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 stimulate prostate cancer in vitro and in vivo. However, evidence from epidemiologic studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent. We investigated the association of serum levels of testosterone, the principal androgen in circulation, and sex hormone-binding globulin (SHBG) with risk in a case-control study nested in cohorts in Finland, Norway and Sweden of 708 men who were diagnosed with prostate cancer after blood collection and among 2,242 men who were not. In conditional logistic regression analyses, modest but significant decreases in risk were seen for increasing levels of total testosterone down to odds ratio for top vs. bottom quintile of 0.80 (95% CI = 0.59-1.06; p(trend) = 0.05); for SHBG, the corresponding odds ratio was 0.76 (95% CI = 0.57-1.01; p(trend) = 0.07). For free testosterone, calculated from total testosterone and SHBG, a bell-shaped risk pattern was seen with a decrease in odds ratio for top vs. bottom quintile of 0.82 (95% CI = 0.60-1.14; p(trend) = 0.44). No support was found for the hypothesis that high levels of circulating androgens within a physiologic range stimulate development and growth of prostate cancer.
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PMID:High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. 1464 9

The incidence of and mortality from prostatic cancer in the West is higher than that in Asian countries. Migrants from Asia to western countries, who maintain their traditional diet, do not have an increased risk of prostatic cancer. This has been attributed in part to 'phyto-oestrogens' in vegetarian Asian diets. Prostatic cancer is a hormone-dependent disease and oestrogens retard the growth of prostatic tumours by interfering with the action of testosterone. Oestrogen increases the level of sex hormone-binding globulin that binds testosterone, resulting in lower free testosterone levels, thereby decreasing androgenic stimulation of the prostate. Oestrogens used to retard the growth of prostatic cancer are associated with certain undesirable side-effects. Phyto-oestrogens have weak oestrogenic potency and anticancer effects. Thus, these phytochemicals have a possible role in the prevention of hormone-dependent diseases such as prostatic cancer. Although the relative potencies of various phyto-oestrogens compared with oestradiol are low, the oestrogen receptor (ER) complexes formed byoestradiol and isoflavones have functional similarities. Also, phyto-oestrogens have a higher affinity to bind to ER-beta than ER-alpha. They are antiproliferative and inhibit tyrosine and other protein kinases which play a key role in tumorigenesis, and also inhibit the production of the potent androgen 5alpha dihydrotestosterone in the prostate. Since prostatic cancer cells usually multiply slowly and the development of this cancer can take many years before symptoms appear, the latent period provides a chemopreventive opportunity for natural therapy with phyto-oestrogens. Although phyto-oestrogens have not yet been used in long-term trials to evaluate their ability to reduce the risk of prostate carcinoma, the evidence thus far suggests that they have a protective effect against the growth of prostate tumours.
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PMID:Phyto-oestrogens and prostatic growth. 1511 28

Racial differences in disease risk (eg, osteoporosis, metabolic cardiovascular syndrome, and prostate cancer) may arise partly on a hormonal basis. While reports of racial differences in gonadal steroid hormone levels in middle-aged men have produced conflicting results, there is evidence that high sex hormone-binding globulin (SHBG) and estradiol levels are more common among young adult African American men than white men. To determine whether this difference relates to pituitary-testicular functioning or to other factors, we conducted a cross-sectional study of 47 healthy prepubertal African American and white boys aged 5 to 9 years at the time of their annual school physical examination. Height, weight, blood pressure, waist and hip circumference, and Tanner staging were determined, and a fasting blood sample was obtained. The African Americans studied were slightly older than the whites (mean +/- SD, 82.4 +/- 15.0 vs 70.5 +/- 10.3 months, P = .003). African Americans were also slightly taller and heavier and had a lower waist-to-hip ratio, but these differences could be explained by the difference in age. Mean SHBG levels were 25% higher (P = .15) in African Americans than in whites (197 +/- 104 vs 157 +/- 79 nmol/L), and when adjusted for age, values were 46 nmol/L higher among African Americans. The fifth quintile for SHBG (values > 245 nmol/L) included 1 (4.2%) of 24 whites and 8 (35%) of 23 African Americans studied (P = .003). There was no significant correlation between age, body mass index, waist circumference, or fasting insulin and SHBG. Total testosterone, the free androgen index, and dehydroepiandrosterone increased with age in both groups, but after adjusting for age, no racial differences were found. Estradiol, estrone, and inhibin B levels, as well as systolic and diastolic blood pressures, were also comparable in both groups. We conclude that high levels of SHBG are more common among African American than in white boys and hypothesize that this difference and its effect on the ratio between bound and free steroid hormones may contribute to racial differences in disease risk in adult men.
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PMID:Racial difference in circulating sex hormone-binding globulin levels in prepubertal boys. 1556 86

