Eur J Endocrinol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

DOI: 10.1530/EJE-08-0321
European Journal of Endocrinology, Vol 160, Issue 1, 101-106
Copyright © 2009 by European Society of Endocrinology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
EJE-08-0321v1
160/1/101    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nicolaiew, N.
Right arrow Articles by Cussenot, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nicolaiew, N.
Right arrow Articles by Cussenot, O.
CLINICAL STUDY

Association between estrogen and androgen receptor genes and prostate cancer risk

Nathalie Nicolaiew2, Geraldine Cancel-Tassin1, Abdel Rahmene Azzouzi1,4, Beatrice Le Grand5, Philippe Mangin1,6, Luc Cormier1,6, Georges Fournier1,7, Jean-Pierre Giordanella8, Michel Pouchard8, Jean-Louis Escary9, Antoine Valeri1,7 and Olivier Cussenot1,3

1 CeRePP, Hôpital Tenon, 75020 Paris, France2 Faculté de Médecine, Institut Mondor de Médecine Moléculaire (IFR10), Université Paris 12, Créteil F-94010, France3 Assistance Publique-Hôpitaux de Paris, Department of Urology, Tenon Hospital, GHU Est, University Paris VI, Paris, France4 CHU d'Angers,, Department of Urology, Angers, France5 Université Paris 5, UFR Biomédicale des Saints-Pères, Paris, France6 CHU Brabois,, Department of Urology, Nancy, France7 Department of Urology,, Hopital de la Cavale Blanche, Brest, France8 Centres d'examen de Santé de l'Assurance Maladie, CNAM, Paris, France and 9 GenOdyssee SA, Evry, France

(Correspondence should be addressed to G Cancel-Tassin who is now at CeRePP, Laboratoire Urologie, Hôpital TENON APHP, Bâtiment Recherche, 5e étage, 4 rue de la Chine, 75970 Paris Cedex 20, France; Email: geraldine.cancel-tassin{at}tnn.aphp.fr)


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 
Objective: Prostate cancer (PC) is one of the principal causes of death among men. Steroid hormones are involved in normal prostate growth and carcinogenesis. The purpose of our study was to investigate the effects on PC risk of polymorphisms from three steroid hormone receptor genes: the androgen (AR), and the {alpha} (ESR1) and β (ESR2) estrogen receptors.

Design and methods: The study was performed on a Caucasian population of 1045 PC patients and 814 controls. Using a logistic regression model, the different alleles and genotypes from those polymorphisms were analyzed according to case/control status, the tumor aggressiveness, and the age at onset.

Results: A significant association between PC risk and the pooled 4/5, 5/6, and 6/6 genotypes of the GGGA repeat located in the first intron of ESR1 (odds ratio (OR)=3.00, 95% CI=1.32–6.82, P=0.008) was observed. When we stratified the cases, this association was confined to patients with a Gleason score of 2–4 (OR=8.34, 95% CI=2.91–23.91, P<0.0001) or late onset PC (OR=2.91, 95% CI=1.22–6.93, P=0.016). An association between a short AR CAG repeat (less than 17 repeats) was also observed among patients with late onset PC (OR=2.34, 95% CI=1.15–4.76, P=0.019).

Conclusions: These findings suggest that the GGGA repeat from ESR1 and the CAG repeat from AR may be associated with risk of late onset PC.


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 
Prostate cancer (PC) is one of the major causes of death among men in developed countries (1). The principal risk factors are age, familial history, and ethnicity. Sex steroid hormones like androgens and estrogens are important in PC development. Indeed, evidence supports the hypothesis that exposure to endogenous variations in androgens and estrogens across a man's life span contributes to or may be a causal factor in the development of PC. While androgen deprivation and administration of estrogens are recognized therapies for PC, early exposure to estrogens is suspected to initiate carcinogenesis among different tissues, including the prostate gland. A decrease in the ratio of androgens to estrogens with aging could also be responsible for prostate carcinogenesis.

