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)

Androgens via the androgen receptor (AR) play crucial roles in prostate physiology and pathophysiology. These androgen actions can be either inhibited or potentiated by estrogens. The mechanisms of these seemingly opposing estrogen effects are unclear. We studied the effects of estrogens on the modulation of androgen induction of prostate specific antigen (PSA) gene expression and prostate tumor cell growth. Cotransfection analyses in CV-1, DU-145, and PC-3 cells showed that dihydrotestosterone (DHT)-induced PSA transcription activity was inhibited by 17beta-estradiol, diethylstilbestrol, ICI182780, and 17alpha-estradiol, but not by tamoxifen via estrogen receptor alpha (ERalpha). In the presence of ERbeta, 17beta-estradiol and diethylstilbestrol had no significant effect, while 17alpha-estradiol inhibited and ICI182780 and tamoxifen potentiated DHT action. When both ERalpha and ERbeta were present, all ER-ligands except tamoxifen inhibited DHT action. The inhibition of DHT action by 17beta-estradiol via ERalpha was mainly dependent on the DNA binding domain, while the 17alpha-estradiol effect was mainly dependent on the ERalpha carboxyl terminus. Treatment with DHT in LAPC-4 prostate tumor cells that express a wild-type AR and both ERbeta and ERalpha greatly increased the PSA gene expression and cell growth. These DHT effects were significantly attenuated by the addition of 17alpha-estradiol, 17beta-estradiol, or cyproterone acetate in a dose-dependent manner. These results indicate that estrogens produce an ER-isoform- and ER-ligand-specific modulation of DHT induction of PSA gene expression and prostate tumor cell growth, providing a molecular basis for designing favorable agents for the prevention and control of prostate cancer.
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PMID:Receptor isoform and ligand-specific modulation of dihydrotestosterone-induced prostate specific antigen gene expression and prostate tumor cell growth by estrogens. 1595 89

The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor alpha (ERalpha)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERalpha binding. Cyclin D1 and BRCA1 were both capable of binding ERalpha in a common region of the ERalpha hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERalpha and for rescue of BRCA1-mediated ERalpha transcriptional repression. In chromatin immunoprecipitation assays, 17beta-estradiol (E2) enhanced ERalpha and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERalpha recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERalpha recruitment at 12 hours. Cyclin D1 expression antagonized BRCA1 inhibition of ERalpha recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERalpha repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.
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PMID:Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity. 1606 35

Sex steroid hormone signaling regulates the development, growth, and functioning of the breast and the prostate and plays a role in the development and progression of cancer in these organs. The intracellular concentration of active sex steroid hormones in target tissues is regulated by several enzymes, including 17beta-hydroxysteroid dehydrogenases (17HSDs). Changes in the expression patterns of these enzymes may play a pathophysiological role in malignant transformation. We recently analyzed the mRNA expressions of the 17HSD type 1, 2, and 5 enzymes in about 800 breast carcinoma specimens. Both 17HSD type 1 and 2 mRNAs were detected in normal breast tissue from premenopausal women but not in specimens from postmenopausal women. The patients with tumors expressing 17HSD type 1 mRNA or protein had significantly shorter overall and disease-free survival than the other patients. The expression of 17HSD type 5 was significantly higher in breast tumor specimens than in normal tissue. Cox multivariate analyses showed that 17HSD type 1, tumor size, and estrogen receptor alpha (ERalpha) had independent prognostic significance. We developed, using a LNCaP prostate cancer cell line, a model to study the malignant transformation of prostate cancer and showed that androgen-sensitive LNCaP cells are transformed into neuroendocrine-like cells when cultured without androgens and, eventually into highly proliferating androgen-independent cells. We conducted Northern hybridizations and microarrays to analyze the gene expression during these processes. Substantial changes in the expressions of steroid metabolizing enzymes occurred during the transformation process. The variations in steroid-metabolizing enzymes during cancer progression may be crucial in the regulation of the growth and function of organs.
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PMID:Control of cell proliferation by steroids: the role of 17HSDs. 1640 64

