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)

The androgen receptor (AR) binds to and activates transcription of target genes in response to androgens. In an attempt to isolate cofactors capable of influencing AR transcriptional activity, we used an immunoprecipitation method and identified a 44-kDa protein, designated p44, as a new AR-interacting protein. p44 interacts with AR in the nucleus and with an androgen-regulated homeobox protein (NKX3.1) in the cytoplasm of LNCaP cells. Transient-transfection assays revealed that p44 enhances AR-, glucocorticoid receptor-, and progesterone receptor-dependent transcription but not estrogen receptor- or thyroid hormone receptor-dependent transcription. p44 was recruited onto the promoter of the prostate-specific antigen gene in the presence of the androgen in LNCaP cells. p44 exists as a multiprotein complex in the nuclei of HeLa cells. This complex, but not p44 alone, enhances AR-driven transcription in vitro in a cell-free transcriptional system and contains the protein arginine methyltransferase 5, which acts synergistically with p44 to enhance AR-driven gene expression in a methyltransferase-independent manner. Our data suggest a novel mechanism by which the protein arginine methyltransferase is involved in the control of AR-driven transcription. p44 expression is dramatically enhanced in prostate cancer tissue compared with adjacent benign prostate tissue.
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PMID:Purification and identification of a novel complex which is involved in androgen receptor-dependent transcription. 1297 18

The androgen receptor (AR) may recruit multiple coregulators for proper or optimal transactivation. Here we report the identification and characterization of ARA67/PAT1 as an AR coregulator from a prostate cDNA library. ARA67/PAT1 was screened out as an AR N terminus interacting protein. Interaction mapping shows that the cooperation of multiple domains within ARA67/PAT1 may be required for the maximal interaction with AR. ARA67/PAT1 functions as a repressor with better suppressive effects on AR compared to glucocorticoid receptor and estrogen receptor. Further mechanism dissection reveals that the interrupted AR cytoplasmic-nuclear shuttling may play a major role in ARA67/PAT1 mediated suppression on AR. Together, these results suggest that ARA67/PAT1 may function as a novel repressor that can modulate AR function in prostate cancer.
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PMID:ARA67/PAT1 functions as a repressor to suppress androgen receptor transactivation. 1472 52

Despite the historical use of estrogens in the treatment of prostate cancer (PCa) little is known about their direct biological effects on the prostate, their role in carcinogenesis, and what mechanisms mediate their therapeutic effects on PCa. It is now known that estrogens alone, or in synergism with an androgen, are potent inducers of aberrant growth and neoplastic transformation in the prostate. The mechanisms of estrogen carcinogenicity could be mediated via induction of unscheduled cell proliferation or through metabolic activation of estrogens to genotoxic metabolites. Age-related changes and race-/ethnic-based differences in circulating or locally formed estrogens may explain differential PCa risk among different populations. Loss of expression of estrogen receptor (ER)-beta expression during prostate carcinogenesis and prevention of estrogen-mediated oxidative damage could be exploited in future PCa prevention strategies. Re-expression of ER-beta in metastatic PCa cells raises the possibility of using ER-beta-specific ligands in triggering cell death in these malignant cells. A variety of new estrogenic/anti-estrogenic/selective estrogen receptor modulator (SERM)-like compounds, including 2-methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. Increasing numbers of patients self-medicate with herbal formulations such as PC-SPES. Some of these compounds are selective ER-beta ligands, while most of them have minimal interaction with ER-alpha. Although many may inhibit testosterone production by blockade of the hypothalamal-pituitary-testis axis, the most effective agents also exhibit direct cytostatic, cytotoxic, or apoptotic action on PCa cells. Some of them are potent in interfering with tubulin polymerization, blocking angiogenesis and cell motility, suppressing DNA synthesis, and inhibiting specific kinase activities. Further discovery of other compounds with potent apoptotic activities but minimal estrogen action should promote development of a new generation of effective PCa preventive or treatment regimens with few or no side-effects due to estrogenicity. Further advancement of our knowledge of the role of estrogens in prostate carcinogenesis through metabolic activation of estrogens and/or ER-mediated pathways will certainly result in better preventive or therapeutic modalities for PCa.
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PMID:Estrogens and anti-estrogens: key mediators of prostate carcinogenesis and new therapeutic candidates. 1475 80

Men with high-grade prostatic intraepithelial neoplasia (PIN) evident on prostate biopsy are at high risk for the eventual development of prostate cancer. The ability to reverse high-grade PIN may reduce the incidence or delay the development of prostate cancer. Toremifene (GTx-006, Acapodene trade mark ) is a selective estrogen receptor modulator that has been shown in the transgenic mouse model of prostate cancer to eliminate high-grade PIN and reduce the incidence of prostate cancer. This study was aimed at the evaluation of the safety and efficacy of toremifene in men diagnosed with high-grade PIN. This was an open-label, phase IIA clinical trial that enrolled 21 men (mean age, 64.7 years) with evidence of high-grade PIN on biopsy within 6 months of entry into the study. Eighteen of these men (86%) completed toremifene treatment (60 mg/day orally for 4 months) and then underwent follow-up prostate biopsy (8 cores) to determine high-grade PIN status. The effect of the drug on serum prostate-specific antigen (PSA), percentage of free PSA, testosterone, estradiol, and quality of life was also measured. After toremifene treatment, 72% of these 18 men (vs. 17.9% of historical controls) had no high-grade PIN on subsequent prostate biopsies. Mean PSA trended higher, and percentage of free PSA was increased. Quality of life was not significantly affected by treatment. There were 3 mild adverse events, and no serious adverse events. Toremifene appeared to reduce high-grade PIN in this small, exploratory trial. The drug was well tolerated. A double-blind, dose-finding, randomized, placebo-controlled phase IIB/III study is currently open to further study toremifene's activity against high-grade PIN and prostate cancer incidence.
Clin Prostate Cancer 2003 Jun
PMID:Phase IIA clinical trial to test the efficacy and safety of Toremifene in men with high-grade prostatic intraepithelial neoplasia. 1504 81

Estrogens, including diethylstilbestrol (DES), were used as the primary medical treatment for metastatic prostate cancer for many years but have been superceded in the past two decades by luteinizing hormone-releasing hormone (LHRH) agonists, primarily because of the cardiovascular toxicity associated with oral estrogen therapy. Recently, a renewed interest in estrogen therapy for prostate cancer in the United States has developed as a result of 3 major issues. First, when measured by declines in prostate-specific antigen of > or = 50%, clinical trials have demonstrated activity of DES, DES-diphosphate, and the estrogenic herbal therapy PC-SPES in 21%-86% of patients treated in phase II trials of androgen-independent prostate cancer patients. Second, the recent description of estrogen receptor (ER)-b has led to a reevaluation of the role of estrogens in normal prostate development and cancer pathogenesis. In contrast to ER-a, ER-b is strongly expressed in normal prostate epithelium. Furthermore, loss of ER-b expression has been demonstrated in prostate cancers, suggesting a possible role for this pathway in the development of cancer. Finally, the issues of cost and safety of estrogens are being reassessed in the current environment of rising health care costs and improved cardiovascular care. In Europe, estrogen therapy is more accepted as a low-cost and effective alternative to LHRH agonists and antiandrogens. Toxicity of DES and other estrogens has also been attenuated by strategies that use lower doses and parenteral routes of administration, thereby avoiding hepatic first-pass metabolism and decreasing the risk of thromboembolism. Nonetheless, there remain many unanswered questions about the role of estrogen therapy in prostate cancer, including differences between specific drugs, optimal dose, timing, and patient selection. Further research is needed.
Clin Prostate Cancer 2002 Sep
PMID:The evolving role of estrogen therapy in prostate cancer. 1504 98

Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally related to protection against hormone-dependent cancers. The incidence of colorectal cancer is at least 30% lower in women than in men in the United States. This suggests that estrogen and, conceivably, nutritional phytoestrogens are protective compounds against colorectal cancer for both sexes. Prevention of colorectal, mammary, and prostate cancer may also depend on optimal synthesis of the antimitotic prodifferentiating vitamin D hormonal metabolite 1,25-(OH)(2)-cholecalciferol (1,25-D3). Cytochrome-P450-hydroxylases responsible for synthesis (CYP27B1; 25-D3-1 alpha-hydroxylase) and catabolism (CYP24; 1,25-D3-24-hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of CYP27B1, vitamin D receptor, and estrogen receptor-beta (the high-affinity receptor for phytoestrogens) are enhanced early during human colorectal cancer, which suggests an interactive physiological defense against tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of CYP27B1 and of CYP24 by genistein at 0.05-50 micromol/L. The high concentration of 50 micromol/L is very effective in eliminating CYP24 expression in prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively genistein feeding, elevates CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional calcium, CYP24 rises in parallel to enhanced colonic proliferation, and genistein counteracts both. We suggest that nutritional soy or genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of tumor progression.
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PMID:Phytoestrogens and vitamin D metabolism: a new concept for the prevention and therapy of colorectal, prostate, and mammary carcinomas. 1511 73

The traditional role of the Cdc25 family of dual-specificity phosphatases is to activate cyclin-dependent kinases (CDKs) to enable progression through the cell cycle. This chapter reports that in addition to its cell cycle role, Cdc25B functions as a novel steroid receptor coactivator (SRC). When overexpressed in transgenic mammary glands, Cdc25B can up-regulate the expression of two estrogen receptor (ER)-target genes: cyclin D1 and Lactoferrin. In addition, when coexpressed with ER, Cdc25B can coactivate an ER-dependent reporter in the presence of estradiol. The coactivation of Cdc25B can be extended to the glucocorticoid receptor (GR), progesterone receptor (PR), and androgen receptor (AR). Because of the respective importance of ER and AR in breast and prostate cancer, this chapter focuses on the coactivation of both receptors by Cdc25B. We demonstrate that Cdc25B can interact directly with these nuclear receptors, recruit and enhance the activity of histone acetyltransferases (HATs), and potentiate cell-free transcription independent of its cell cycle regulatory function. Furthermore, because Cdc25B is up-regulated in highgrade and poorly differentiated prostate tumors, which are likely transiting from the hormone-dependent to hormone-independent state, we hypothesize that the coactivation of AR by Cdc25B may induce genes responsible for this progression. Taken together, it is highly conceivable that Cdc25B can promote neoplasia by its two disparate functions of (1) coactivation to induce higher levels of expression of steroid receptor target genes and (2) its role of activating CDKs to deregulate progression of the cell cycle, DNA replication, and mitosis.
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PMID:Cdc25B as a steroid receptor coactivator. 1519 57

Grb14 is an adapter protein that is known to be overexpressed in estrogen receptor positive breast cancers, and in a number of prostate cancer cell lines. Grb14 has been demonstrated to bind to a number of activated receptor tyrosine kinases (RTKs) and to modulate signals transduced through these receptors. The RTKs to which Grb14 binds include the insulin receptor (IR), the fibroblast growth factor receptor (FGFR), the platelet-derived growth factor receptor (PDGFR), and the tunica endothelial kinase (Tek/Tie2) receptor. Grb14 has been shown to bind to these activated RTKs through its Src homology 2 (SH2) domain, with the exception of the insulin receptor, where the primary binding interaction is via a small domain adjacent to the SH2 domain (the BPS or PIR domain). Grb14 is a member of the Grb7 family of proteins, which also includes Grb7 and Grb10. We have solved the solution structure of the human Grb14-SH2 domain and compared it with the recently determined Grb7-SH2 and Grb10-SH2 domain structures.
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PMID:Solution structure of the human Grb14-SH2 domain and comparison with the structures of the human Grb7-SH2/erbB2 peptide complex and human Grb10-SH2 domain. 1532 92

Carcinogenesis of the prostate involves androgen influences, and associations between genetic polymorphisms of androgen receptor and metabolizing enzymes and prostate cancer risk have been reported. Roles for non-androgenic hormones are not well defined, but they also may have an impact judging from epidemiological and animal experimental alphalambda zeta of data. The purpose of the study was to determine whether hormone-related polymorphisms are associated with prostate cancer risk. A case-control study was performed with 147 Japanese prostate cancer patients and 266 urological controls. Polymorphisms of target genes [cytochrome P450 (CYP) 1B1, Leu432Val; debrisoquine hydroxylase, (CYP2D6)*4; aromatase (CYP19), Arg264Cys; estrogen receptor (ER)alpha-Xx (Xba I) and Pp (Pvu II); ERbeta-Rr (Rsa I); progesterone receptor (PR) Alu in intron 7] were examined by PCR-based methods. The capital and small letters signify the absence and presence of restriction sites, respectively. Odds ratios (OR) were adjusted for age using multiple logistic regression analysis with SPSS Medical Pack. Among the seven examined genetic polymorphisms, significant associations between CYP1B1 Leu432Val (OR 4.80; 95% confidence interval (CI), 1.21-19.05) and Alu in intron 7 of PR (OR 4.17; 95%CI, 1.26-13.85) were found. As for combined effects, the CYP1B1 polymorphisms (Leu/Val+Val/Val) together with heterozygosity for Alu in the PR were more frequent among prostate cancer patients (1.45%) than controls (0.41%), although without significance (OR, 3.99; 95%CI, 0.36-44.8). The combination of ERalpha (P/p+p/p) polymorphisms with heterozygosity for Alu in the PR demonstrated an OR of 4.56 (95%CI, 1.01-20.6). This pilot study showed that CYP1B1 and PR polymorphisms, alone or in combination, might be associated with prostate cancer risk. They might, therefore, have potential as a tool for identifying high-risk individuals.
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PMID:Genetic polymorphisms of hormone-related genes and prostate cancer risk in the Japanese population. 1533 Jan 95

The vitamin D receptor (VDR) is a member of the steroid/retinoid receptor superfamily of nuclear receptors and has potential tumor-suppressive functions in prostate and other cancer types. Vitamin D3 (VD3) exerts its biological actions by binding within cells to VDR. The VDR then interacts with specific regions of the DNA in cells, and triggers changes in the activity of genes involved in cell division, cell survival, and cellular function. Using human primary cultures and the prostate cancer (PCa) cell line, ALVA-31, we examined the effects of VD3 under different culture conditions. Complete G0/G1 arrest of ALVA-31 cells and approximately 50% inhibition of tumor stromal cell growth was observed. To determine changes in gene expression patterns related to VD3 activity, microarray analysis was performed. More than approximately 20,000 genes were evaluated for twofold relative increases and decreases in expression levels. A number of the gene targets that were up- and down-regulated are related to potential mechanisms of prostatic growth regulation. These include estrogen receptor (ER), heat shock proteins: 70 and 90, Apaf1, Her-2/neu, and paxillin. Utilizing antibodies generated against these targets, we were able to confirm the changes at the protein level. These newly reported gene expression patterns provide novel information not only potential markers, but also on the genes involved in VD3 induced apoptosis in PCa.
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PMID:Vitamin D3 modulated gene expression patterns in human primary normal and cancer prostate cells. 1536 55


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