Growth and differentiation of the prostate are controlled by androgens such as testosterone and 5{alpha}-dihydrotestosterone. Their effects are mediated through their interaction with the androgen receptor (AR) that is expressed in the prostatic epithelial cells (2). Estrogens could also have an indirect role through repression of the hypothalamic–pituitary–gonadal axis and direct effects on the testis. Estrogens produced by peripheral aromatization of testosterone exert their effects on prostatic tissue by interaction with their receptors, estrogen receptor {alpha} (ESR1), and β (ESR2). These receptors are expressed with distinct tissue and cell-specific patterns. In the normal prostate, ESR1 is only found in stromal cells whereas ESR2 is expressed in the majority of epithelial cells and in some stromal cells (3).

In tumoral tissue, AR expression is observed in primary cancers and during progression to hormone refractory carcinoma. Immunohistological studies have shown a heterogeneous expression pattern of AR in PC (4). ESR1 has been reported to be expressed in both stromal and epithelial cells in prostate tumors (5); however, results are inconsistent among studies with other reports showing only stromal expression (3). By contrast, ESR2 is commonly expressed in the epithelial cells of prostate tumors (3).

A reduction in ESR2 expression has been observed during carcinogenesis, suggesting a role for this receptor in the maintenance of normal prostate epithelium (6, 7). Cancers retaining ESR2 expression seem to be associated with a highly malignant phenotype (8). Decreased expression of the ESR1 gene has also been found in PC and particularly, in hormone refractory tumors (7).

Moreover, experimental studies performed in rodents have also demonstrated that estrogens through their receptors are potentially carcinogenic in the prostate. In rodents, neonatal estrogenization inhibits prostate growth and function, and promotes the development of dysplastic lesions (9). Experiments with ER-deficient mice have indicated that the effects of neonatal exposure to high doses of estrogens are largely mediated through stromal ESR1, but are not associated with ESR2 (10). Weihua et al. (11) reported that ERβKO mice displayed hyperplastic foci and increased expression of the proliferation marker Ki-67 in prostate. By contrast, in another study, no prostatic abnormality was observed in other ERβKO mice (12). Estrogens have also been shown to induce prostate tumors in rats when associated with androgens (13, 14).

To study the role of estrogen receptors in the risk of PC, we screened the ESR2 gene for polymorphisms and compared their distribution in PC patients and healthy controls. We also evaluated two previously reported polymorphisms in the ESR1 and AR genes in a large population. The first polymorphism is the GGGA repeat localized in the first intron of the ESR1 gene, which our group has previously shown to be associated with increased PC risk in a smaller study (15). The second is the highly variable CAG repeat (encoding polyglutamine) which is located in the first exon of the AR gene corresponding to the transactivation domain (16).


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Declaration of interest
 References
 
Study population

In this study, 1045 PC cases and 814 controls of Caucasian origin were included. All the participants gave informed consent. The protocol was approved by the Institutional Review Board (IRB) from CCP Ile de France IV (Paris Saint-Louis). Cases were recruited from three French departments of urology (Paris, Nancy, and Brest) and were diagnosed with a histological confirmed adenocarcinoma of the prostate. Aggressiveness of the cancer was based on pathological TNM Classification 2004, Gleason score and PSA level (mean±S.D.: 99.36 ng/ml±707.43 ng/ml). Subjects ranged from 40 to 98 years of age (mean=67 years).

Controls were selected from men invited to a systematic health screening, under the proposition of the national health insurance, performed in the same geographical areas than the hospitals where the cases were collected. They were checked by digital rectal examination, their prostate specific antigen (PSA) value had to be less than 4 ng/ml, and they could exhibit no signs of prostate carcinoma. Their mean age was 63 years (range 40–92 years).

Genomic DNA was extracted from peripheral blood leukocytes using standard methods.

Detection of polymorphisms in the ESR2 gene

Specific primers encompassing each coding exon of the human estrogen β receptor were designed. Each fragment of the gene was amplified as follows. In a final volume of 25 µl, 5 ng genomic DNA, 200 µM dNTP, 0.02 M MgSO4, 0.2 µM of each primer, and 0.375 U of Taq Platinum (Gibco) were mixed. To rapidly screen for the presence or absence of polymorphisms, three PCR products either from three patients or three controls were pooled. The pooled samples were then analyzed by DHPLC as described in patent FR-2793262.

