Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues

Prostate Cancer and Prostatic Diseases volume 10, pages 360–368 (2007)Cite this article

Abstract

To investigate contraction of CAG repeats within the androgen receptor gene (AR) as shorter CAG repeats have been implicated as a possible risk factor in prostate cancer (PCa). AR CAG repeat lengths were analyzed in DNA from microdissected diseased prostates, leukocytes from matched peripheral blood, and control non-diseased prostates. Consistently, all prostatic tissues, whether from benign or cancerous areas of diseased prostates, or from control prostates, showed multiple AR CAG repeat contractions. Germline DNA from blood leukocytes had single CAG repeat lengths in the normal range. AR CAG repeat length contraction may be involved in prostate carcinogenesis and may precede the pathological process.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Gelmann EP . Molecular biology of the androgen receptor. J Clin Oncol 2002; 20: 3001–3015.

    Article  CAS  Google Scholar 

  2. Palmberg C, Koivisto P, Kakkola L, Tammela TL, Kallioniemi OP, Visakorpi T . Androgen receptor gene amplification at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer. J Urol 2000; 164: 1992–1995.

    Article  CAS  Google Scholar 

  3. Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM et al. Integrative molecular concept modeling of prostate cancer. Nat Genet 2007; 39: 41–51.

    Article  CAS  Google Scholar 

  4. Gottlieb B, Beitel LK, Wu J, Elhaji YA, Trifiro M . Nuclear receptors and disease: androgen receptor. Essays Biochem 2004; 40: 121–136.

    Article  CAS  Google Scholar 

  5. Mhatre AN, Trifiro MA, Kaufman M, Kazemi-Esfarjani P, Figlewicz D, Rouleau G et al. Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat Genet 1993; 5: 184–188.

    Article  CAS  Google Scholar 

  6. Beilin J, Ball EM, Favaloro JM, Zajac JD . Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: Specificity in prostate and non-prostate cell lines. J Mol Endocrinol 2000; 25: 85–96.

    Article  CAS  Google Scholar 

  7. Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 1997; 94: 3320–3323.

    Article  CAS  Google Scholar 

  8. Stanford JL, Just JJ, Gibbs M, Wicklund KG, Neal CL, Blumenstein BA et al. Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 1997; 57: 1194–1198.

    CAS  PubMed  Google Scholar 

  9. Hsing AW, Gao YT, Wu G, Wang X, Deng J, Chen YL et al. Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case–control study in China. Cancer Res 2000; 60: 5111–5116.

    CAS  PubMed  Google Scholar 

  10. Edwards A, Hammond HA, Jin L, Caskey CT, Chakraborty R . Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 1992; 12: 241–253.

    Article  CAS  Google Scholar 

  11. Irvine RA, Yu MC, Ross RK, Coetzee GA . The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 1995; 55: 1937–1940.

    CAS  PubMed  Google Scholar 

  12. Bratt O, Borg A, Kristoffersson U, Lundgren R, Zhang QX, Olsson H . CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk. Br J Cancer 1999; 81: 672–676.

    Article  CAS  Google Scholar 

  13. Shimbo M, Suzuki H, Kamiya N, Imamoto T, Komiya A, Ueda T et al. CAG polymorphic repeat length in androgen receptor gene combined with pretreatment serum testosterone level as prognostic factor in patients with metastatic prostate cancer. Eur Urol 2005; 47: 557–563.

    Article  CAS  Google Scholar 

  14. Suzuki H, Akakura K, Komiya A, Ueda T, Imamoto T, Furuya Y et al. CAG polymorphic repeat lengths in androgen receptor gene among Japanese prostate cancer patients. Potential predictor of prognosis after endocrine therapy. Prostate 2002; 51: 219–224.

    Article  CAS  Google Scholar 

  15. Lange EM, Chen H, Brierley K, Livermore H, Wojno KJ, Langefeld CD et al. The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer. Cancer Epidemiol Biomarkers Prev 2000; 9: 439–442.

    CAS  PubMed  Google Scholar 

  16. Epstein J . Neoplasms of the prostate. In: Bostwick DG, Eble JN (eds). Urologic Surgical Pathology. Mosby: New York, NY, 1997, pp 343–432.