Metabolic syndrome was initially described as an aggregation of risk factors for the development of coronary artery disease with insulin resistance and compensatory hyperinsulinemia as the underlying factor. In an earlier review, we suggested that hyperinsulinemia may also lead to prostate cancer (PCa), the most common male cancer in industrialized nations. Furthermore, we suggested that diet and exercise, known to be important in the development of insulin resistance, may also be important in the development of PCa. When we placed men from the United States on a low-fat diet and/or exercise program, serum levels of insulin, free testosterone, estradiol and insulin-like growth factor (IGF)-1 were reduced while sex hormone-binding globulin (SHBG) and insulin-like growth factor binding protein (IGFBP)-1 were elevated. These in vivo serum changes directly impacted on androgen-dependent prostate cancer cell lines in vitro to reduce cell growth and induce apoptosis. The reduction in serum IGF-1 and increase in IGFBP-1 with diet and exercise appear to be the most significant, as these changes lead to an increase in tumor cell p53 protein and its down-stream effector p21, which are responsible for the reduction in cell growth and induced apoptosis. Preliminary results from a clinical study with men on "watchful waiting" indicate that the observed in vitro effects of diet and exercise on prostate cancer cell growth also occur in vivo.
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PMID:Preclinical models relevant to diet, exercise, and cancer risk. 1564 82

This experiment examined the effects of delays in separation and freezing of whole blood components on analytes of interest in studies of prostate cancer prevention, in order to evaluate the feasibility of centralized processing of blood for the multisite Selenium and Vitamin E Cancer Prevention Trial. Blood from 40 healthy men was subjected to four treatment protocols, allowing the contrast of immediate processing to delays of 32, 72, and 144 hours. At 32 hours, simulating refrigerated storage and overnight shipping, there was a 2.9% decrease (95% confidence interval, 0.7-5.1) in insulin-like growth factor-I (IGF-I) but no significant change in carotenoids, tocopherols, testosterone, 3alpha-androstanediol glucuronide (AAG), sex hormone-binding globulin (SHBG) or insulin-like growth factor binding protein 3 (IGFBP3). A 144-hour processing delay, simulating weekend blood collection or shipping delay, resulted in significant changes in gamma-tocopherol (-1.5%), IGF-I (-5.7%), IGFBP3 (-2.9%), SHBG (-4.0%), testosterone (+4.7%), and AAG (+5.5%). The rank-order and intraclass correlations between analytes from blood processed immediately and those subjected to delayed processing were 0.96 or higher for carotenoids, tocopherols, AAG, and SHBG, and between 0.87 and 0.95 for IGF-I, IGFBP3, and testosterone. A 32-hour delay decreased lymphocyte viability from 82.5% to 75.0% (P = 0.45), but a 72-hour delay decreased viability to 36.8% (P < 0.001). Overnight shipping and centralized processing is an acceptable approach to blood collection in large multisite trials examining the cancer-related measures proposed in the Selenium and Vitamin E Cancer Prevention Trial. Longer processing delays, however, have small but statistically significant effects on many analytes and substantially decrease lymphocyte viability.
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PMID:Centralized blood processing for the selenium and vitamin E cancer prevention trial: effects of delayed processing on carotenoids, tocopherols, insulin-like growth factor-I, insulin-like growth factor binding protein 3, steroid hormones, and lymphocyte viability. 1576 58