Genotyping

Genotyping of the ESR2 polymorphisms was done using fluorescence polarization template-direct dye-terminator incorporation technology, as described in (15). The AcycloPrime-FP SNP Detection Kit (Perkin–Elmer Life Sciences Inc., Boston, MA, USA) was used for the extension step. Fluorescence polarization of the two dye terminators was analyzed directly in the final reaction mix with an Analyst fluorescence reader from LJL Biosystems (Boston, MA, USA).

Genotyping was performed as already described in (17) for the CAG repeat from AR and in (15) for the GGGA repeat from ESR1. Briefly, primers encompassing the CAG repeat (5'-tccagaatctgttccagagcgtgc-3' and 5'-actgcggctgtgaaggttgctgt-3') or the GGGA repeat (5'-gcccgctgatgctactgc-3' and 5'-tgggtggagagtacgtttttt-3') were selected. One primer was fluorescently labeled. For the AR CAG repeat, PCR amplification was carried out in a final volume of 50 µl, containing 50 ng DNA, 20 pmol of each primer, 100 µM each of dNTP, 1.5 mM MgCl2, 10 mM Tris–HCl pH 8.3, 50 mM KCl, and 1 unit Taq DNA polymerase (Applied Biosystems, Foster City, CA, USA), in the following cycling conditions: 10 min at 94 °C, then 35 cycles of 40 s at 94 °C, 30 s at 60 °C, 30 s at 72 °C. For the ESR1 GGGA repeat, PCR was carried out in a final volume of 20 µl, containing 50 ng genomic DNA, 250 µM dNTP, 1 µM each primer, 2.5 U Taq Gold (Applied Biosystems), 2.5 mM MgCl2, and 5% DMSO, in the following cycling conditions: 5 min at 95 °C, then 35 cycles of 30 s at 94 °C, 30 s at 53 °C, 30 s at 72 °C. The final extension step at 72 °C was extended to 10 min. PCR products were then loaded on 5% denaturing polyacrylamide gel and detected with an ABI Prism 377 DNA automated sequencer. Genotypes were determined with Genescan Analysis 3.1 software (Applied Biosystems).

Statistical analysis

Genotypes of ESR1 and ESR2 were tested for Hardy–Weinberg equilibrium. The distribution of polymorphisms was tested with a {chi}2 test or Fisher's exact test. Odds ratios and a 95% confidence interval (95% CI) were calculated with logistic regression with adjustment for age. Statistical analyses were performed using SPSS software version 14.0 (SPSS Inc., Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Declaration of interest
 References
 
The coding sequence of the ESR2 gene was initially screened for polymorphisms in 96 patients (mean age at diagnosis: 67.9; range 45–86 years) and 96 controls (mean age: 69.2; range 59–86). Eleven polymorphisms were identified (Table 1), four in the coding region (one was already reported: rs1256049), two in introns (one already described: rs944050), and five in the 3'UTR (three already described: rs4986938, rs928554 and rs28440970). Three of the four polymorphisms located in exons modified the protein sequence: S112Stop, Del-N181 and R221G. When we compared the genotype or allele distribution between cases and controls, none of the polymorphisms showed significant association with PC risk (Table 1). Four of them (S112Stop, rs4986938, rs928554, and rs28440970) were further investigated in 290 patients (mean age at diagnosis: 69.2; range 45–98 years) and 290 controls (mean age: 69.8; range 48–92). Their genotype distributions were in agreement with Hardy–Weinberg equilibrium. Again, we noted an absence of association with PC risk (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1 Localization and distribution of ESR2 polymorphisms in prostate cancer cases and controls.

