR that is approximately 50% of the maximal activity induced by androgen. At low concentrations of androgen, IL-6 and androgen synergistically activate AR. Nonsteroidal antiandrogens usually antagonize this activation, but they switch to an agonist effect in the presence of oncostatin M, an IL-6-related cytokine. The growth of parental LNCaP cells is initially inhibited by exposure to IL-6, but long-term treatment renders the cells resistant to such inhibition and confers a growth advantage. Both IL-6 and oncostatin M stimulate AR activity, but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens. It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies.
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PMID:Role of the androgen receptor axis in prostate cancer. 1460 14

Androgen receptor (AR) mutations that modify both the ligand binding and the transactivation capacities of the AR represent one of the mechanisms involved in the transition of prostate cancer (PCa) from androgen-dependent to androgen-independent growth. We use a yeast-based functional assay to detect and analyze mutant ARs in PCa. We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation. Concomitantly to the widely described T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop just downstream the DNA binding domain together with the T877A point mutation. This type of mutation, which leads to a c-terminal truncated AR, has not been described yet in PCa. Using luciferase reporter assays we demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation-induced constitutive activation of the AR could be a mechanism used by PCa cells to escape androgen deprivation.
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PMID:Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer. 1461 30

When prostate cancer is first detected it generally is dependent on the presence of androgens for growth, and responds to androgen ablation therapies. However, the disease often recurs in a disseminated and apparently androgen independent (AI) form, and in this state is almost invariably fatal. Considerable evidence indicates that the Androgen receptor (AR) continues to be required even in androgen independent (AI) disease. Thus, a key to understanding hormone independent prostate cancer is to determine the mechanism(s) by which the AR can function even in the absence of physiologic levels of androgen. In this article, we argue that growth factors and receptors that utilize Ras family members drive prostate cancer progression to a state of androgen hypersensitivity; and that post-translational modifications (e.g., phosphorylations) of transcriptional cofactors might be responsible for modulating the function of the AR so that it is active even at low concentrations of androgen.
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PMID:Ras signaling in prostate cancer progression. 1468 77

Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.
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PMID:Molecular determinants of resistance to antiandrogen therapy. 1470 29

Androgen receptor trapped clone-27 (ART-27) is a newly described transcriptional coactivator that binds to the N terminus of the androgen receptor (AR). Given the vital importance of AR signaling in prostate growth and differentiation, we investigated the role of ART-27 in these processes. Immunohistochemical studies indicate that ART-27 protein is expressed in differentiated epithelial cells of adult human prostate and breast tissue. In prostate, ART-27 is abundant in AR-positive prostate luminal epithelial cells, in contrast to the stroma, where cells express AR but not ART-27. The use of a rat model of androgen depletion/reconstitution indicates that ART-27 expression is associated with the elaboration of differentiated prostate epithelial cells. Interestingly, regulated expression of ART-27 in the androgen-sensitive LNCaP prostate cancer cell line inhibits androgen-mediated cellular proliferation and enhances androgen-mediated transcription of the prostate-specific antigen (PSA) gene. Consistent with a growth suppressive function, we show that ART-27 expression levels are negligible in human prostate cancer. Importantly, examination of ART-27 protein expression in early fetal prostate development demonstrates that ART-27 is detected only when the developing prostate gland has proceeded from a solid mass of undifferentiated cells to a stage in which differentiated luminal epithelial cells are evident. Thus, ART-27 is an AR cofactor shown to be subject to both cell type and developmental regulation in humans. Overall, the results suggest that decreased levels of ART-27 protein in prostate cancer tissue may occur as a result of de-differentiation, and indicate that ART-27 is likely to regulate a subset of AR-responsive genes important to prostate growth suppression and differentiation.
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PMID:ART-27, an androgen receptor coactivator regulated in prostate development and cancer. 1471 28