    Google Scholar 

  17. Lexander H, Franzen B, Hirschberg D, Becker S, Hellstrom M, Bergman T et al. Differential protein expression in anatomical zones of the prostate. Proteomics 2005; 5: 2570–2576.

    Article  CAS  Google Scholar 

  18. Alvarado C, Beitel LK, Sircar K, Aprikian A, Trifiro M, Gottlieb B . Somatic mosaicism and cancer: a micro-genetic examination into the role of the androgen receptor gene in prostate cancer. Cancer Res 2005; 65: 8514–8518.

    Article  CAS  Google Scholar 

  19. Obiakor H, Sehgal D, Dasso JF . A comparison of hydraulic and laser capture microdissection methods for collection of single B cells, PCR, and sequencing of antibody VDJ. Anal Biochem 2002; 306: 55–62.

    Article  CAS  Google Scholar 

  20. Ito S, Obga T, Saeki H, Nakamura T, Watanabe M, Tanaka S et al. p53 mutation profiling of multiple esophageal carcinoma using laser capture microdissection to demonstrate field carcinogenesis. Int J Cancer 2005; 113: 22–28.

    Article  CAS  Google Scholar 

  21. Chen G, Shukeir N, Potti A, Sircar K, Aprikian A, Goltzman D et al. Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer 2004; 101: 1345–1356.

    Article  CAS  Google Scholar 

  22. Gottlieb B, Beitel LK, Wu JH, Trifiro M . The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 2004; 14: 103–114.

    Article  Google Scholar 

  23. Yeap BB, Wilce JA, Leedman PJ . The androgen receptor mRNA. BioEssays 2004; 26: 672–682.

    Article  CAS  Google Scholar 

  24. Choong CS, Kemppainen JA, Zhou ZX, Wilson EM . Reduced androgen receptor expression with first exon CAG repeat expansion. Mol Endocrinol 1996; 10: 1527–1535.

    CAS  PubMed  Google Scholar 

  25. Kim D, Gregory CW, Smith GJ, Mohler JL . Immunohistochemical quantitation of androgen receptor expression using color video image analysis. Cytometry 1999; 35: 2–10.

    Article  CAS  Google Scholar 

  26. Gaston KE, Ford III OH, Singh S, Gregory CW, Weyel DE, Smith GJ et al. A novel method for the analysis of the androgen receptor. Curr Urol Rep 2002; 3: 67–74.

    Article  Google Scholar 

  27. Nabi G, Seth A, Dinda AK, Gupta NP . Computer based receptogram approach: an objective way of assessing immunohistochemistry of androgen receptor staining and its correlation with hormonal response in metastatic carcinoma of prostate. Pathol 2004; 57: 146–150.

    CAS  Google Scholar 

  28. Mohler JL, Gregory CW, Ford III OH, Kim D, Weaver CM, Petrusz P et al. The androgen axis in recurrent prostate cancer. Clin Can Res 2004; 10: 440–448.

    Article  CAS  Google Scholar 

  29. Tayeb MT, Clark C, Murray GI, Sharp L, Haites NE, McLeod HL . Length and somatic mosaicism of CAG and GGN repeats in the androgen receptor gene and the risk of prostate cancer in men with benign prostatic hyperplasia. Ann Saudi Med 2004; 24: 21–26.

    Article  Google Scholar 

  30. Tsujimoto Y, Takakuwa T, Takayama H, Nishimura K, Okuyama A, Aozasa K et al. In situ shortening of CAG repeat length within the androgen receptor gene in prostatic cancer and its possible precursors. Prostate 2004; 58: 283–290.

    Article  CAS  Google Scholar 

  31. Azzouzi AR, Catto JW, Rehman I, Larre S, Roupret M, Feeley KM et al. Clinically localized prostate cancer is microsatellite stable. BJU Int 2007 (PMID: 17233803).

  32. Ferro P, Catalano MG, Raineri N, Reato G, dell'Eva R, Risio M et al. Somatic alterations of the androgen receptor CAG repeat in human colon cancer delineate a novel mutation pathway independent of microsatellite instability. Cancer Genet Cytogenet 200; 123: 35–40.

    Article  Google Scholar 

  33. Yeh S-H, Chiu C-M, Chen C-L, Lu S-F, Hsu H-C, Chen D-S . Somatic mutations at the trinucleotide repeats of the androgen receptor gene in male hepatocellular carcinoma. Int J Cancer 2007; 120: 1610–1617.

    Article  CAS  Google Scholar 

  34. Takeda H, Akakura K, Masai M, Akimoto S, Yatani R, Shimazaki J . Androgen receptor content of prostate carcinoma cells estimated by immunohistochemistry is related to prognosis of patients with stage D2 prostate carcinoma. Cancer 1996; 77: 934–940.

    Article  CAS  Google Scholar 

  35. Miyamoto KK, McSherry SA, Dent GA, Sar M, Wilson EM, French FS et al. Immunohistochemistry of the androgen receptor in human benign and malignant prostate tissue. J Urol 1993; 149: 1015–1019.

    Article  CAS  Google Scholar 

  36. Sweat SD, Pacelli A, Bergstralh EJ, Slezak JM, Bostwick DG . Androgen receptor expression in prostatic intraepithelial neoplasia and cancer. J Urol 1999; 161: 1229–1232.

    Article  CAS  Google Scholar 

  37. Li R, Wheeler T, Dai H, Frolov A, Thompson T, Ayala G . High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate: Cancer patients treated with radical prostatectomy. Am J Surg Pathol 2004; 28: 928–934.

    Article  Google Scholar 

  38. Ford III OH, Gregory CW, Kim D, Smitherman AB, Mohler JL . Androgen receptor gene amplification and protein expression in recurrent prostate cancer. J Urol 2003; 170: 1817–1821.

    Article  CAS  Google Scholar 

  39. Wang Q, Udayakumar TS, Vasaitis TS, Brodie AM, Fondell JD . Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells. J Biol Chem 2004; 279: 17319–17328.

    Article  CAS  Google Scholar 

  40. Shi XB, Ma AH, Xia L, Kung HJ, de Vere White RW . Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res 2002; 62: 1496–1501.

    CAS  PubMed  Google Scholar 

  41. Yu YP, Landsittel D, Jing L, Ren B, Liu L, McDonald C et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol 2004; 22: 2790–2799.

    Article  CAS  Google Scholar 

  42. Kovtun IV, Thornhill AR, Murray CT . Somatic deletion events occur during early embryonic development and modify the extent of CAG expansion in subsequent generations. Hum Mol Genet 2004; 13: 3057–3068.

    Article  CAS  Google Scholar 

  43. Lin Y, Dion V, Wilson JH . Transcription promotes contraction of CAG repeat tracts in human cells. Nat Struct Mol Biol 2006; 13: 179–180.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study has been supported by grants to Dr Mark Trifiro and Dr Bruce Gottlieb from the Canadian Institutes of Health Research and to Dr Mark Trifiro from the Prostate Cancer Research Foundation of Canada. This work was supported by Canadian Institutes for Health Research Grant # MOP-57869.

Author information

Authors and Affiliations

  1. Department of Pathology, McGill University Health Center, Montreal, Quebec, Canada

    K Sircar & M Alam-Fahmy

  2. Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada

    B Gottlieb, C Alvarado, L K Beitel & M Trifiro

  3. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

    B Gottlieb, L K Beitel & M Trifiro

  4. Department of Biology, John Abbott College, Montreal, Quebec, Canada

    B Gottlieb

  5. Department of Urology, McGill University, Montreal, Quebec, Canada

    A Aprikian

  6. Department of Medicine, McGill University, Montreal, Quebec, Canada

    L K Beitel & M Trifiro

  7. Department of Pathology, Hopital du Sacré-Loeur, Montreal, Quebec, Canada

    L Begin

Authors
  1. K Sircar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Gottlieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Alvarado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Aprikian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L K Beitel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Alam-Fahmy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Begin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Trifiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Gottlieb.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sircar, K., Gottlieb, B., Alvarado, C. et al. Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues. Prostate Cancer Prostatic Dis 10, 360–368 (2007). https://doi.org/10.1038/sj.pcan.4500967

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.pcan.4500967

Keywords

This article is cited by

Search

Advanced search

Quick links