 
We identified three alleles for the GGGA repeat from the ESR1 gene corresponding to four, five, or six repeats; the five-repeat allele was the most frequent. The Hardy–Weinberg equilibrium was respected in the control population. Twenty-three PC cases, but only eight controls had a genotype other than 5/5. A significant association was then observed between the pooled genotypes 4/5, 5/6, and 6/6 and PC risk (OR=3.00, 95% CI=1.32–6.82, P=0.008; Table 2). When the alleles 4 and 6 were pooled, the association was also statistically significant (OR=3.65, 95% CI=1.73–7.72, P=0.001).


View this table:
[in this window]
[in a new window]

  		Table 2 Association between ESR1 and AR polymorphisms and prostate carcinoma risk.

 
The AR CAG repeats from cases ranged from 10 to 34 with a mean length of 21.9 repeats (S.D. 3.04, median=22). In controls, they ranged from 11 to 34 with a mean length of 22.1 repeats (S.D. 3.03, median=22). For the statistical analyses, study subjects were considered as having a short CAG repeat allele (less than 17) or a long allele (17 or more) as already performed in a previous study (16). No significant association was observed between this polymorphism and PC risk (P=0.085; Table 2).

To study the impact of these polymorphisms on PC aggressiveness, patients were stratified according to Gleason score and divided in four classes: 2–4, 5–6, 7, and 8–10. We found that the association between the pooled genotypes 4/5, 5/6, and 6/6 of ESR1 and PC was confined to patients with Gleason score of 2–4 (OR=8.34, 95% CI=2.91–23.91, P<0.0001; Table 3).


View this table:
[in this window]
[in a new window]

  		Table 3 Association between ESR1 and AR polymorphisms and risk of prostate cancer, stratified by Gleason score or by age at onset.

 
The age at onset of the PC cases was also divided in two classes: early onset if their cancer was diagnosed ≤64 years and late onset if it was diagnosed >64 years. The association between the ESR1 pooled genotypes (4/5, 5/6, and 6/6) or AR CAG repeat <17 alleles and PC risk was confined to cases with late onset: OR=2.91, 95% CI=1.22–6.93, P=0.016 and OR=2.34, 95% CI=1.15–4.76, P=0.019 respectively (Table 3).


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Declaration of interest
 References
 
By screening the coding sequence of the ESR2 gene, we identified eleven polymorphisms but did not find any association between those polymorphisms and PC risk. Our results agree with a previous study performed by Thellenberg–Karlsson et al. (18), which analyzed 28 SNPs spanning the entire ESR2 gene in 1415 PC cases and 801 controls. In this study, only one polymorphism (rs29877983) located in the promoter region was significantly associated with PC risk (OR=1.22, 95% CI=1.02–1.46) and with localized carcinomas (OR=1.33, 95% CI=1.08–1.64). Because our study focused on the ESR2 coding region, this part of the promoter was not analyzed. Together, these results are not in favor of a major role of the ESR2 gene in PC susceptibility. Among the identified exonic polymorphisms, the S112Stop, which leads to a truncated protein, was observed in one of the 288 PC cases and none of the 288 controls. This variant should thus be considered as an infrequent mutation.

We also did not find a significant association between the AR CAG repeat and the risk of PC, even when the cases were stratified according to Gleason score. This is in agreement with other studies including a multiethnic cohort study of 1014 cases (19) and another study of 460 cases (20), which did not observe any association between AR CAG repeats and PC risk. Indeed, results regarding the AR CAG repeat polymorphism and association with PC risk have been very contradictory as reviewed by Simard et al. (21). Several studies have found an association between short CAG repeats (≤20 or 22) and the risk of PC in Caucasian populations (22, 23) whereas others have reported a reduced risk of PC associated with short alleles (≤22) after an analysis of 1461 and 288 cases respectively (24, 25). Finally, a meta-analysis of 19 case-control studies comprising a total of 4274 cases and 5275 controls with 79% of Caucasians concluded that a modest association existed between the shorter repeats (≤21) and PC risk (OR=1.19, 95% CI=1.07–1.31) (26).

