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PubMed1988

Androgen and erythropoiesis: evidence for an androgen receptor in erythroblasts from human bone marrow cultures.

The techniques for culturing erythroid precursors made possible the study of the effect of steroids on these cells, and it has been well established that androgens and 5 beta-steroids have a direct effect on erythroid precursor cells from animal or human bone marrow. By contrast, their mechanisms of intracellular action remain poorly understood. We used tritiated methyltrienolone (R1881), a synthetic androgen that binds strongly to the androgen receptor, to characterize the binding activity in nuclear extracts of erythroblasts from human bone marrow cultures. The nuclear extracts contained binding sites that were saturable at low concentrations of 3H-R1881 (8-12 nM). Scatchard analysis revealed that the dissociation constant of the hormone-receptor complexes (Kd) was 10-20 nM, and the number of binding sites was 64-103 fmol/mg of protein. On linear sucrose density gradient analysis (5-20%), the hormone-receptor complexes sedimented in the region of 3.9 S. Finally, 5 beta-dihydrotestosterone had also a strong affinity for the binding sites. The nuclear component binding has all the physicochemical characteristics usually attributed to androgen receptors. These data strongly suggest that androgen action on erythropoiesis is mediated by a nuclear androgen receptor.

Bone Marrow Cells↗

PubMedDate not supplied

Peripubertal exposure to the antiandrogenic fungicide, vinclozolin, delays puberty, inhibits the development of androgen-dependent tissues, and alters androgen receptor function in the male rat.

Vinclozolin is a well-characterized antiandrogenic fungicide. It produces adverse effects when administered during sexual differentiation, and it alters reproductive function in adult male rats by acting as an androgen-antagonist. Two active metabolites of vinclozolin, M1 and M2, compete with natural androgens for the rat and human androgen receptors (ARs), an effect that blocks androgen-induced gene expression in vivo and in vitro. In addition to their effects during perinatal life, androgens play a key role in pubertal maturation in young males. In this regard, the present study was designed to examine the effects of peripubertal oral administration of vinclozolin (0, 10, 30, or 100 mg kg-1 day-1) on morphological landmarks of puberty, hormone levels, and sex accessory gland development in male rats. In addition, as binding of the M1 and M2 to AR alter the subcellular distribution of AR by inhibiting AR-DNA binding, we examined the effects of vinclozolin on AR distribution in the target cells after in vivo treatment. We also examined serum levels of vinclozolin, M1, and M2 in the treated males so that these could be related to the effects on the reproductive tract and AR distribution. Vinclozolin treatment delayed pubertal maturation (at 30 and 100 mg kg-1 day-1) and retarded sex accessory gland and epididymal growth. Serum luteinizing hormone (LH; significant at all dosage levels) and testosterone and 5 alpha-androstane, 3 alpha, 17 beta-diol (at 100 mg kg-1 day-1) levels were increased. Testis size and sperm production, however, were unaffected. It was apparent that these effects were concurrent with subtle alterations in the subcellular distribution of AR. In control animals, most AR were in the high salt cell fraction, apparently bound to the natural ligand and DNA. Vinclozolin treatment reduced the amount of AR in the high salt (bound to DNA) fraction and it increased AR levels in the low salt (inactive, not bound to DNA) fraction. M1 and M2 were found in the serum of animals from the two highest dosage groups, but they were present at levels well below their K1 values. In summary, these results suggest that when the vinclozolin metabolites occupy a small percentage of AR in the cell, this prevents maximal AR-DNA binding and alters in vivo androgen-dependent gene expression and protein synthesis, which in turn results in obvious alterations of morphological development and serum hormone levels. It is noteworthy that similar exposures during prenatal life result in a high incidence of malformations in male rats.

Administration, Oral↗

PubMed2002

Androgen modulation of adhesion and antiadhesion molecules in PC-3 prostate cancer cells expressing androgen receptor.

