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Background Selenium status is inversely associated with the incidence of prostate cancer. However, supplementation trials have not indicated a benefit of selenium supplementation in reducing cancer risk. Polymorphisms in the gene encoding selenoprotein 15 (SELENOF) are associated with cancer incidence/mortality and present disproportionately in African Americans. Relationships among the genotype of selenoproteins implicated in increased cancer risk, selenium status, and race with prostate cancer were investigated. Methods Tissue microarrays were used to assess SELENOF levels and cellular location in prostatic tissue. Sera and DNA from participants of the Chicago-based Adiposity Study Cohort were used to quantify selenium levels and genotype frequencies of the genes for SELENOF and the selenium-carrier protein selenoprotein P (SELENOP). Logistic regression models for dichotomous patient outcomes and regression models for continuous outcome were employed to identify both clinical, genetic, and biochemical characteristics that are associated with these outcomes. Results SELENOF is dramatically reduced in prostate cancer and lower in tumors derived from African American men as compared to tumors obtained from Caucasians. Differing frequency of SELENOF polymorphisms and lower selenium levels were observed in African Americans as compared to Caucasians. SELENOF genotypes were associated with higher histological tumor grade. A polymorphism in SELENOP was associated with recurrence and higher serum PSA. Conclusions These results indicate an interaction between selenium status and selenoprotein genotypes that may contribute to the disparity in prostate cancer incidence and outcome experienced by African Americans.

BACKGROUND Alpha-methylacyl-CoA racemase (AMACR) is an enzyme involved in fatty acid metabolism that is markedly over-expressed in virtually all prostate cancers (PCa), relative to benign tissue. One of AMACR's primary substrates, phytanic acid, is derived predominately from red meat and dairy product consumption. Epidemiological evidence suggests links between dairy/red meat intake, as well as phytanic acid levels, and elevated PCa risk. This study investigates the relationships among dietary intake, serum and tissue concentrations of phytanic acid, and AMACR expression (mRNA and protein) in the histologically benign human prostate. METHODS Men undergoing radical prostatectomy for the treatment of localized disease provided a food frequency questionnaire (n = 68), fasting blood (n = 35), benign fresh frozen prostate tissue (n = 26), and formalin-fixed paraffin-embedded (FFPE) sections (n = 67). Serum and tissue phytanic acid concentrations were obtained by gas chromatography–mass spectrometry. We extracted RNA from epithelial cells using laser capture microdissection and quantified mRNA expression of AMACR and other genes involved in the peroxisomal phytanic acid metabolism pathway via qRT-PCR. Immunohistochemistry for AMACR was performed on FFPE sections and subsequently quantified via digital image analysis. Associations between diet, serum, and tissue phytanic acid levels, as well as AMACR and other gene expression levels were assessed by partial Spearman correlation coefficients. RESULTS High-fat dairy intake was the strongest predictor of circulating phytanic acid concentrations (r = 0.35, P = 0.04). Tissue phytanic acid concentrations were not associated with any dietary sources and were only weakly correlated with serum levels (r = 0.29, P = 0.15). AMACR gene expression was not associated with serum phytanic acid (r = 0.13, P = 0.47), prostatic phytanic acid concentrations (r = 0.03, P = 0.88), or AMACR protein expression (r = −0.16, P = 0.20). CONCLUSIONS Our data underscore the complexity of the relationship between AMACR and its substrates and do not support the unifying hypothesis that excess levels of dietary phytanic acid are responsible for both the overexpression of AMACR in prostate cancer and the potential association between PCa risk and intake of dairy foods and red meat. Prostate 75:200–210, 2015. © 2014 Wiley Periodicals, Inc.

BACKGROUND Field cancerization, which is not yet well-characterized in the prostate, occurs when large areas of an organ or tissue surface are affected by a carcinogenic insult, resulting in the development of multi-focal independent premalignant foci and molecular lesions that precede histological change. METHODS Herein, we review the cumulative body of evidence concerning field effects in the prostate and critically evaluate the methods available for the identification and validation of field effect biomarkers. Validated biomarkers for field effects have an important role to play as surrogate endpoint biomarkers in Phase II prevention trials and as clinical predictors of cancer in men with negative biopsies. RESULTS Thus far, field effects have been identified involving nuclear morphometric changes, gene expression, protein expression, gene promoter methylation, DNA damage and angiogenesis. In addition to comparing cancer-adjacent benign tissue to more distant areas or to “supernormal” tissue from cancer-free organs, investigators can use a nested case–control design for negative biopsies that offers a number of unique advantages. CONCLUSIONS True carcinogenic field effects should be distinguished from secondary responses of the microenvironment to a developing tumor, although the latter may still lead to useful clinical prediction tools. Prostate 69: 1470–1479, 2009. © 2009 Wiley-Liss, Inc.