Nevertheless, when the cases were stratified according to age at onset, we observed a significant association between CAG repeats less than 17 and PC risk among patients with an age at diagnosis above 64 years (OR=2.34, 95% CI=1.15–4.76, P<0.019). By contrast, Hardy et al. (27) found a positive correlation between CAG repeats ≥23 with increased age at diagnosis. However, this divergent study only included 109 cases and the statistical analysis was based on correlations between length of CAG repeats and age at diagnosis. Finally, the association between the AR CAG repeat and PC risk seems to be limited. These contradictory results could be due to the heterogeneity of many factors such as the number of cases, the various ethnicities, the different gravity and age at diagnosis of cases, and the cut-point of CAG repeats.

In this study, we showed that rare alleles consisting of four or six GGGA repeats from the ESR1 gene were significantly associated with PC risk (OR=3.65, 95% CI=1.73–7.72, P<0.001). In a previous study including 300 cases and 300 controls, we reported that this ESR1 GGGA repeat polymorphism was significantly associated with PC risk (P=0.036) (15). Here, in a larger population, we confirmed this result and showed a stronger association among patients with Gleason score of 2–4 (OR=8.34, 95% CI=2.91–23.91, P<0.0001) or with an age at onset of the cancer above 64 years (OR=2.91, 95% CI=1.22–6.93, P=0.016). These results indicate that this ESR1 polymorphism could be a useful indicator of PC low gravity.

No other study has been performed on the ESR1 GGGA repeat polymorphism and until now, only a few studies of other ESR1 polymorphisms and PC risk have been undertaken. Two other polymorphisms: PvuII (rs2234693) and XbaI restriction sites (rs9340799), located in the first intron of the ESR1 gene were studied in different ethnic populations. Modugno et al. (28) analyzed these polymorphisms in a small population of 88 Caucasian patients and 241 controls and found no significant association with PC risk. However, when the ESR1 XbaI polymorphism was combined with the AR CAG repeat, they observed that individuals with a short AR repeat (<23) and ESR1XbaI–/– or ESR1XbaI–/+ had an increased PC risk. When we performed the same kind of analysis in our population, we also found a significant increased PC risk for individuals with a short AR (<17) and an ESR1 genotype 4/5, 5/6, or 6/6 (OR=2.57, 95% CI=1.11–5.95, P=0.028). No significant association was found between the PvuII polymorphism and PC risk in another study on non-Hispanic Caucasian and African-American men including 488 PC cases and 617 controls (29). These two ESR1 polymorphisms were also analyzed in three populations of 260 black, 1013 non-Hispanic white and 423 Hispanic white men (30). Only in black men, XbaI polymorphism was associated with PC risk (OR=2.25, 95% CI=1.07–4.70, P=0.031). The limited number of studies, the small size, and the different origins of the population do not allow firm conclusions to be made regarding the real implication of these two polymorphisms. The association between the GGGA repeat from ESR1 and PC risk seems to be the most significant. Further studies in other ethnic populations will be worthwhile to confirm our results.

Our results suggested that the role of the ESR2 gene in PC susceptibility is limited in Caucasian populations. We confirmed an association between the ESR1 GGGA repeat and PC risk. This polymorphism seemed to be associated with a favorable Gleason score (2–4) and a late onset PC, whereas the AR CAG repeat (<17) was only associated with a late onset PC.


   Declaration of interest
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
References
 
We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.


   Funding
 
This work was supported by the ANVAR.


   Acknowledgements
 
The authors thank the men who volunteered to participate in the PROGENE study.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 

    1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C & Thun MJ. Cancer statistics. CA: A Cancer Journal for Clinicians 2006; 56:106–130.[Abstract/Free Full Text]

    2. De Marzo AM, Nelson WG, Meeker AK & Coffey DS. Stem cell features of benign and malignant prostate epithelial cells. Journal of Urology 1998; 160:2381–2392.[CrossRef][Web of Science][Medline]

    3. Harkonen PL & Makela SI. Role of estrogens in development of prostate cancer. Journal of Steroid Biochemistry and Molecular Biology 2004; 92:297–305.[CrossRef][Web of Science][Medline]

