Advertisement

Breast Cancer Research and Treatment

, Volume 88, Issue 3, pp 239–246 | Cite as

Increased frequency of long androgen receptor CAG repeats in male breast cancers

  • Helen E. Maclean
  • Robert W. Brown
  • Jonathan Beilin
  • Garry L. Warne
  • Jeffrey D. Zajac
Report

Abstract

We have investigated the possible link between androgen hyposensitivity caused by long androgen receptor (AR) CAG repeats, and breast carcinogenesis, in men. AR gene mutations have been described in men with androgen insensitivity syndrome and breast carcinoma, and some studies have shown long CAG repeats are associated with increased risk of breast cancer in women. DNA was isolated from male breast cancer biopsies, and the AR CAG repeat sized. Forty one male breast cancer samples were studied, including one sample from a man with spinal and bulbar muscular atrophy (SBMA), which is caused by an AR CAG repeat expansion. The man with breast cancer and SBMA had 49 CAG repeats (normal range 6–35), but all other breast cancer samples had repeats within the normal range. The frequency of CAG repeats ≥24 was significantly higher in the breast cancer group (excluding the SBMA subject) than in the normal population (p<0.05), and was more marked in grade I and II tumors (p=0.001). There was no correlation between AR CAG repeat length and age at diagnosis. In conclusion, longer AR CAG repeats are more common in men with breast cancer than in the control male population. Androgen hyposensitivity, caused by long AR CAG repeats, may increase the risk of breast cancer in men.