BACKGROUND Although growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF)-α, and TGF-β are important regulators of prostate cell growth in vitro and in animal models, evidence to support their role in human prostate cancer development remains sparse. We previously showed that men without prostate cancer have concentrations of EGF and TGF-α in expressed prostatic fluid (EPF) that are individually distinct and stable over time. This study addressed whether growth factor levels in EPF are associated with the presence or progression of prostate cancer. METHODS We measured levels of immunoreactive EGF, TGF-α, and TGF-β1 in stored EPF samples from three age-matched groups: 19 men with untreated, histologically diagnosed prostate cancer (CaP), 38 with benign prostate hyperplasia (BPH), and 19 with normal prostate glands (NPD). RESULTS Median TGF-α was lower in the BPH group (0.45 ng/ml) than in either CaP (0.63 ng/ml) or NPD (0.58 ng/ml) groups (P = 0.03 and 0.12, respectively). For EGF, the median was lowest in the CaP group and highest in the NPD group (92.5 ng/ml vs. 175.5 ng/ml, P = 0.006). For TGF-β1, the median level in CaP was 2.7 times higher than the median level among all controls (6.65 ng/ml vs. 2.46 ng/ml, P = 0.002). Growth factor levels were not associated with tumor stage or Gleason score. However, the single case with distant metastases had TGF-β1 levels 23-fold higher than the CaP median. CONCLUSIONS The results suggest that at the time of CaP diagnosis, EGF levels in EPF are significantly lower, and TGF-β1 levels significantly higher, than normal. Marked overexpression of TGF-β1 in advanced CaP might be reflected in extremely high EPF levels. Prostate 40:248–255, 1999. © 1999 Wiley-Liss, Inc.

BACKGROUND CAG repeat length in exon 1 of the androgen receptor (AR) gene correlates inversely with transcriptional transactivation activity of the AR. Men with shorter AR CAG repeat lengths are at higher risk of prostate cancer. Because benign prostatic hyperplasia (BPH) is an androgen-dependent condition, we examined the hypothesis that a shorter AR gene CAG repeat length increases the risk of developing of BPH. METHODS Among 14,916 men of the Physicians' Health Study who had provided a blood sample in 1982, we measured AR gene CAG repeat lengths for 310 men who had surgery for BPH up to 7.5 years of follow-up and 1,041 controls. RESULTS Risk of surgery for BPH increased linearly with decreasing AR CAG repeat length (P (trend) = 0.03). Relative to men with a CAG repeat length ⩾25, men with a repeat length ⩽19 had an odds ratio of BPH surgery of 1.76 (95% confidence interval, 1.16–2.65). CONCLUSIONS Variability in the AR gene CAG repeat influences the development of symptomatic BPH. Prostate 39:130–134, 1999. © 1999 Wiley-Liss, Inc.

BACKGROUND Prostatic fluid (PF) provides a unique medium for noninvasive evaluation of critical growth and differentiation signals in the prostatic microenvironment. The purpose of this study was to establish the feasibility of measuring two prostatic mitogens, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) in PF, and specifically to quantify extraneous variability attributable to the assay itself, sample handling, or biological variation within an individual over time. METHODS PF was collected by transrectal massage from consecutive patients attending a urology clinic. Pooled PF and individual samples from 25 men with stable benign prostatic hyperplasia (BPH) were analyzed for EGF and TGF-alpha by radioimmunoassay and for total protein. RESULTS Reproducibility was adequate at dilutions as low as 1:50 (2-microliter pooled sample) and 1:5 (20 microliters) for EGF and TGF-alpha, respectively. Results were not affected by freeze-thaw cycles, time in storage, or protease inhibition in fresh PF. EGF and TGF-alpha were detectable in 100% and 92% of individual men, with respective means of 152 and 0.2 ng/ml. Correlations between two samples obtained from the same man within 12 months were highly significant (EGF r = 0.89, TGF-alpha r = 0.71). Protein concentrations were consistent over time; expression of either peptide per weight of protein rather than per volume did not improve within-man correlation. Between-man variability far exceeded within-man variability for both peptides, and was estimated to account for 84% and 61% of the total variability in EGF and TGF-alpha, respectively. There was no correlation between EGF and TGF-alpha in the same samples. CONCLUSIONS We conclude that men with BPH secrete consistent and distinct levels of EGF-related peptides in PF, and that these levels can be detected with acceptable sensitivity and precision by radioimmunoassay (RIA). Measurement of TGF-alpha, which has not been reported previously, requires a relatively larger sample.

We assessed the relation of plasma hormone levels and nonhormonal factors with subsequent occurrence of surgical treatment for benign prostatic hyperplasia (BPH) among participants in the Physicians' Health Study. Frozen plasma samples, collected at the study onset, were available for 320 men who developed surgically treated BPH up to 9 years later and for 320 age-matched controls. Plasma testosterone (T), dihydrotestosterone (DHT), androstenedione, estradiol (E2), and estrone (E1) were measured for each case-control pair. In unadjusted analyses, none of the hormones or hormone ratios were associated with BPH; for example, for T and E2 the odds ratios (OR) comparing the highest quintile (Q5) with the lowest (Q1) were 0.74 (95% CI = 0.42, 1.30) and 1.07 (95% CI = 0.51, 2.22), respectively. However, in multivariate analyses controlling diastolic blood pressure, exercise, alcohol, E1, and DHT:T ratio, we observed a strong trend for increasing risk across quintiles for E2 (Q5 vs. Q1 OR = 3.56, P trend = 0.009), and a weak inverse trend for E1 (Q5 vs Q1 OR = 0.51, P trend = 0.07). The excess risk associated with E2 was confined to men with relatively low androgen levels. Three nonhormonal factors previously suspected as risk factors were independently associated with surgical BPH in these data. The OR for a 1-mm Hg difference in diastolic blood pressure was 1.04 (95% CI = 1.01, 1.07). Alcohol use and infrequent exercise were inversely associated with risk of BPH surgery; however, risk estimates were not consistent across categories of exercise and alcohol frequency. Our results indicate that normal variation in circulating androgen levels does not influence development of BPH, but that variation in estrogen levels might be important.

Field cancerization, which is not yet well-characterized in the prostate, occurs when large areas of an organ or tissue surface are affected by a carcinogenic insult, resulting in the development of multi-focal independent premalignant foci and molecular lesions that precede histological change.Herein, we review the cumulative body of evidence concerning field effects in the prostate and critically evaluate the methods available for the identification and validation of field effect biomarkers. Validated biomarkers for field effects have an important role to play as surrogate endpoint biomarkers in Phase II prevention trials and as clinical predictors of cancer in men with negative biopsies.Thus far, field effects have been identified involving nuclear morphometric changes, gene expression, protein expression, gene promoter methylation, DNA damage and angiogenesis. In addition to comparing cancer-adjacent benign tissue to more distant areas or to "supernormal" tissue from cancer-free organs, investigators can use a nested case-control design for negative biopsies that offers a number of unique advantages.True carcinogenic field effects should be distinguished from secondary responses of the microenvironment to a developing tumor, although the latter may still lead to useful clinical prediction tools. Prostate 69: 1470-1479, 2009. (c) 2009 Wiley-Liss, Inc.

BACKGROUND Alpha-methylacyl-CoA racemase (AMACR) is strongly expressed in prostate cancer with variable expression in high-grade prostatic intraepithelial neoplasia (HGPIN) and low expression in normal prostate. We examined whether AMACR expression in HGPIN and normal tissue was associated with subsequent diagnosis of cancer or proximity to a cancer focus. METHODS Needle core biopsies from 45 patients with isolated HGPIN, 12 radical prostatectomy (RP) specimens with prostatic carcinoma and 6 cystoprostatectomies without prostatic carcinoma were immunostained for AMACR. Among patients with HGPIN, 23 (cases) showed cancer on a later biopsy and 22 (controls) had no cancer with at least 3 consecutive negative biopsies. RESULTS In the biopsy set, the mean AMACR expression per gland in the normal compartment of the cases (0.29) was significantly higher than the controls (0.21) (P = 0.0006). In the RP set, normal glands near a cancer focus had higher mean AMACR expression than those that were distant (P = 0.0006). There was no difference within the HGPIN compartment between cases and controls in the biopsies, or between near and distant glands in the RP set. Mean AMACR staining of normal glands in the cystoprostatectomy specimens was significantly lower than in normal glands in close proximity to a cancer focus. CONCLUSIONS Higher expression of AMACR in normal glands near a focus of cancer, as well as in the subjects eventually showing cancer, suggests a possible field effect in prostatic carcinogenesis. AMACR expression in normal glands therefore might be a useful predictor for repeat biopsy outcomes or as an intermediate endpoint in chemoprevention studies. © 2004 Wiley-Liss, Inc.