    4. Ruizeveld De Winter JA, Janssen PJ, Sleddens HM, Verleun-Mooijman MC, Trapman J, Brinkmann AO, Santerse AB, Schroder FH & Van Der Kwast TH. Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. American Journal of Pathology 1994; 144:735–746.[Abstract]

    5. Bonkhoff H, Fixemer T, Hunsicker I & Remberger K. Estrogen receptor expression in prostate cancer and premalignant prostatic lesions. American Journal of Pathology 1999; 155:641–647.[Abstract/Free Full Text]

    6. Horvath LG, Henshall SM, Lee CS, Head DR, Quinn DI, Makela S, Delprado W, Golovsky D, Brenner PC, O'Neill G, Kooner R, Stricker PD, Grygiel JJ, Gustafsson JA & Sutherland RL. Frequent loss of estrogen receptor-beta expression in prostate cancer. Cancer Research 2001; 61:5331–5335.[Abstract/Free Full Text]

    7. Latil A, Bieche I, Vidaud D, Lidereau R, Berthon P, Cussenot O & Vidaud M. Evaluation of androgen, estrogen (ER {alpha} and ER β), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. Cancer Research 2001; 61:1919–1926.[Abstract/Free Full Text]

    8. Leav I, Lau KM, Adams JY, McNeal JE, Taplin ME, Wang J, Singh H & Ho SM. Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. American Journal of Pathology 2001; 159:79–92.[Abstract/Free Full Text]

    9. Santti R, Newbold RR, Makela S, Pylkkanen L & McLachlan JA. Developmental estrogenization and prostatic neoplasia. Prostate 1994; 24:67–78.[Web of Science][Medline]

    10. Prins GS, Birch L, Couse JF, Choi I, Katzenellenbogen B & Korach KS. Estrogen imprinting of the developing prostate gland is mediated through stromal estrogen receptor alpha: studies with alphaERKO and betaERKO mice. Cancer Research 2001; 61:6089–6097.[Abstract/Free Full Text]

    11. Weihua Z, Lathe R, Warner M & Gustafsson JA. An endocrine pathway in the prostate, ERβ, AR, 5{alpha}-androstane-3β,17β-diol, and CYP7B1, regulates prostate growth. PNAS 2002; 99:13589–13594.[Abstract/Free Full Text]

    12. Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P & Mark M. Effect of single and compound knockouts of estrogen receptors alpha (ER{alpha}) and beta (ERβ) on mouse reproductive phenotypes. Development 2000; 127:4277–4291.[Abstract]

    13. Cavalieri EL, Devanesan P, Bosland MC, Badawi AF & Rogan EG. Catechol estrogen metabolites and conjugates in different regions of the prostate of Noble rats treated with 4-hydroxyestradiol: implications for estrogen-induced initiation of prostate cancer. Carcinogenesis 2002; 23:329–333.[Abstract/Free Full Text]

    14. Bosland MC, Ford H & Horton L. Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague–Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol. Carcinogenesis 1995; 16:1311–1317.[Abstract/Free Full Text]

    15. Cancel-Tassin G, Latil A, Rousseau F, Mangin P, Bottius E, Escary JL, Berthon P & Cussenot O. Association study of polymorphisms in the human estrogen receptor alpha gene and prostate cancer risk. European Urology 2003; 44:487–490.[Web of Science][Medline]

    16. Hakimi JM, Schoenberg MP, Rondinelli RH, Piantadosi S & Barrack ER. Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clinical Cancer Research 1997; 3:1599–1608.[Abstract]

    17. Latil AG, Azzouzi R, Cancel GS, Guillaume EC, Cochan-Priollet B, Berthon PL & Cussenot O. Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Cancer 2001; 92:1130–1137.[CrossRef][Web of Science][Medline]

    18. Thellenberg-Karlsson C, Lindstrom S, Malmer B, Wiklund F, Augustsson-Balter K, Adami HO, Stattin P, Nilsson M, Dahlman-Wright K, Gustafsson JA & Gronberg H. Estrogen receptor beta polymorphism is associated with prostate cancer risk. Clinical Cancer Research 2006; 12:1936–1941.[Abstract/Free Full Text]