The metastatic spread of cancer cells involves a complex process of detachment via antiadhesion molecules and attachment and migration through adhesion. In the prostate, androgens are generally thought to contribute to the development and progression of prostate cancer by promoting cell proliferation and survival through poorly defined mechanisms. We have reported previously that PC-3 prostate cancer cells, which are unresponsive to androgens, show androgen-dependent detachment and ultimately apoptosis when stably transfected with a full-length human androgen receptor (AR) cDNA. We now demonstrate that treatment of these cells with 5alpha-dihydrotestosterone (DHT) for 24 or 48 h increased the expression of antiadhesion mucin MUC-1 at the cell surface as detected by flow cytometry with two independent antibodies. This increase in protein was concordant with up-regulation of MUC-1 mRNA in the AR-transfected PC-3 sublines, as determined by quantitative RT-PCR. Treatment with DHT for 48 h also down-regulated the cell surface expression of alpha2beta1-integrin but having little effect on the levels of alpha3beta1- and alpha5beta1-integrins. Androgen also decreased, in a dose-dependent manner, the adhesion of AR-transfected PC-3 cells to collagen type I, which was shown to be specifically inhibited by blocking antibody to alpha2beta1-integrin. The present data demonstrate that DHT can modulate expression of adhesion and antiadhesion molecules and suggest that this effect of androgen might contribute to prostate cancer progression.

Cell Adhesion↗

PubMed1982

Androgen-dependent regulation of androgen nuclear receptor in the rat ventral prostate.

Methods have been developed for the measurement of nonradioactive or radioactive dihydrotestosterone (DHT) bound to androgen receptor in rat ventral prostate nuclei (DHTRn). Using 1-day-castrated adult Sprague-Dawley rats (300--320 g body weight), the effects of testosterone (T) on nuclear androgen receptor formation were investigated in the absence and presence of cycloheximide or emetine. DHTRn was measured 4 h after injection of increasing amounts of T, and a maximal value of 14.6--17.8 pmol DHTRn/prostate was reached with doses of T greater than 37.5 micrograms. The amount of DHTRn 30 min after administration of 75 micrograms T was already 3 times greater than the concentration of cytosol receptor initially present in untreated castrated rats (2.0 +/- 0.3 pmol/prostate). In rats that received 2 mg cycloheximide ip 30 min before T, DHTRn did not exceed 5 pmol/prostate; in rats pretreated with 10 mg emetine administered at 1 h and 15 min before T, DHTRn did not exceed 8 pmol/prostate. These results suggest a two-component mechanism: 1) the translocation of preexisting cytosolic-receptor-hormone complexes to the nucleus; and 2) de novo formation of androgen receptor dependent on protein synthesis, which upon interaction with exogenous steroid is likewise accumulated in the nucleus. Progesterone (1 mg) and estradiol (0.6 mg) were also injected in amounts calculated to produce the same degree of occupancy of androgen receptor sites as did T. With both of these steroids, nuclear accumulation of androgen receptor was observed, but neither progesterone nor estradiol induced de novo synthesis of androgen receptor.

Animals↗

PubMed1984

Control of androgen cytosol receptor concentrations in Sertoli cells: effect of androgens.

Androgen receptor concentrations were measured in Sertoli cells under a variety of conditions. After brief (30- to 60-min) incubation of cultured cells with [3H]R1881 (methyltrienolone), cytosol receptor concentrations were greatly diminished, and nuclear bound steroid was elevated. Removal of the exogenous steroid was accompanied by a return of cytosol receptor to preincubation concentrations by 1 h and a slower decline in nuclear bound steroid. In the continued presence of R1881 or testosterone, cytoplasmic receptor concentrations declined and then returned to or above preincubation concentrations by 6-17 h. Actinomycin-D and cycloheximide did not alter this pattern. Over this same interval, nuclear bound steroid concentrations remained elevated. Exposure of the cells to R1881 or testosterone for the entire 72-h culture period did not alter cytoplasmic receptor concentrations. Cytoplasmic androgen receptor concentrations were decreased in Sertoli cells from hypophysectomized rats 15-22 days after surgery compared to those in cells from intact controls. Treatment with testosterone propionate (0.5 mg/day) or FSH (75 micrograms/day) prevented the decline in receptor concentrations. Cryptorchidy (33 days) also decreased cytosol receptor concentrations. These data indicate that exposure to androgens can influence Sertoli cell cytosol androgen receptor concentrations in vitro and in vivo. The Sertoli cell adapts to the continual presence of androgens with a return of cytosol receptor while maintaining elevated concentrations of nuclear bound steroid. In vivo, androgen treatment can maintain cytoplasmic receptor concentrations in the absence of pituitary hormones in the immature rat.