Keywords

androgen receptor breast cancer CAG repeat male breast cancer polymorphism spinal and bulbar muscular atrophy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Sasco, AJ, Lowenfels, AB, Pasker-de Jong, P 1993Review article: epidemiology of male breast cancer. A meta-analysis of published case–control studies and discussion of selected aetiological factors.Int J Cancer53538549Google Scholar
  2. Haraldsson, K, Loman, N, Zhang, QX, Johannsson, O, Olsson, H, Borg, A 1998BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the diseaseCancer Res5813671371Google Scholar
  3. G, Jenster, Korput, HA, Trapman, J, Brinkmann, AO 1995Identification of two transcription activation units in the N-terminal domain of the human androgen receptorJ Biol Chem27073417346Google Scholar
  4. Beilin, J, Harewood, L, Frydenberg, M, Mameghan, H, Martyres, RF, Farish, SJ, Yue, C, Deam, DR, Byron, KA, Zajac, JD 2001A case–control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjectsCancer92941949Google Scholar
  5. La Spada, AR, Wilson, EM, Lubahn, DB, Harding, AE, Harding, KH 1991Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophyNature3527779Google Scholar
  6. MacLean, HE, Choi, WT, Rekaris, G, Warne, GL, Zajac, JD 1995Abnormal androgen receptor binding affinity in subjects with Kennedy’s disease (spinal and bulbar muscular atrophy)J Clin Endocrinol Metab80508516Google Scholar
  7. Mhatre, AN, Trifiro, MA, Kaufman, M, Kazemi-Esfarjani, P, Figlewicz, D, Rouleau, G, Pinsky, L 1993Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophyNat Genet5184188Google Scholar
  8. Beilin, J, Ball, EM, Favaloro, JM, Zajac, JD 2000Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell linesJ Mol Endocrinol258596Google Scholar
  9. Szelei, J, Jimenez, J, Soto, AM, Luizzi, MF, Sonnenschein, C 1997Androgen-induced inhibition of proliferation in human breast cancer MCF7 cells transfected with androgen receptorEndocrinology13814061412Google Scholar
  10. Ortmann, J, Prifti, S, Bohlmann, MK, Rehberger-Schneider, S, Strowitzki, T, Rabe, T 2002Testosterone and 5 alpha-dihydrotestosterone inhibit in vitro growth of human breast cancer cell linesGynecol Endocrinol16113120Google Scholar
  11. Bryan, RM, Mercer, RJ, Bennett, RC, Rennie, GC, Lie, TH, Morgan, FJ 1984Androgen receptors in breast cancerCancer5424362440Google Scholar
  12. Wooster, R, Mangion, J, Eeles, R, Smith, S, Dowsett, M, Averill, D, Barrett-Lee, P, Easton, DF, Ponder, BA, Stratton, MR 1992A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndromeNat Genet2132134Google Scholar
  13. Lobaccaro, JM, Lumbroso, S, Belon, C, Galtier-Dereure, F, Bringer, J, Lesimple, T, Namer, M, Cutuli, BF, Pujol, H, Sultan, C 1993Androgen receptor gene mutation in male breast cancerHum Mol Genet217991802Google Scholar
  14. Zhu, X, Daffada, AA, Chan, CM, Dowsett, M 1997Identification of an exon 3 deletion splice variant androgen receptor mRNA in human breast cancerInt J Cancer72574580Google Scholar
  15. Nelson, KA, Witte, JS 2002Androgen receptor CAG repeats and prostate cancerAm J Epidemiol155883890Google Scholar
  16. Rebbeck, TR, Kantoff, PW, Krithivas, K, Neuhausen, S, Blackwood, MA, Godwin, AK, Daly, MB, Narod, SA, Garber, JE, Lynch, HT, Weber, BL, Brown, M 1999Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeatAm J Hum Genet6413711377Google Scholar
  17. Haiman, CA, Brown, M, Hankinson, SE, Spiegelman, D, Colditz, GA, Willett, WC, Kantoff, PW, Hunter, DJ 2002The androgen receptor CAG repeat polymorphism and risk of breast cancer in the Nurses’ Health StudyCancer Res6210451049Google Scholar
  18. Elhaji, YA, Gottlieb, B, Lumbroso, R, Beitel, LK, Foulkes, WD, Pinsky, L, Trifiro, MA 2001The polymorphic CAG repeat of the androgen receptor gene: a potential role in breast cancer in women over 40Breast Cancer Res Treat70109116Google Scholar
  19. Giguere, Y, Dewailly, E, Brisson, J, Ayotte, P, Laflamme, N, Demers, A, Forest, VI, Dodin, S, Robert, J, Rousseau, F 2001Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general populationCancer Res6158695874Google Scholar
  20. Yu, H, Bharaj, B, Vassilikos, EJ, Giai, M, Diamandis, EP 2000Shorter CAG repeat length in the androgen receptor gene is associated with more aggressive forms of breast cancerBreast Cancer Res Treat59153161Google Scholar
  21. Spurdle, AB, Dite, GS, Chen, X, Mayne, CJ, Southey, MC, Batten, LE, Chy, H, Trute, L, McCredie, MR, Giles, GG, Armes, J, Venter, DJ, Hopper, JL, Chenevix-Trench, G 1999Androgen receptor exon 1 CAG repeat length and breast cancer in women before age forty yearsJ Natl Cancer Inst91961966Google Scholar
  22. Kadouri, L, Easton, DF, Edwards, S, Hubert, A, Kote-Jarai, Z, Glaser, B, Durocher, F, Abeliovich, D, Peretz, T, Eeles, RA 2001CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriersBr J Cancer853640Google Scholar
  23. Menin, C, Banna, GL, Salvo, G, Lazzarotto, V, Nicolo, A, Agata, S, Montagna, M, Sordi, G, Nicoletto, O, Chieco-Bianchi, L, D’Andrea, E 2001Lack of association between androgen receptor CAG polymorphism and familial breast/ovarian cancerCancer Lett1683136Google Scholar
  24. Given, HF, Radbourne, R, Oag, H, Merritt, S, Barclay, E, Hanby, AM, Lamlum, H, McGrath, J, Curran, C, Tomlinson, IP 2000The androgen receptor exon 1 trinucleotide repeat does not act as a modifier of the age of presentation in breast cancerEur J Cancer36533534Google Scholar
  25. Dagan, E, Friedman, E, Paperna, T, Carmi, N, Gershoni-Baruch, R 2002Androgen receptor CAG repeat length in Jewish Israeli women who are BRCA1/2 mutation carriers: association with breast/ovarian cancer phenotypeEur J Hum Genet10724728Google Scholar
  26. Elston, CW, Ellis, IO 1991Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-upHistopathology19403410Google Scholar
  27. Wright, DK, Manos, MM 1990Sample preparation from paraffin-embedded tissuesInnis, MAGelfand, DHSninsky, JJWhite, TJ eds. PCR Protocols: a Guide to Methods and ApplicationsAcademic Press, Inc.,San Diego153158Google Scholar
  28. Thomas, DB, Jimenez, LM, McTiernan, A, Rosenblatt, K, Stalsberg, H, Stemhagen, A, Stemhagen, WD, Curnen, MG, Satariano, W, Austin, DF,  et al. 1992Breast cancer in men: risk factors with hormonal implicationsAm J Epidemiol135734748Google Scholar
  29. Dejager, S, Bry-Gauillard, H, Bruckert, E, Eymard, B, Salachas, F, LeGuern, E, Tardieu, S, Chadarevian, R, Giral, P, Turpin, G 2002A comprehensive endocrine description of Kennedy’s disease revealing androgen insensitivity linked to CAG repeat lengthJ Clin Endocrinol Metab8738933901Google Scholar
  30. Poujol, N, Lobaccaro, JM, Chiche, L, Lumbroso, S, Sultan, C 1997Functional and structural analysis of R607Q and R608K androgen receptor substitutions associated with male breast cancerMol Cell Endocrinol1304351Google Scholar
  31. Davis, SE, Wallace, AM 2001A 19 year old with complete androgen insensitivity syndrome and juvenile fibroadenoma of the breastBreast J7430433Google Scholar
  32. Young, IE, Kurian, KM, Mackenzie, MA, Kunkler, IH, Cohen, BB, Hooper, ML, Wyllie, AH, Steel, CM 2000The CAG repeat within the androgen receptor gene in male breast cancer patientsJ Med Genet37139140Google Scholar
  33. Syrjakoski, K, Hyytinen, ER, Kuukasjarvi, T, Auvinen, A, Kallioniemi, OP, Kainu, T, Koivisto, PA 2003Androgen receptor gene alterations in Finnish male breast cancerBreast Cancer Res Treat77167170Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Helen E. Maclean
    • 1
  • Robert W. Brown
    • 2
  • Jonathan Beilin
    • 3
  • Garry L. Warne
    • 4
  • Jeffrey D. Zajac
    • 1
  1. 1.Department of MedicineUniversity of Melbourne, Austin HospitalHeidelbergAustralia
  2. 2.Melbourne PathologyCollingwood
  3. 3.Department of Medicine University of Melbourne, Royal Melbourne HospitalParkville
  4. 4.Murdoch Children’s Research InstituteRoyal Children’s HospitalParkville

Personalised recommendations