    19. Freedman ML, Pearce CL, Penney KL, Hirschhorn JN, Kolonel LN, Henderson BE & Altshuler D. Systematic evaluation of genetic variation at the androgen receptor locus and risk of prostate cancer in a multiethnic cohort study. American Journal of Human Genetics 2005; 76:82–90.[CrossRef][Web of Science][Medline]

    20. Platz EA, Leitzmann MF, Rifai N, Kantoff PW, Chen YC, Stampfer MJ, Willett WC & Giovannucci E. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiology, Biomarkers and Prevention 2005; 14:1262–1269.[Abstract/Free Full Text]

    21. Simard J, Dumont M, Labuda D, Sinnett D, Meloche C, El-Alfy M, Berger L, Lees E, Labrie F & Tavtigian SV. Prostate cancer susceptibility genes: lessons learned and challenges posed. Endocrine-Related Cancer 2003; 10:225–259.[Abstract]

    22. Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A, Talcott J, Hennekens CH & Kantoff PW. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. PNAS 1997; 94:3320–3323.[Abstract/Free Full Text]

    23. Andersson P, Varenhorst E & Soderkvist P. Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk. European Journal of Cancer 2006; 42:2833–2837.[Web of Science][Medline]

    24. Lindstrom S, Zheng SL, Wiklund F, Jonsson BA, Adami HO, Balter KA, Brookes AJ, Sun J, Chang BL, Liu W, Li G, Isaacs WB, Adolfsson J, Gronberg H & Xu J. Systematic replication study of reported genetic associations in prostate cancer: strong support for genetic variation in the androgen pathway. Prostate 2006; 66:1729–1743.[CrossRef][Web of Science][Medline]

    25. Forrest MS, Edwards SM, Houlston R, Kote-Jarai Z, Key T, Allen N, Knowles MA, Turner F, Ardern-Jones A, Murkin A, Williams S, Oram R, Bishop DT & Eeles RA. Association between hormonal genetic polymorphisms and early-onset prostate cancer. Prostate Cancer and Prostatic Diseases 2005; 8:95–102.[CrossRef][Web of Science][Medline]

    26. Zeegers MP, Kiemeney LA, Nieder AM & Ostrer H. How strong is the association between CAG and GGN repeat length polymorphisms in the androgen receptor gene and prostate cancer risk? Cancer Epidemiology, Biomarkers and Prevention 2004; 13:1765–1771.[Abstract/Free Full Text]

    27. Hardy DO, Scher HI, Bogenreider T, Sabbatini P, Zhang ZF, Nanus DM & Catterall JF. Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. Journal of Clinical Endocrinology and Metabolism 1996; 81:4400–4405.[Abstract]

    28. Modugno F, Weissfeld JL, Trump DL, Zmuda JM, Shea P, Cauley JA & Ferrell RE. Allelic variants of aromatase and the androgen and estrogen receptors: toward a multigenic model of prostate cancer risk. Clinical Cancer Research 2001; 7:3092–3096.[Abstract/Free Full Text]

    29. Berndt SI, Chatterjee N, Huang WY, Chanock SJ, Welch R, Crawford ED & Hayes RB. Variant in sex hormone-binding globulin gene and the risk of prostate cancer. Cancer Epidemiology, Biomarkers and Prevention 2007; 16:165–168.[Abstract/Free Full Text]

    30. Hernandez J, Balic I, Johnson-Pais TL, Higgins BA, Torkko KC, Thompson IM & Leach RJ. Association between an estrogen receptor alpha gene polymorphism and the risk of prostate cancer in black men. Journal of Urology 2006; 175:523–527.[CrossRef][Medline]

Received 29 August 2008
Accepted 30 September 2008





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
EJE-08-0321v1
160/1/101    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nicolaiew, N.
Right arrow Articles by Cussenot, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nicolaiew, N.
Right arrow Articles by Cussenot, O.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS