Association of variants in estrogen-related pathway genes with prostate cancer risk.
ABSTRACT BACKGROUND: Through mediation of estrogen receptors, estradiol has been shown to have both carcinogenic and anti-carcinogenic effects on the prostate. We performed a population-based case-control study to investigate variants in estrogen-related genes ESR1, ESR2, CYP19A1, CYP1A1, and CYP1B1 and the potential association with risk of prostate cancer (PCa). MATERIALS AND METHODS: We evaluated PCa risk conferred by 73 single nucleotide polymorphisms in 1,304 incident PCa cases and 1,266 age-matched controls. Analysis included stratification by clinical features and assessment of environmental modifiers. RESULTS: There was evidence of altered risk of developing PCa for variants in ESR1, CYP1A1, and CYP1B1, however, only CYP1B1 rs1056836 retained significance after adjustment for multiple comparisons. An association with risk for more aggressive PCa was observed for variants in ESR1, ESR2, and CYP19A1, but none was significant after adjustment for multiple comparisons. There was no effect modification by obesity. CONCLUSIONS: Germline genetic variation of these estrogen pathway genes may contribute to risk of PCa. Additional studies to validate these results and examine the functional consequence of validated variants are warranted. Prostate © 2012 Wiley Periodicals, Inc.
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ABSTRACT: The aim of this work was to study simultaneously the expression profile of the 23 CYP mRNAs of CYP1, CTP2 and CYP3 families in 22 different human tissues namely adrenal gland, bladder, bone marrow, colon, fetal liver, heart, kidney, liver, lung, mammary gland, ovary, placenta, prostate, salivary gland, skeletal muscle, small intestine, spleen, testis, thymus, thyroid, trachea and uterus. Analysis of the mRNA levels of each of these CYP isoforms was performed on total RNA from pooled specimens of human organs using reverse transcriptase-PCR-based CYP mRNA assays previously validated for their sensitivity and their specificity. Our results confirmed previously reported data in the literature concerning isoforms expression in the most currently studied tissues. Moreover, they provided a great deal of new information, mainly about the expression of mRNA of little-known CYP isoforms. Among the 23 CYP isoforms studied, 12 were mainly hepatic (CYP1A2, 2A6, 2A7, 2A13, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4 and 3A43). Two CYP mRNAs were predominantly expressed in several extrahepatic tissues: CYP1B1 mRNA was the predominant CYP in seven extrahepatic tissues (bone marrow, kidney, mammary gland, prostate, spleen, thyroid and uterus) and CYP2J2 in four extrahepatic tissues (heart, placenta, salivary gland and skeletal muscle). Finally, some CYPs were nearly exclusively expressed in only one extrahepatic tissue. CYP2R1 was found in testis, CYP2U1 in the thymus and CYP2F1 in the respiratory tract (lung and trachea). This description will broaden the understanding of the physiological functions of these CYPs.Pharmacogenetics and Genomics 10/2007; 17(9):731-42. · 3.61 Impact Factor
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ABSTRACT: 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.Journal of Cellular Biochemistry 03/2004; 91(3):491-503. · 3.06 Impact Factor
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ABSTRACT: Sex hormones have been implicated in prostate carcinogenesis and are thought to modulate cell proliferation and growth. To investigate the association between polymorphisms in hormone-related genes and prostate cancer risk, we conducted a two-stage, case-control study within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Using DNA extracted from blood specimens, we initially genotyped 14 single nucleotide polymorphisms in genes involved in hormone regulation or metabolism (AKR1C3, CYP1A1, CYP1B1, CYP3A4, ESR1, GNRH1, HSD173B, HSD3B2, SHBG, and SRD5A2) in 488 prostate cancer cases and 617 matched controls. Heterozygotes at SHBG D356N were found to be associated with an increased risk of prostate cancer compared with the homozygous wild type, particularly among non-Hispanic whites (odds ratio, 1.54; 95% confidence interval, 1.13-2.09; P = 0.006). No significant associations were observed with the other polymorphisms. The SHBG D356N polymorphism, which has potential functional significance, was subsequently genotyped in additional 769 cases and 1,168 controls. Overall, SHBG D356N heterozygotes were found to have an increased risk of prostate cancer among whites (odds ratio, 1.34; 95% confidence interval, 1.10-1.63; P = 0.0007). This study suggests that genetic variation in SHBG may influence prostate cancer susceptibility.Cancer Epidemiology Biomarkers & Prevention 02/2007; 16(1):165-8. · 4.56 Impact Factor