Animals↗

PubMed1995

Effects of luteinizing hormone (LH) and androgen on steady state levels of messenger ribonucleic acid for LH receptors, androgen receptors, and steroidogenic enzymes in rat Leydig cell progenitors in vivo.

Adult Leydig cells differentiate postnatally from mesenchymal-like progenitor cells. The relative scarcity of LH receptors (LHRs) in progenitor cells indicates that additional hormones may be important in the initial phases of Leydig cell differentiation. High levels of androgen receptor (AR) in progenitor cells point to a role for androgen in these cells. In the present study, an LHRH antagonist, [Ac-D2Nal1,4C1DPhe2,D3Pal3,Arg5,DGlu6(anis ole adduct), DAla10]GnRH (NalGlu; 250 micrograms/kg body weight), was used to suppress endogenous secretion of both LH and androgen during days 14 to 21 postpartum in vivo. To examine the effects of LH and androgen on regulation of Leydig cell progenitors (PLCs), exogenous LH (5 micrograms/day), testosterone (T; 30 micrograms/day), or both were administered to NalGlu-treated rats. After 7 days of treatment, we examined the effects on testis weight, Leydig cell morphology, and T production. The steady state messenger RNA (mRNA) levels for LHR, AR, cytochrome P450 17 alpha-hydroxylase, and 3 alpha-hydroxysteroid dehydrogenase in purified PLCs were measured by reverse transcription-polymerase chain reaction, with ribosomal protein S16 as the internal control. Treatment with NalGlu significantly decreased testis weight, resulted in an abundance of mesenchymal-like cells over immature Leydig cells, lowered T production, and reduced the levels of several Leydig cell mRNAs. Treatment with exogenous LH or T maintained testis weight and Leydig cell morphology in NalGlu-treated rats. The mRNA levels for LHR, AR, and 3 alpha-hydroxysteroid dehydrogenase were significantly increased by LH or T. P450 17 alpha-hydroxylase mRNA levels were elevated by LH to control level but strikingly reduced by T. Combined treatment with LH and T further increased basal T production but did not elevate mRNAs beyond the levels obtained with each hormone alone. LH and androgen act similarly in PLCs in promoting Leydig cell differentiation with respect to morphological and molecular landmarks. These findings support the hypothesis that androgen as well as LH is involved in the differentiation of immature Leydig cells from mesenchymal-like progenitors.

3-Hydroxysteroid Dehydrogenases↗

PubMed2002

Androgen inactivation in human lung fibroblasts: variations in levels of 17 beta-hydroxysteroid dehydrogenase type 2 and 5 alpha-reductase activity compatible with androgen inactivation.

Androgens delay lung maturation through their action on lung fibroblasts. Knowing that testosterone is secreted by the lung epithelial-like cell line A-549, we have studied the metabolism of androgens by several human lung diploid fibroblasts cell lines. No 17-ketosteroid reductase activity was detected. In contrast, testosterone was transformed mainly into androstenedione and androstanedione with no 5 alpha-dihydrotestosterone formed, indicating the presence of 17 beta- hydroxysteroid dehydrogenase (HSD) type 2 and 5 alpha-reductase activities. The eight cell lines analyzed had either a low or high 17 beta-HSD type 2 activity level. No correlation between these levels and the sex or age stage of cells was established, but Northern blot analysis of human lung RNA samples of five adult subjects revealed very similar variations between subjects in the level of 17 beta-HSD type 2 mRNA. The 5 alpha-reductase activity had a marked substrate preference for androstenedione, the product of 17 beta-HSD type 2. When tritiated testosterone was used as substrate, only barely detectable levels of 5 alpha-dihydrotestosterone were observed by HPLC in the presence of the 17 beta-HSD type 2 inhibitor EM-919. The use of unlabeled testosterone or of the antiandrogen hydroxyflutamide demonstrated that the tritiated testosterone substrate itself had no effect on levels of 5 alpha-reduction. In fact, in these cells, 5 alpha-reductase has no significant activity on testosterone, but it further converts the product of 17 beta-HSD type 2, thus playing a role with 17 beta-HSD type 2 in androgen inactivation. Because androgens delay lung maturation and surfactant synthesis by their action on lung fibroblasts, it is of particular interest to find that the steroid metabolism of these lung fibroblast cells is oriented toward androgen inactivation. Because lung fibroblasts of subjects with low 17 beta-HSD type 2 expression levels are likely to be exposed to higher levels of androgens, an allelic variation of the 17 beta-HSD-2 gene is suspected, which would result in familial incidence of respiratory distress. This is in line with reported cases of familial incidence of respiratory distress.

17-Hydroxysteroid Dehydrogenases↗

PubMed1988

Proliferative response of seminal vesicle cells to androgen in mice castrated neonatally and pretreated with estrogen or androgen at adulthood.

Seminal vesicle cells of neonatally castrated adult mice show poor response to androgen, compared to those of mice castrated at adulthood; effects of pretreatment with androgen or estrogen at adulthood on androgen-induced proliferation of the seminal vesicle cells were examined in neonatally castrated mice. Male mice castrated at day 0 after birth were pretreated with daily injections of testosterone propionate (TP, 100 micrograms/mouse), 17 beta-estradiol (E2, 5 micrograms/mouse) or vehicle for 20 days starting from day 60; daily TP injections (100 micrograms/mouse) for 30 days were started again from day 110 in all the pretreated mice to examine androgen-induced proliferation by incorporation of 5-[125I]iodo-2'-deoxyuridine into the whole seminal vesicles. Both TP and E2 pretreatments significantly increased the seminal vesicle weight found before TP treatment. However, androgen-induced proliferation of the seminal vesicle found in neonatally castrated mice (poor response; long duration with a low peak on day 3) was changed at least in part to that found in mice castrated at adulthood (good response; short duration with a high peak on day 3) only following the TP pretreatment but not at all following the E2 pretreatment. The E2 pretreatment induced poor androgen-induced proliferation with a low peak on day 7.

Age Factors↗

PubMed1998

Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta). 2. Effects of prenatal anti-androgens.

Pregnant spotted hyaenas were treated with anti-androgens to interfere with the unusually masculine 'phallic' development that characterizes females of this species. The effects on genital morphology and plasma androgen concentrations of infants were studied during the first 6 months of life. Although there were consistent 'feminizing' effects of prenatal anti-androgen treatment on genital morphology in both sexes, such exposure did not produce males with extreme hypospadia, as it does in other species, nor did it produce females with a 'typical' mammalian clitoris and external vagina. 'Feminization' of males resulted in a penis with the morphological features of the hyaena clitoris, and 'feminization' of females exaggerated the sex differences that are typical of this species. The effects of treatment were present at birth and persisted for at least 6 months. Treatment of pregnant females with flutamide and finasteride also markedly reduced circulating concentrations of testosterone and dihydrotestosterone in maternal plasma during pregnancy. Plasma delta 4-androstenedione was reduced in the female, but not the male, infants of treated mothers, consistent with an epigenetic hypothesis previously advanced to explain hormonal 'masculinization' of females. The present 'feminizing' effects of prenatal anti-androgen treatment are consistent with contemporary understanding of sexual differentiation, which accounts for morphological variation between the sexes in terms of steroids. However, current theory does not account for the basic genital structure of females and the present data suggest that development of the male penis and scrotum, and the female clitoris and pseudoscrotum, in spotted hyaenas may involve both androgen-dependent and androgen-independent components.

5-alpha Reductase Inhibitors↗

PubMed1986

Androgen regulation of the androgen receptor of the quail uropygial gland: application of a [3H]mibolerone exchange assay.

An exchange assay for androgen receptors in the quail uropygial gland using [3H]mibolerone was established. The most efficient exchange conditions were 3 days of incubation at 15 degrees C. Under these conditions, androgen receptors were stable in the presence of sodium molybdate, and the exchange of [3H]mibolerone with endogenous testosterone bound to cytosolic or nuclear androgen receptors was maximal. Less than 5% of [3H]mibolerone-binding sites occurred in the extracted nuclear pellets. Using this exchange technique, it was shown that androgen receptors in the uropygial gland of photostimulated male quail or castrated quail treated with testosterone were activated and that their concentrations in both cytosolic and nuclear fractions were increased. These results confirm the androgen dependency of the quail uropygial gland, and show that it is an organ which can be used as a model for the study of androgen action in sebaceous glands.

Animals↗

PubMed2006

Androgen-replacement therapy depresses the ex vivo production of inflammatory cytokines by circulating antigen-presenting cells in aging type-2 diabetic men with partial androgen deficiency.

Androgens are considered to have immunomodulatory effects but their cellular mechanisms of action remain largely unknown. In the present study we prospectively analyzed the serial effects of androgen-replacement therapy on both the distribution of peripheral blood lymphocytes, monocytes and dendritic cells as well as on the production of interleukin (IL)-1beta, IL-6 and tumor necrosis factor alpha (TNFalpha) inflammatory cytokines by circulating monocytes and CD33 myeloid, CD16 and plasmacytoid dendritic cell subsets, the most potent antigen-presenting cells (APCs) in type-2 diabetic men with partial androgen deficiency. Analyses were performed before therapy and at 1, 3, 6 and 12 months after treatment with 150 mg testosterone enanthate every 2 weeks in a group of 13 type-2 diabetic men. Our results show for the first time that testosterone-replacement therapy is associated with a reduction or complete abrogation of spontaneous ex vivo production of IL-1beta, IL-6 and TNFalpha by APCs. Meanwhile, the in vitro production of inflammatory cytokines by these cells after stimulation with lipopolysaccharide plus recombinant human interferon-gamma remained unchanged, suggesting that APCs preserve their constitutive machinery to produce inflammatory cytokines under androgen treatment. These results confirm and extend previous observations about the anti-inflammatory effects of androgen therapy on APCs in a new, previously unexplored model of androgen deficiency; namely, aging type-2 diabetic men. A decreased production of inflammatory cytokines by APCs might have important consequences for sex differences in susceptibility to autoimmune diseases, inflammatory response to injury and atheromatosis.

Aged↗

PubMedDate not supplied

Up-regulation of neuroendocrine differentiation in prostate cancer after androgen deprivation therapy, degree and androgen independence.

The up-regulation of neuroendocrine (NE) differentiation after hormonal therapy, as well as the relationship between the degree of NE differentiation and androgen independence was investigated. One hundred and thirty-seven whole prostate specimens that were derived from surgery and autopsy (group A: no hormonal therapy, 44 patients; group B: with hormonal therapy less than 12 months, 25 patients; group C: with hormonal therapy more than 13 months, 68 patients) were studied. Neuroendocrine differentiation was evaluated by immunostaining with chromogranin A. The degree of NE differentiation was evaluated by the percentage area of positive NE cell expression (grade 0, negative; grade 1, 1-33%; grade 2, 34-66%; grade 3, 67-100%). The degree of NE differentiation was compared in androgen-independent and -dependent tumors in group C. Neuroendocrine differentiation was expressed as 31.8% in group A, 44% in group B and 70.5% in group C (p<0.001, Chi-squared test). Group C included 20 androgen-independent cases in which 3 cases were grade 0, 2 were grade 1, 6 were grade 2 and 9 were grade 3. Conversely, for androgen-dependent cases, there were 16, 16, 11 and 5 cases, respectively. Neuroendocrine cells, whether positive or not, alone was not significantly different (p=0.124, Chi-squared test); however, the percentage area of positive NE cell expression was significantly different between the androgen-independent and -dependent tumors (p=0.0044, Chi-squared test). Hormonal therapy may play an important role in the up-regulation of NE differentiation. As well as NE cell expression, whether positive or not, the degree of expression should also be observed to evaluate a poor prognosis, tumor progression and androgen independence.

Androgens↗

PubMed2002

Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells.

OBJECTIVES: The pineal hormone melatonin inhibits the growth of benign human prostate epithelial cells and the androgen-dependent prostate cancer LNCaP cells. In the androgen-nonresponsive prostate carcinoma PC3 cells melatonin inhibits cell growth only at high but not low cell density. We have recently found that melatonin causes nuclear exclusion of the AR and attenuates it transcriptional activity in LNCaP cells as well as PC3 cells stably transfected with a wild type AR expressing vector (PC3-AR). The aim of this study was to investigate whether melatonin inhibits effects of AR on cell growth in PC3-AR cells and whether inhibition of AR DNA binding is involved. METHODS: The effects of androgen, melatonin and their combination on the growth of the PC3-AR cells and on AR DNA binding in PC3-AR and LNCaP cells were studied. RESULTS: DHT suppressed cell growth in the PC3-AR cells and enhanced AR binding to the androgen responsive element (ARE). Melatonin had no effect on cell growth in the absence of DHT but counteracted the androgen-induced inhibition at low androgen concentrations. Melatonin did not suppress and even slightly enhanced the capacity of AR binding to the ARE in the PC3-AR as well as in LNCaP cells. CONCLUSIONS: Attenuation by melatonin of AR activity in the prostate cancer cells is not due to suppression of AR binding to the ARE, and is presumably caused by its effects on AR protein interaction and intracellular trafficking.

Antioxidants↗

PubMed2003

Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator.

The partial agonist effect of antiandrogens has been well documented, and such effect is amplified by derived mutant androgen receptors (ARs) in prostate cancer cells. Here we report the identification of gelsolin (GSN) as an AR-associated protein. Hydroxyflutamide (HF), as well as androgens, can promote the interaction between AR and GSN in a dose-dependent manner. GSN interacts with AR DNA-binding domain and ligand-binding domain via its COOH-terminal domain. Immunolocalization studies show that GSN interacts with AR during nuclear translocation. Functional analyses additionally demonstrate that GSN enhances AR activity in the presence of either androgen or HF. Two peptides representing partial regions of the AR DNA-binding domain and the ligand-binding domain can block the GSN-enhanced AR activity. The expression of GSN is enhanced in LNCaP cells, LNCaP xenografts, and human prostate tumors after androgen depletion. Increasing expression of GSN enhances the AR activity in the presence of HF. Together, these data suggest that the weak androgenic effect of HF may be amplified by increasing the amount of GSN after androgen ablation treatment. Therefore, blockage of the interaction between AR and GSN could become a potential therapeutic target for the treatment of prostate cancer.

Animals↗

PubMedDate not supplied

Androgen withdrawal inhibits tumor growth and is associated with decrease in angiogenesis and VEGF expression in androgen-independent CWR22Rv1 human prostate cancer model.

Recent evidence suggests that androgens stimulate growth of human prostate cancer partly by regulating expression of growth factors such as vascular endothelial growth factor (VEGF) in vitro and in vivo. In this study, we used CWR22Rv1, a novel androgen-responsive but androgen-independent human prostate cancer model, to evaluate the effect of androgen withdrawal on tumor growth, expression of VEGF and the cell proliferation marker Ki-67, and angiogenesis. A time-release testosterone pellet was implanted three days before inoculation of CWR22Rv1 cells in the mice. The tumor volumes were measured every three days. Serum PSA was measured on days 1, 12, 20, 27 and 34 post inoculation. Castration was performed on the 20th day post inoculation. Immunohistochemical assays were used to evaluate cell proliferation and microvessel density. Enzyme-linked immunosorbent assay (ELISA) was used to quantify VEGF expression. The average tumor volumes in the castration group on the 27th and 34th days were 122 and 168 mm3, respectively, compared to 156 and 210 mm3 in the non-castration group (p<0.01). Serum PSA level in the castration group decreased to about 41% of the level of the non-castration group (p<0.01). The VEGF protein levels in the tumors of castrated and non-castrated mice on day 34 were 0.62 pg and 1.36 pg/100 microg total protein, respectively (p<0.001). The mean percentage of Ki-67-positive tumor cells in the castrated and non-castrated groups were 1.8% and 2.8%, respectively (p=0.015). The mean microvessel densities in the castrated and non-castrated groups were 15 and 22 vessels/field, respectively (p<0.01) We conclude androgen withdrawal reduced both VEGF and microvessel density, and this was associated with decreased cellular proliferation in androgen-independent CWR22Rv1 human prostate cancer tumor in vivo.

Androgens↗

PubMed1992

Replacement of arginine 773 by cysteine or histidine in the human androgen receptor causes complete androgen insensitivity with different receptor phenotypes.

We have discovered two different point mutations in a single codon of the X-linked androgen-receptor (AR) gene in two pairs of unrelated families who have complete androgen insensitivity (resistance) associated with different AR phenotypes in their genital skin fibroblasts. One mutation is a C-to-T transition at a CpG sequence near the 5' terminus of exon 6; it changes the sense of codon 773 from arginine to cysteine, ablates specific androgen-binding activity at 37 degrees C, and eliminates a unique KpnI site at the intron-exon boundary. The other mutation is a G-to-A transition that changes amino acid 773 to histidine and eliminates an SphI site. This mutant AR has a normal androgen-binding capacity at 37 degrees C but has a reduced affinity for androgens and is thermolabile in their presence. Transient transfection of COS cells with cDNA expression vectors yielded little androgen-binding activity at 37 degrees C from Arg773Cys and abundant activity with abnormal properties from Arg773His, thereby providing the pathogenicity of both sequence alterations. This conclusion coincides with the following facts about evolutionary preservation of the position homologous to Arg773 in the AR: it is occupied by Arg or lysine in the progesterone, glucocorticoid, and mineralocorticoid receptors, and it is within a 14-amino-acid region of their steroid-binding domains that share approximately 85% amino acid identity.

Adolescent↗

PubMedDate not supplied

In situ androgen production in human gastric carcinoma--androgen synthesizing and metabolizing enzymes.

BACKGROUND: It is well known that the incidence of gastric carcinoma is lower in females than in males. Therefore, androgens have been proposed to play an important role in modifying the development of gastric carcinoma. 5Alpha-reductase (5alpha-reductase) types 1 and 2 and 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD type 5) are considered important local regulators of androgen production in human androgen-responsive tissues and cancer. MATERIALS AND METHODS: The immunoreactivities of these steroidogenic enzymes, as well as of the androgen receptor (AR), were evaluated in human gastric carcinoma obtained from endoscopic mucosal resection (EMR) (n = 117). RESULTS: 17beta-HSD type 5 immunoreactivity was detected in 99 cases (85%), 5alpha-reductase type 1 in 69 cases (59%), 5alpha-reductase type 2 in 57 cases (49%) and AR in 46 cases (39%). CONCLUSION: These androgen-producing enzymes are expressed in human gastric carcinomas and are involved in the in situ production and possible regulation of androgenic activity in human gastric carcinoma.

17-Hydroxysteroid Dehydrogenases↗

PubMed1997

Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer.

Progression of prostate cancer during endocrine therapy is a major clinical problem, the molecular mechanisms of which remain poorly understood. Amplification of the androgen receptor (AR) gene was recently described in recurrent prostate carcinomas from patients who had failed androgen deprivation therapy. To evaluate the hypothesis that amplification of the AR gene is a cause for the failure of androgen deprivation therapy in prostate cancer, we studied whether AR amplification leads to gene overexpression, whether the amplified AR gene is structurally intact, and whether tumors with AR amplification have distinct biological and clinical characteristics. Tumor specimens were collected from 54 prostate cancer patients at the time of a local recurrence following therapy failure. In 26 cases, paired primary tumor specimens from the same patients prior to therapy were also available. Fifteen (28%) of the recurrent therapy-resistant tumors, but none of the untreated primary tumors, contained AR gene amplification as determined by fluorescence in situ hybridization. According to single-stranded conformation polymorphism analysis, the AR gene was wild type in all but one of the 13 AR amplified cases studied. In one tumor, a presumed mutation in the hormone-binding domain at codon 674 leading to a Gly --> Ala substitution was found, but functional studies indicated that this mutation did not change the transactivational properties of the receptor. AR amplification was associated with a substantially increased level of mRNA expression of the gene by in situ hybridization. Clinicopathological correlations indicated that AR amplification was most likely to occur in tumors that had initially responded well to endocrine therapy and whose response duration was more than 12 months. Tumors that recurred earlier or those that showed no initial therapy response did not contain AR amplification. The median survival time after recurrence was two times longer for patients with AR amplification in comparison to those with no amplification (P = 0.03, Willcoxon-Breslow test). In conclusion, failure of conventional androgen deprivation therapy in prostate cancer may be caused by a clonal expansion of tumor cells that are able to continue androgen-dependent growth despite of the low concentrations of serum androgens. Amplification and the increased expression of a wild-type AR gene may play a key role in this process.

Aged↗