The patient was an 80-year-old man with scrotal and penile extramammary Paget's disease and prostate cancer. Both diseases were in advanced stages. Tumor cells of extramammary Paget's disease strongly expressed estrogen receptor alpha. The patient was concurrently treated with two kinds of hormonal therapy: the anti-estrogen tamoxifen (20 mg/day orally) for extramammary Paget's disease and the anti-androgen bicalutamide (80 mg/day orally) for prostate cancer. The toxicity of the therapy was mild. All of the metastatic lesions remained stable for 2 months after initiation of dual hormonal therapy. During a follow-up period of 22 months, performance status was well maintained for 17 months. Hormonal therapy may be an alternative for selected cases of advanced extramammary Paget's disease.
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PMID:Estrogen-receptor-alpha-positive extramammary Paget's disease treated with hormonal therapy. 1690 92

Epidemiological studies suggest an inverse association between soy intake and prostate cancer risk. Genistein, the predominant phytoestrogen in soy food, has been proposed as a potential chemopreventive agent due to its anti-estrogen and tyrosine kinase inhibitory effects. To determine the most effective period for genistein chemoprevention, the Transgenic adenocarcinoma mouse prostate (TRAMP) model was used. The treatments were 250 mg genistein/kg AIN-76A diet 1) prepubertally only, 2) in adulthood only or 3) through out life. Controls received AIN-76A diet. By 28 weeks of age, 100% TRAMP mice fed control diet developed prostatic intraepithelial neoplasia (PIN) or adenocarcinomas with 6%, 16%, 44% and 34% developing high grade PIN, well differentiated, moderately differentiated and poorly differentiated prostatic adenocarcinomas, respectively. Prepubertal only (1-35 days postpartum) and adult only genistein treatments (12-28 weeks) resulted in 6% and 29% decreases in poorly-differentiated cancerous lesions compared with controls, respectively. The most significant effect was seen in the TRAMP mice exposed to genistein throughout life (1-28 weeks) with a 50% decrease in poorly-differentiated cancerous lesions. In a separate experiment in castrated TRAMP mice, dietary genistein suppressed the development of advanced prostate cancer by 35% compared with controls. Of the tumors that developed in castrated TRAMP mice, 100% were poorly-differentiated in contrast to the 37% of noncastrated TRAMP mice that developed poorly-differentiated tumors. ICI 182,780 (ICI), genistein and estrogen down-regulated androgen receptor (AR), estrogen receptor alpha (ER-alpha) and progesterone receptor (PR) in the prostates of C57BL/6 mice, and act independently of ER. Our data obtained in intact and castrated transgenic mice suggest that genistein may be a promising chemopreventive agent against androgen-dependent and independent prostate cancers.
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PMID:Genistein chemoprevention of prostate cancer in TRAMP mice. 1736 28

Androgen receptor (AR) functions as a transcriptional factor for genes involved in proliferation and differentiation of normal and cancerous prostate cells. Coactivators that bind to AR are required for maximal androgen action. Here we report that increasing the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a prostate cancer cell line by as little as 1.8-fold enhances transcriptional activity of AR (but not the transcriptional activity of glucocorticoid receptor or estrogen receptor alpha) in a ligand-dependent manner and results in an increased expression of prostate-specific antigen. Small interference RNA-mediated knockdown of GAPDH significantly attenuated ligand-activated AR transactivation. Immunoprecipitation analysis revealed the presence of an endogenous protein complex containing GAPDH and AR in both the cytoplasm and nucleus. Addition of a nuclear localization signal (NLS) to GAPDH (GAPDH-NLS) completely abolished the ability of GAPDH to transactivate AR. Neither wild-type GAPDH nor GAPDH-NLS enhanced transcriptional activity of mutant AR (AR Delta C-Nuc) that is a constitutively active form of AR in the nucleus, even though GAPDH-NLS formed a complex with wild-type AR or AR Delta C-Nuc. AR transactivation was enhanced by a mutant GAPDH lacking dehydrogenase activity. GAPDH enhanced the transcriptional activity of AR(T875A) activated by an antagonist such as hydroxyflutamide or cyproterone acetate. These results indicate that GAPDH functions as a coactivator with high selectivity for AR and enhances AR transactivation independent of its glycolytic activity. Further, these data suggest that formation of a GAPDH.AR complex in the cytoplasm rather than nucleus is essential for GAPDH to enhance AR transactivation.
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PMID:Glyceraldehyde-3-phosphate dehydrogenase enhances transcriptional activity of androgen receptor in prostate cancer cells. 1755 95

Different polymorphisms have been described in steroid hormone receptors which are related with variable human diseases. Polymorphisms of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are related not only with reproductive diseases, but also with osteoporosis, cardiovascular disease, malignancy such as breast cancer, and disorders involving central nervous system. They are also related with individual reactivity to medications. Polymorphisms of androgen receptor are known to be associated with prostate cancer. Polymorphisms of glucocorticoid receptor are related with severity of inflammation and allergy. Analysis of steroid hormone receptor polymorphisms will make it possible to develop tailored medicine for human diseases.
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PMID:[Polymorphisms of steroid hormone receptors]. 1819 42

Androgen receptor (AR) acts as a ligand-activated transcription factor that regulates the expression of genes involved in prostate development and tumorigenesis. RanBP10 shares significant amino acid sequence similarity with RanBPM that is a well-known AR coactivator. Here, we demonstrate that RanBP10 enhances the ligand-dependent transcriptional activity of AR and forms a complex with AR. RanBP10 together with RanBPM exerted an additive effect on AR transactivation. Overexpression of RanBP10 enhanced transcriptional activity of glucocorticoid receptor, but not estrogen receptor alpha. RanBP10 was highly expressed in AR-positive prostate cancer LNCaP cells, while RanBPM was abundant in WI-38 and MCF-7 cells rather than prostate cancer cells. RanBP10 was mostly co-localized with RanBPM throughout the cytoplasm and nucleus and formed a protein complex with itself or RanBPM. These results suggest that RanBP10 enhances AR transactivation as a homo-oligomer or a hetero-oligomer with RanBPM.
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PMID:RanBP10 acts as a novel coactivator for the androgen receptor. 1822 18

The hereditary predisposition to prostate cancer is rare and accounts for <5% of cases. Except for younger age at diagnosis, no phenotypic features have been clearly associated with hereditary prostate cancer. The aim of the study was to analyze the expression of genes related to androgen and estrogen metabolism in both hereditary and sporadic prostate cancers in patients matched for clinicopathologic features. Tissues were obtained from patients included in a national familial prostate cancer registry. From the 120 cases of hereditary forms suggesting autosomal dominant Mendelian inheritance, 21 patients were treated by radical prostatectomy for whom formalin-fixed tissue was available. Twenty-one sporadic cases were then matched according to age, Gleason score, and pathologic stage. Immunohistochemistry was done on tissue microarray using antibodies directed against androgen receptor (AR), estrogen receptor alpha (ERA), estrogen receptor beta, 5alpha-reductase I and II, aromatase, and the proliferation marker Ki67. The percentage of AR-positive cancer cells was higher in hereditary cancer compared with sporadic cases (P < 0.004). In contrast, the mean number of ERA-positive stromal cells was lower in hereditary versus sporadic cancer (P < 0.03). This differential expression of AR and ERA suggests that a specific pattern of hormone receptors is associated with hereditary predisposition to prostate cancer.
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PMID:Differential expression of genes related to androgen and estrogen metabolism in hereditary versus sporadic prostate cancer. 1855 68

LRP16 is a special member of the macro domain superfamily, containing only a stand-alone macro domain functional module. Previous study demonstrated that the estrogenically regulated LRP16 cooperates with the estrogen receptor alpha and enhances the receptor's transcriptional activity in an estrogen-dependent manner. Here, we discovered that LRP16 binds to androgen receptor (AR) via its macro domain and amplifies the transactivation function of AR in response to androgen. Similarly, we also discovered that LRP16 acts as a potential coactivator to amplify the transactivation of at least other four nuclear receptors (NRs). Importantly, we show that the single macro domain in LRP16 can serve as the AR coactivator. RNA interference knockdown of LRP16 leads to impaired AR function and greatly attenuates the coactivation of AR by other AR coactivators such as ART-27 and steroid receptor coactivator-1. This interference also markedly inhibits the androgen-stimulated proliferation of androgen-sensitive LNCaP prostate cancer cells. However, LRP16 knockdown did not significantly affect the growth rate of AR-negative PC-3 prostate cancer cells. Furthermore, we observed the induction effect of LRP16 expression by androgen and established a feedforward mechanism that activated AR transactivation. Our results suggest that the macro domain protein LRP16 represents a novel type of cofactor of NR. They also indicate that LRP16 plays an essential role in AR transactivation.
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PMID:The single-macro domain protein LRP16 is an essential cofactor of androgen receptor. 1902 49


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