Phytoestrogens have been hypothesized to protect against prostate cancer via modulation of circulating androgen concentrations. We conducted a cross-sectional study of 267 men in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with 2 aims: first, to investigate the association between phytoestrogen exposure (measured from diet, urine, and serum) and plasma concentrations of sex hormone-binding globulin (SHBG), androstanediol glucuronide, testosterone and Free Androgen Index (FAI); and second, whether the association may be modified by polymorphisms in CYP19 and SHBG genes. Dietary daidzein and genistein intakes were obtained from food diaries and computed using an in-house food composition database. Urinary and serum concentrations of 3 isoflavones (daidzein, genistein, glycitein), 2 daidzein metabolites O-desmethylangolensin (O-DMA) and 2 lignan metabolites (enterodiol and enterolactone) were measured using mass spectrometry. There was no association between dietary, urinary, and serum phytoestrogens and plasma SHBG concentrations. Enterolactone was positively associated with plasma androstanediol glucuronide concentrations (urinary enterolactone: r = 0.127, P = 0.043; serum enterolactone: r = 0.172, P = 0.006) and FAI (urinary enterolactone: r = 0.115, P = 0.067; serum enterolactone: r = 0.158, P = 0.011). Both urinary and serum equol were associated with plasma testosterone (urinary equol: r = 0.332, P = 0.013; serum equol: r = 0.318, P = 0.018) and FAI (urinary equol: r = 0.297, P = 0.027; serum equol: r = 0.380, P = 0.004) among men with the TT genotype but not the CC or CT genotypes (r = -0.029 to -0.134, P = 0.091-0.717) for the CYP19 3'untranslated region (UTR) T-C polymorphism. Urinary and serum enterolactone showed similar genotype-dependent associations with testosterone but not with FAI. In this first study on phytoestrogen-gene associations in men, we conclude that enterolactone and equol are positively associated with plasma androgen concentrations, and interactions with CYP19 gene may be involved.
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PMID:Polymorphisms in the CYP19 gene may affect the positive correlations between serum and urine phytoestrogen metabolites and plasma androgen concentrations in men. 1625 30

Proper management of prostate cancer patients is highly dependent on the spread of the disease. High expression levels of the androgen receptor (AR) in prostate tumor offer a target for identifying cancer metastasis. We investigated the use of nonsteroidal AR ligands for receptor-mediated imaging as a diagnostic tool for prostate cancer staging. Compound S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide]was identified from a series of iodinated ether-linked derivatives of bicalutamide due to its high-AR binding affinity of 3.3 nM (which is similar to testosterone and approximately 25% of the binding affinity of dihydrotestosterone) in an in vitro competitive binding assay using rat prostate cytosol. Furthermore, S-26 exhibited a greater binding affinity (K(i) = 4.4 nM) in a whole-cell binding assay using COS-7 cells transfected with human AR than testosterone (K(i) = 32.9 nM) and dihydrotestosterone (K(i) = 45.4 nM). We also confirmed that sex hormone-binding globulin (SHBG), a plasma protein that binds steroids with high affinity, does not bind with S-26. Cotransfection studies with the estrogen, progesterone, and glucocorticoid receptor indicated that S-26 does not cross-react with other members of the steroid hormone receptor family. The nonsteroidal structure, high-AR binding affinity, specificity, and lack of binding to SHBG indicate that S-26 exhibits favorable properties for further development as an imaging agent for prostate cancer.
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PMID:Preclinical pharmacology of a nonsteroidal ligand for androgen receptor-mediated imaging of prostate cancer. 1643 67

