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AR Expression (ar + expression)
Selected AbstractsAdvanced fluorescence in situ hybridization to localize and quantify gene expression in Japanese medaka (Oryzias latipes) exposed to endocrine-disrupting compoundsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2009June-Woo Park Abstract In an earlier study, we described the development of fluorescence in situ hybridization (FISH) using confocal microscopy to localize and quantify gene expression in fish. Here, we report the results of FISH application to investigate effects of model endocrine-disrupting chemicals (EDCs), 17,-ethinylestradiol (EE2) and 17,-trenbolone (TB), on expressions of EDC-responsive genes in Japanese medaka (Oryzias latipes) at the cellular/tissue level paired with histological observation. Gene expressions of vitellogenin-II (Vit-II), androgen receptor (AR), and cytochrome P450 gonadal aromatase (CYP19a) were determined after exposure to 5, 50, or 500 ng/L of EE2 or 50, 500, or 5,000 ng/L of TB for 7 d. Exposure to the greatest concentration of EE2 or TB significantly reduced fecundity and caused histological alterations in gonads. 17,-Ethinylestradiol induced Vit-II expression in both male gonads and liver relative to controls and resulted in greater intensity of hematoxylin staining in hepatocytes, which was significantly correlated with Vit-II induction in liver. When exposed to EE2 at less than 50 ng/L, CYP19a expression associated with early stage oocytes was greater than that in controls. However, at 500 ng/L, this trend was reversed. The greater Vit-II expression in testis from all EE2 groups, and the lesser expression of CYP19a in ovaries from the 500 ng/L group, likely is related to changes in the number of cells in which these genes are predominantly expressed rather than to an increase in expression per cell. 17,-Trenbolone significantly induced AR expression in ovaries but did not alter AR expression in female liver. It was concluded that FISH combined with histology enables advanced elucidation of molecular effects of chemicals by associating changes in gene expression with certain tissues and/or cell types and allows these changes to be related to histological effects. [source] Decrease in stromal androgen receptor associates with androgen-independent disease and promotes prostate cancer cell proliferation and invasionJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6b 2008Yirong Li Abstract Androgen receptor (AR) is expressed in both stromal and epithelial cells of the prostate. The majority of studies on AR expression and function in prostate cancer is focused on malignant epithelial cells rather than stromal cells. In this study, we examined the levels of stromal AR in androgen-dependent and -independent prostate cancer and the function of stromal AR in prostate cancer growth and invasion. We showed that stromal AR levels were decreased in the areas surrounding cancerous tissue, especially in androgen-independent cancer. Using two telomerase-immortalized human stromal cell lines, one AR-positive and the other AR-negative, we demonstrated that stromal cells lacking AR stimulated cell proliferation of co-cultured prostate cancer cells in vitro and enhanced tumour growth in vivo when co-injected with PC3 epithelial cells in nude mice. In contrast, stromal cells expressing AR suppressed prostate cancer growth in vitro and in vivo. In parallel with cancer growth, in vitro invasion assays revealed that stromal cells lacking AR increased the invasion ability of PC3 cell by one order of magnitude, while stromal cells expressing AR reduced this effect. These results indicate a negative regulation of prostate cancer growth and invasion by stromal AR. This provides potentially new mechanistic insights into the failure of androgen ablation therapy, and the reactivation of stromal AR could be a novel therapeutic approach for treating hormone refractory prostate cancer. [source] Aldose Reductase and AGE,RAGE pathways: central roles in the pathogenesis of vascular dysfunction in aging ratsAGING CELL, Issue 5 2010Kellie McCormick Hallam Summary Aging is inevitably accompanied by gradual and irreversible innate endothelial dysfunction. In this study, we tested the hypothesis that accentuation of glucose metabolism via the aldose reductase (AR) pathway contributes to age-related vascular dysfunction. AR protein and activity levels were significantly increased in aged vs. young aortic homogenates from Fischer 344 rats. Immunostaining revealed that the principal site of increased AR protein was the aortic endothelium as well as smooth muscle cells. Studies revealed that endothelial-dependent relaxation (EDR) in response to acetylcholine was impaired in aged rats compared to young rats and that treatment with the AR inhibitor (ARI) zopolrestat significantly improved EDR in aged rats. Methylglyoxal (MG), a key precursor of advanced glycation endproducts (AGEs), was significantly increased in the aortas of aged rats vs. young rats. Consistent with central roles for AR in generation of MG in aging, ARI treatment significantly reduced MG levels in aged rat aorta to those in young rats. Treatment of aged rats with soluble(s) RAGE, a soluble form of the chief signal transduction receptor for AGEs, RAGE, significantly improved EDR in aged rats, thus establishing the contribution of age-related increases in AGEs to endothelial dysfunction. These findings reveal that significant increases in AR expression and activity in aged rat vasculature linked to endothelial dysfunction may be mitigated, at least in part, via ARI and that aging-linked increased flux via AR generates AGEs; species which transduce endothelial injury consequent to their interaction with RAGE. These data demonstrate for the first time that AR mediates aging-related vascular dysfunction, at least in part, via RAGE. [source] Does the panel of cytokeratin 20 and androgen receptor antibodies differentiate desmoplastic trichoepithelioma from morpheaform/infiltrative basal cell carcinoma?JOURNAL OF CUTANEOUS PATHOLOGY, Issue 2 2008Terrence M. Katona Background:, Evaluation of androgen receptor (AR) and cytokeratin 20 (CK20) expression can aid in distinguishing between conventional basal cell carcinoma (characteristically AR+, CK20,) and trichoepithelioma (frequently AR,, CK20+). Within these two groups of tumors, morpheaform/infiltrative basal cell carcinoma (mBCC) and desmoplastic trichoepithelioma (DTE) are particularly challenging to differentiate both clinically and histologically. We investigated whether AR and CK20 immunostains may distinguish between mBCC and DTE. Methods:, Immunohistochemistry for AR and CK20 was performed on 15 DTEs and 31 mBCCs. Any immunoreactivity within the tumor for AR or CK20 was considered positive. Results:, AR expression was seen in 13% (2/15) of DTE and 65% (20/31) of mBCC cases (chi-square p = 0.0011). CK20-positive Mërkel cells were identified in 100% (15/15) of DTE and 3% (1/31) of mBCC (chi-square p < 0.0001). The expected pattern of AR,, CK20+ immunophenotype was present in 87% (13/15) of DTE cases. In mBCC, 61% (19/31) was AR+, CK20,. No DTE was AR+, CK20, and no mBCC was AR,, CK20+. Conclusions:, Immunohistochemical stains for AR and CK20 are useful to differentiate DTE from mBCC. The AR,, CK20+ immunophenotype is sensitive (87%) and specific for DTE (100%). The AR+, CK20, immunophenotype is specific (100%) and moderately sensitive (61%) for mBCC. [source] Androgen Receptor Expression in the Levator Ani Muscle of Male MiceJOURNAL OF NEUROENDOCRINOLOGY, Issue 10 2007J. A. Johansen The spinal nucleus of the bulbocavernosus (SNB) is a sexually dimorphic group of motoneurones that innervates the bulbocavernosus (BC) and levator ani (LA), skeletal muscles that attach to the base of the penis. In many species, including mice, rats and hamsters, the LA and BC have been found to be highly responsive to androgen and, in rats, these muscles mediate several effects of androgen on the SNB system. However, characterising the SNB system in mice is important because of the availability of genetic models in this species. In the present study, we examined AR expression in skeletal muscles of C57/BlJ6 adult male mice using immunoblotting and immunocytochemistry, comparing the BC/LA to the androgen-unresponsive extensor digitorum longus (EDL). We found similar differences in AR expression for these muscles in the mouse as previously reported for rats. In mice, the BC/LA contains more AR protein than does the EDL. At the cellular level, the LA contains a higher percentage of AR positive myonuclei and fibroblasts than does the EDL. Finally, AR expression is enriched at the neuromuscular junction of mouse LA fibres. The increased expression of AR in the LA compared to the EDL in both muscle fibres and fibroblasts indicates that each cell type may critically mediate androgen action on the SNB system in mice. [source] Up-Regulation and Functional Effect of Cardiac ,3 -Adrenoreceptors in Alcoholic MonkeysALCOHOLISM, Issue 7 2010Heng-Jie Cheng Background:, Recent studies link altered cardiac ,-adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of ,3 -AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up-regulation of cardiac ,3 -AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM. Methods:, We compared myocyte ,3 - and ,1 -AR expression and myocyte contractile ([Ca2+]i), transient ([Ca2+]iT), and Ca2+ current (ICa,L) responses to ,- and ,3 -AR stimulation in myocytes obtained from left ventricle (LV) tissue samples obtained from 10 normal control (C) and 16 monkeys with self-administered alcohol for 12 months prior to necropsy: 6 moderate (M) and 10 heavy (H) drinkers with group average alcohol intakes of 1.5 ± 0.2 and 3.3 ± 0.2 g/kg/d, respectively. Results:, Compared with control myocytes (C), in alcoholic cardiomyocytes, basal cell contraction (dL/dtmax, ,39%, H: 69.8 vs. C: 114.6 ,m/s), relaxation (dR/dtmax, ,37%, 58.2 vs. 92.9 ,m/s), [Ca2+]iT (,34%, 0.23 vs. 0.35), and ICa,L (,25%, 4.8 vs. 6.4pA/pF) were all significantly reduced. Compared with controls, in moderate and heavy drinkers, ,1 -AR protein levels decreased by 23% and 42%, but ,3 -AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to ,-AR agonist, isoproterenol (ISO), and ,3 -AR agonist, BRL-37344 (BRL). Compared with controls, in alcoholic myocytes, ISO (10,8 M) produced significantly smaller increases in dL/dtmax (H: 40% vs. C: 71%), dR/dtmax (37% vs. 52%), [Ca2+]iT (17% vs. 37%), and ICa,L (17% vs. 27%), but BRL (10,8 M) produced a significantly greater decrease in dL/dtmax (H: ,23% vs. C: ,11%), [Ca2+]iT (,30% vs. ,11%), and ICa,L (,28% vs. ,17%). Conclusions:, Chronic alcohol consumption down-regulates cardiac ,1 - and up-regulates ,3 -ARs, contributing to the abnormal response to catecholamines in ACM. The up-regulation of cardiac ,3 -AR signaling enhances inhibition of LV myocyte contraction and relaxation and exacerbates the dysfunctional [Ca2+]i regulation and, thus, may precede the development of ACM. [source] Aggressive invasive micropapillary salivary duct carcinoma of the parotid glandPATHOLOGY INTERNATIONAL, Issue 5 2008Hidetaka Yamamoto The presence of invasive micropapillary component has been reported to be associated with salivary duct carcinoma and poor outcomes. Herein is described a rare case of invasive micropapillary salivary duct carcinoma of the parotid gland in a 60-year-old man. The micropapillary component was approximately 70% of the area of the tumor. Squamous differentiation was focally seen adjacent to the micropapillary component. On immunohistochemistry the ordinary salivary duct carcinoma component was positive for gross cystic disease fluid protein-15 (GCDFP-15), androgen receptor (AR), and HER2/neu, whereas both micropapillary and squamous components were negative for GCDFP-15 and AR. Immunohistochemical staining for D2-40 highlighted the lymph vessel invasion of tumor cells. This patient developed metastases in the lymph nodes of the neck, and also in the liver, lung, and brain. The lymph nodes and liver metastases had both ordinary salivary duct carcinoma and micropapillary components. The patient died of tumor 11 months after the initial surgical operation. The results support that the presence of micropapillary component is associated with more aggressive behavior of salivary duct carcinoma. It is also important for pathologists to recognize that GCDFP-15 and AR expression can be reduced in micropapillary carcinoma in the differential diagnosis of metastatic tumor. [source] Androgen receptor as a potential sign of prostate cancer metastasisTHE PROSTATE, Issue 15 2009Marie-Hélène Lévesque Abstract BACKGROUND Androgen receptor (AR) expression and its modulation through the carcinogenesis process have been investigated in several studies with conflicting results. MATERIALS AND METHODS In situ hybridization and immunocytochemistry were used to examine AR expression in prostatic needle core biopsies of benign, high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma. RESULTS A significant increase in AR mRNA levels was found in the cancerous prostatic cells when compared with the benign tissue biopsies. AR abundance in HGPIN was found to be almost half-way between that observed in benign and in cancerous tissue. In the benign prostatic epithelium, the immunocytochemistry data show that AR is exclusively expressed in the nuclei of epithelial cells. However, in 72% of examined cancer biopsies, AR was expressed in both the cytoplasm and nuclei. After examination of medical records of 100 patients diagnosed with prostate cancer, it was found that the AR was expressed in both cellular compartments of cancer cells in 81% of cases when cancer was found to have metastasized outside the prostate. In contrast, when the cancer was organ-confined, AR was localized in both the nuclei and cytoplasm in only 66% of cases. Moreover, when the AR was expressed in the cytoplasm of cancerous cells, consecutive serial sections immunostained with the mitochondrial marker suggest that AR is localized in the mitochondria. CONCLUSIONS AR mRNA expression is significantly higher in prostate cancer when compared to benign prostatic tissue. Prostate 69: 1704,1711, 2009. © 2009 Wiley-Liss, Inc. [source] Antisense MDM2 enhances the response of androgen insensitive human prostate cancer cells to androgen deprivation in vitro and in vivoTHE PROSTATE, Issue 6 2008Zhaomei Mu Abstract Background Antisense MDM2 oligonucleotide (AS-MDM2) sensitizes androgen sensitive LNCaP cells to androgen deprivation (AD) in vitro and in vivo. In this study, we investigated the effects of AS-MDM2 combined with AD on androgen resistant LNCaP (LNCaP-Res) and moderately androgen resistant bcl-2 overexpressing LNCaP (LNCaP-BST) cells. Methods The LNCaP-Res cell line was generated by culturing LNCaP cells in medium containing charcoal-stripped serum for more than 1 year. Apoptosis was quantified in vitro by Annexin V staining and caspase 3,+,7 activity. For the in vivo studies, orthotopic tumor growth was monitored by magnetic resonance imaging (MRI). AS-MDM2 and the mismatch control were given by i.p. injection at doses of 25 mg/kg per day, 5 days/week for 15 days. Results LNCaP-Res cells expressed high levels of androgen receptor (AR) and bcl-2, and displayed no growth inhibition to AD. AS-MDM2 caused significant reductions in MDM2 and AR expression, and increases in p53 and p21 expression in both cell lines. AS-MDM2,+,AD resulted in the highest levels of apoptosis in vitro and tumor growth inhibition in vivo in both cell lines; although, these effects were less pronounced in LNCaP-BST cells. Conclusions AS-MDM2,+,AD enhanced apoptotic cell death in vitro and tumor growth inhibition in vivo in androgen resistant cell lines. The action of AS-MDM2,+,AD was influenced somewhat by bcl-2 expression as an isolated change (LNCaP-BST cells), but not when accompanied by other molecular changes associated with androgen insensitivity (LNCaP-Res cells). MDM2 knockdown has promise for the treatment of men with early hormone refractory disease. Prostate 68: 599,609, 2008. © 2008 Wiley-Liss, Inc. [source] Androgen-mediated cholesterol metabolism in LNCaP and PC-3 cell lines is regulated through two different isoforms of acyl-coenzyme A: Cholesterol Acyltransferase (ACAT)THE PROSTATE, Issue 1 2008Jennifer A. Locke Abstract BACKGROUND The objective of this work was to determine the effect of an androgen agonist, R1881, on intracellular cholesterol synthesis and esterification in androgen-sensitive (AS) prostate cancer (LNCaP) cells. METHODS We investigated the activity and expression of cholesterol metabolism enzymes, HMG-CoA-reductase and ACAT in the LNCaP and PC-3 (androgen-independent control) models. RESULTS Microsomal PC-3 HMG-CoA-reductase activity was increased with R1881 despite having similar cholesterol levels while increased cholesterol levels in microsomes from LNCaPs treated with R1881 (L+) were associated with increased HMG-CoA reductase activity. Increased intracellular cholesteryl esters (CE) found in (L+) were not associated with an increased ACAT1 activity. There was no effect from androgen treatment on ACAT1 protein expression in theses cells; however, ACAT2 expression was induced upon R1881 treatment. In contrast, we found an increase in the in vitro ACAT1 activity in PC-3 cells treated with androgen (P+). Only ACAT1 expression was induced in P+. We further assessed the expression of STAT1,, a transcriptional activator that modulates ACAT1 expression. STAT1, expression and phosphorylation were induced in P+. To determine the role of the AR on ACAT1 expression and esterification, we treated PC-3 cells overexpressing the androgen receptor with R1881 (PAR+). AR expression was decreased in PAR+ cells; ACAT1 protein expression and cholesterol ester levels were also decreased, however, ACAT2 remained unchanged. STAT1, expression was decreased in PAR+. CONCLUSIONS Overall, these findings support the importance of cholesterol metabolism regulation within prostate cancer cells and unravel a novel role for STAT1, in prostate cancer metabolism. Prostate 68: 20,33, 2008. © 2007 Wiley-Liss, Inc. [source] The oncogenic potential of a prostate cancer-derived androgen receptor mutantTHE PROSTATE, Issue 6 2007Xu-Bao Shi Abstract BACKGROUND The role of androgen receptor (AR) mutations in the initiation of prostate cancer (CaP) remains unclear. The purpose of this study was to assess the influence of an AR mutation on prostate tumorigenesis and to determine the resulting molecular alterations. METHODS Wild-type AR (ARWT) or the CaP-derived K580R AR (ARK580R) mutant was stably transfected into SV40-immortalized human prostate epithelial pRNS-1-1 cells that lack AR expression and fail to grow in nude mice. The ability of these AR-transfected cell lines to form tumor was investigated in vitro and in vivo. Additionally, gene expression profiling of these cell lines was performed. RESULTS Compared with the ARWT, the ARK580R induced greater than sixfold increase in colony formation in soft agar. In vivo studies confirmed that the ARK580R -transfected pRNS-1-1 cells were able to form tumors in nude mice. Using a combination of microarray and RT-PCR, 29 differentially expressed genes were identified in ARK580R cells. It was found that silencing the expression of placental alkaline phosphatase (ALPP) that was upregulated in ARK580R cells resulted in significant inhibition of cell growth. Furthermore, the ARK580R -transfected pRNS-1-1 cells expressed markedly increased p-Akt and p-p70 S6K. CONCLUSION The ARK580R mutation promoted the malignant transformation of prostate epithelial cells. This was associated with upregulation of ALPP and subsequent activation of the Akt signaling pathway. Prostate 67: 591,602, 2007. © 2007 Wiley-Liss, Inc. [source] Estrogen signaling and disruption of androgen metabolism in acquired androgen-independence during cadmium carcinogenesis in human prostate epithelial cellsTHE PROSTATE, Issue 2 2007Lamia Benbrahim-Tallaa Abstract BACKGROUND Lethal prostate cancers often become androgen-independent due to androgen receptor (AR) overexpression. The role of cadmium in prostate tumor progression was determined. METHODS Control and cadmium-transformed prostate epithelial cells (CTPE) were compared for steroid-induced proliferation, steroid receptor expression, and androgen metabolism. RESULTS CTPE cells showed rapid proliferation in complete medium and sustained proliferation in steroid-reduced medium. Androgens stimulated significantly less cell proliferation and AR-related genes expression in CTPE cells. 5,-Dihydrotestosterone increased PSA expression more effectively in control cells. Flutamide reduced 5,-dihydrotestosterone-stimulated growth less effectively in CTPE cells compared to control. CTPE cells showed decreased p27 expression. Estrogen receptors were overexpressed and estradiol markedly stimulated proliferation in CTPE cells. In CTPE cells 5,-aromatase was markedly increased, while 5,-reductase was decreased. CONCLUSIONS Cadmium-induced malignant transformation stimulates androgen independence, unrelated to AR expression or activity. Increased estrogen receptor and 5,-aromatase expression suggest estrogen signaling may be critical to this process. Prostate © 2006 Wiley-Liss, Inc. [source] An androgen-independent androgen receptor function protects from inositol hexakisphosphate toxicity in the PC3/PC3(AR) prostate cancer cell linesTHE PROSTATE, Issue 12 2006Jean-Simon Diallo Abstract BACKGROUND Inositol hexakisphosphate (IP6) is a phytochemical exhibiting anticancer activity. Because few prostate cancer (PCa) cell lines have been used to study IP6, we assessed its efficacy in a panel of PCa cell lines. METHODS AND RESULTS Using WST-1 assays we observed that, although androgens did not modulate its efficacy, IP6 was more active in androgen receptor (AR) negative cells than in AR-positive cells. Stable expression of the AR in PC3 cells (PC3(AR)) decreased the response to IP6, which was reversed by an AR-targeting siRNA. Furthermore, AR expression in PC3 cells resulted in significantly reduced caspase-3 activation (P,<,0.001) and DNA fragmentation (P,<,0.05) in response to IP6. Similarly, although treatment with IP6 caused the upregulation of NF-,B-responsive (I,B-,, IRF-2) and p53/E2F-responsive genes (Puma, Noxa) in PC3 cells, this increase was reduced in PC3AR cells (P,<,0.01). CONCLUSION We conclude that resistance to IP6 can be linked to a ligand-independent AR function. Prostate © 2006 Wiley-Liss, Inc. [source] Androgen receptor protein expression in prostatic tissues in black and caucasian men,THE PROSTATE, Issue 4 2004E. Oluwabunmi Olapade-Olaopa Abstract BACKGROUND CaP has a higher incidence and mortality in Black men. We hypothesized that subpopulation differences in AR expression may contribute to this phenomenon. METHOD AR immunostaining was compared in epithelium and PES of normal, BPH, and CaP tissues from Black African men and UK Caucasian men. RESULTS AR expression was similar in normal prostatic epithelium of both groups, but was higher in BPH and CaP epithelium of Black than Caucasian men (P,,,0.0001). Also, AR expression in PES was higher in Caucasian than Black men in normal/atrophic and benign hyperplastic tissues, but there was a similar significant loss of AR expression in PES of CaP tissues of both groups (normal and BPH stroma versus CaP stroma (P,,,0.0001). CONCLUSIONS Variations in AR expression between subpopulations may contribute to the phenotypic differences of prostatic diseases in Black and Caucasian men. © 2004 Wiley-Liss, Inc. [source] | |||||||||||||