Androgen receptor (AR) signaling pathways mediate critical events in normal and neoplastic prostate growth. Shortening of the polymorphic N-terminal polyglutamine (poly(Q)) tract of the AR gene leads to transcriptional hyperactivity and has been correlated with an increased risk of prostate cancer. The underlying mechanisms for these effects are poorly understood. We show here that androgen-dependent cellular proliferation and transcription in prostate cancer cells is inversely correlated to the length of the AR poly(Q) region. We further show that AR proteins containing a shortened poly(Q) region functionally respond to lower concentrations of androgens than wild type AR. Whereas DNA binding activity is relatively unaffected by AR poly(Q) variation, we found that ligand binding affinity and the ligand-induced NH(2)- to COOH-terminal intramolecular interaction is enhanced when the poly(Q) region is shortened. Importantly, we show that AR proteins containing a shortened poly(Q) region associate in vivo with higher levels of specific p160 coactivators and components of the SWI/SNF chromatin remodeling complex as compared with the wild type AR. Collectively, our findings suggest that the AR transcriptional hyperactivity associated with shortened poly(Q) length stems from altered ligand-induced conformational changes that enhance coactivator recruitment.
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PMID:Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells. 1496 21

Androgen receptor (AR) is a ligand-activated transcription factor that requires androgen binding to initiate a series of molecular events leading to specific gene activation. AR has been suggested to form an antiparallel homodimer based on the characteristics of high affinity interaction between the amino (N) and carboxyl (C) termini of it. Recently, it is suggested that AR N-to-C interaction is critical for the ability of this receptor to up-regulate the transcription of androgen-responsive genes, and may be a new target for treatment of prostate cancer (PCa). In this study, we investigated the effect of N-terminal (1-34) peptide of AR (ARN34) on androgen-dependent function in PCa cell. Ectopic expression of ARN34 suppressed both androgen-dependent AR N-to-C interaction and prostate specific antigen transcription. Ectopic expression of ARN34 also caused delaying translocation to the nucleus and the decreasing stability of the AR. Stable expression of ARN34 suppressed androgen-dependent cell growth of LNCaP cells. Moreover, transactivation and cell growth of the AR variant in LNCaP cells by the AR antagonist, hydroxyflutamide, were also inhibited by ARN34. Although treatment of LNCaP cells with androgen drove transition of cells from G1 to S-phase, the cells expressing ARN34 were inhibited to enter into S phase in the presence of androgen. This cell cycle arrest was attended by decrease in cyclin E levels and cyclin-dependent-kinase 2 activity, and increase in p27 levels. Our results demonstrated that disruption of AR N-to-C interaction caused by ARN34 leads to AR dysfunction and inhibition of AR-mediated prostate cancer cell growth. This approach is thus considered to provide a useful therapeutic opinion for blocking AR-mediated PCa growth.
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PMID:Ectopic expression of the amino-terminal peptide of androgen receptor leads to androgen receptor dysfunction and inhibition of androgen receptor-mediated prostate cancer growth. 1506 56

Androgen receptor (AR) overexpression is one of the characteristics of prostate cancer (PC) that progresses to hormone independence. An androgen-independent (AI) derivative, with much higher AR-mRNA and protein levels than the parental LNCaP cell line, whose proliferation was androgen dependent (AD), was used to explore the mechanism of AR overexpression. We found that a suppressor element (ARS), previously identified in mouse AR and located in the 5'-untranslated region of human AR gene, malfunctions in AI cells. Transfection of constructs that included ARS element into AD cells reduced the transactivating activities of both AR promoter and a heterologous SV40 promoter. The deletion of ARS resulted in an eightfold increase in AR-promoter activity in AD cells, but had no effect in AI cells. Moreover, the nuclear extracts of AD cells contained proteins that produced a specific, ARS-binding complex, while this complex appeared to have been lost from AI cells. Most importantly, treatment of AI cells with a demethylating agent or histone deacetylase inhibitors restored the lost ARS-binding complex. The restoration of the complex coincided with a reduced expression of AR-mRNA and protein and a reduced rate of AR-gene transcription, determined by nuclear run-on experiment. Thus, epigenetic transcriptional silencing of the suppressor protein(s) may be responsible for AR overexpression in AI cells, and its reversal in hormone-independent PC may normalize AR levels and restore their hormone dependence.
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PMID:Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line. 1515 93


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