Epidemiologic studies have failed to support the hypothesis that circulating androgens are positively associated with prostate cancer risk and some recent studies have even suggested that high testosterone levels might be protective particularly against aggressive cancer. We tested this hypothesis by measuring total testosterone, androstanediol glucuronide, androstenedione, DHEA sulfate, estradiol, and sex hormone-binding globulin in plasma collected at baseline in a prospective cohort study of 17,049 men. We used a case-cohort design, including 524 cases diagnosed during a mean 8.7 years follow-up and a randomly sampled sub-cohort of 1,859 men. The association between each hormone level and prostate cancer risk was tested using Cox models adjusted for country of birth. The risk of prostate cancer was approximately 30% lower for a doubling of the concentration of estradiol but the evidence was weak (P(trend)=0.07). None of the other hormones was associated with overall prostate cancer (P(trend) >or= 0.3). None of the hormones was associated with nonaggressive prostate cancer (all P(trend) >or= 0.2). The hazard ratio [HR; 95% confidence interval (95% CI)] for aggressive cancer almost halved for a doubling of the concentration of testosterone (HR, 0.55; 95% CI, 0.32-0.95) and androstenedione (HR, 0.51; 95% CI, 0.31-0.83), and was 37% lower for a doubling of the concentration of DHEA sulfate (HR, 0.63; 95% CI, 0.46-0.87). Similar negative but nonsignificant linear trends in risk for aggressive cancer were obtained for free testosterone, estradiol, and sex hormone-binding globulin (P(trend)=0.06, 0.2, and 0.1, respectively). High levels of testosterone and adrenal androgens are thus associated with reduced risk of aggressive prostate cancer but not with nonaggressive disease.
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PMID:Circulating steroid hormones and the risk of prostate cancer. 1643 92

The receptor mechanism of testosterone-induced nongenomic Ca2+ signaling in prostate cancer cells is poorly understood. In this study we investigated androgen-induced intracellular Ca2+ increases in LNCaP human prostate cancer cells with Fura-2 as a Ca2+ probe. 5alpha-dihydrotestosterone (DHT) produced fast and transient increases in intracellular Ca2+ in LNCaP cells in a concentration-dependent manner. These effects were abolished by extracellular Ca2+ removal or pretreatment with L-type Ca2+ channel inhibitors (nifedipine, verapamil, and diltiazem). Pretreatment with endoplasmic reticulum ryanodine receptor blocker (procaine) or phospholipase C inhibitor (neomycin sulfate) did not alter DHT-induced Ca2+ influx. The concentration of Ca2+ was also increased by impermeable testosterone conjugated to bovine serum albumin. Neither an antagonist of intracellular androgen receptors (cyproterone acetate) nor a protein synthesis inhibitor (cycloheximide) affected this fast Ca2+ influx. Furthermore, the effect of DHT was abolished in cells incubated with a G protein inhibitor (pertussis toxin) and a nonhydrolyzable analog of guanosine triphosphate (guanosine 5-[beta-thio]disphosphate) but not in cells incubated with the tyrosine kinase inhibitor genistein. These results indicate that androgens induced an L-type calcium channel-dependent intracellular Ca2+ increase in LNCaP prostate cancer cells. The rapid responses triggered by DHT did not appear to be mediated through classic intracellular androgen receptors, c-Src kinase-androgen receptor complex, or sex hormone-binding globulin but through a G protein-coupled receptor in LNCaP prostate cancer cells. These results may provide a new explanation for progression of prostate cancer.
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PMID:Androgens induce increases in intracellular calcium via a G protein-coupled receptor in LNCaP prostate cancer cells. 1672 19

Controversy exists over the significance of associations between the SRD5A2 (5alpha-reductase type 2) polymorphisms, A49T and V89L, and risk of prostate cancer. These potentially functional polymorphisms may alter life-long exposure to androgens with subsequent effects on male health and aging. The aim of this study was to examine the association of these variants with prostate cancer risk, plasma hormone levels and androgenetic alopecia. Subjects include 827 cases and 736 controls from an Australian population-based case-control study of prostate cancer. Information on prostate cancer risk factors and patterns of balding were collected. Plasma levels of testosterone, 3alpha-diol glucuronide (3alpha-diolG), dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and estradiol were measured for controls. No associations with the V89L polymorphism were found. Carriers of the rarer A49T A allele were at a 60% higher risk of prostate cancer (OR = 1.60; 95% CI 1.09-2.36; p = 0.02) and 50% lower risk of vertex and frontal balding (p = 0.03) compared with men homozygous for the more common G allele. Although we found little evidence of association between this variant and plasma levels of 5 measured androgens, circulating 3alpha-diolG levels were 34% lower in A49T A allele carriers (p < 0.0001). Our study provides evidence that the SRD5A2 A49T A variant is associated with an increased risk of prostate cancer, lower levels of circulating 3alpha-diolG and decreased risk of baldness. These findings raise important questions with respect to previous assumptions concerning hormonal influences on prostate cancer risk in ageing males.
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PMID:5alpha-Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia. 1713 62


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