Breast Cancer Research and Treatment

, Volume 61, Issue 2, pp 111–119

Breast cancer prognostic significance of a single nucleotide polymorphism in the proximal androgen response element of the prostate specific antigen gene promoter

  • Bhupinder Bharaj
  • Andreas Scorilas
  • Eleftherios P. Diamandis
  • Maurizia Giai
  • Michael A. Levesque
  • Donald J.A. Sutherland
  • Barry R. Hoffman


Prostate Specific Antigen (PSA) expression by breast epithelial cells is associated with favorable breast cancer prognosis. In preliminary studies, we found that a nucleotide variation (G → A) at position −158 in the androgen response element (ARE-1) of the PSA promoter was present in four out of 9 breast tumors examined and in a breast carcinoma cell line. We have now determined the nucleotide composition at position −158 of DNA extracted from 148 well-characterized breast tumors and compared tumor genotype with that of controls without cancer, with tumor PSA concentration and with clinicopathological variables, overall survival and disease free survival. The G → A base change at position −158 is a polymorphism. Allelotypes were similarly distributed in breast cancer patients and controls. The Mann–Whitney U Test showed a significantly higher tumor PSA concentration in tumors that presented a homozygous G as opposed to homozygous A genotype. Genotype at position −158 was not associated with clinicopathological variables in contingency table analysis. Univariate Cox regression models showed a 28% reduction in risk for death in patients with homozygous G genotype compared to those with homozygous A genotype (P=0.03). However, ARE-I genotype did not significantly add to the prognostic power in the multivariate model of overall survival. In summary, the base change at position −158 is a polymorphism that may affect breast cancer prognosis, but further studies are required to confirm this possibility and to investigate the relevance of this polymorphism in terms of breast cancer susceptibility.

androgen receptor breast cancer mutation polymorphism prognosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Helzlsouer KJ, Couzi R: Hormones and breast cancer [Review]. Cancer 76(10): 2059–2063, 1995Google Scholar
  2. 2.
    Levesque MA, Yu H, D'Costa M, Diamandis EP: Prostate specific antigen expression by various tumors. J Clin Lab Anal 9: 123–128, 1995Google Scholar
  3. 3.
    Smith MR, Biggar S, Hussain M: Prostate specific antigen mRNA is expressed in non prostatic cells; implications for detection of micrometastases. Cancer Res 55: 2640–2644, 1995Google Scholar
  4. 4.
    Lee C, Keefer M, Zhao ZW, Krose R, Berg L, Liu XX, Sensibar J: Demonstration of the role of prostate-specific antigen in semen liquefaction by two-dimensional electrophoresis. J Androl 10: 432–438, 1989Google Scholar
  5. 5.
    Catalona WJ, Smith DS, Ratcliff TL, Dodds KM, Copelan DE, Yuan JJ, Petios JA, Andriole GL: Measurement of prostate specific antigen in serum as a screening test for prostate cancer. N Eng J Med 324: 1156–1161, 1991Google Scholar
  6. 6.
    Oesterling JE: Prostate specific antigen, a critical assessment of the most useful marker for adenocarcinoma of the prostate [Review]. J Urol 145: 907–923, 1991Google Scholar
  7. 7.
    Yu H, Diamandis EP, Levesque M, Giai M, Roagna R, Ponzone R, Sismondi P, Monne M, Croce CM: Prostate specific antigen in breast cancer, benign breast disease and normal breast tissue. Breast Cancer Res Treat 40: 171–178, 1996Google Scholar
  8. 8.
    Diamandis EP, Yu H, Sutherland DJ: Detection of prostatespecific antigen immunoreactivity in breast tumors. Breast Cancer Res Treat 32: 301–310, 1994Google Scholar
  9. 9.
    Yu H, Giai M, Diamandis EP, Katsaros D, Sutherland DJA, Levesque MA, Roagna R, Ponzone R, Sismondi P: Prostate specific antigen is a new favorable prognostic indicator for women with breast cancer. Cancer Res 55: 2104–2110, 1995Google Scholar
  10. 10.
    Yu H, Levesque MA, Clark GM, Diamandis EP: Prognostic value of prostate-specific antigen for women with breast cancer: a large United States cohort study. Clin Cancer Res 4: 1489–1497, 1998Google Scholar
  11. 11.
    Sauter ER, Daly M, Lenahan K, Ehya H, Engstrom PF, Bonney G, Ross EA, Yu H, Diamandis E: Prostate specific antigen levels in nipple aspirate fluid correlate with breast cancer. Cancer Epidemiol Biomarkers Prev 5: 967–970, 1996Google Scholar
  12. 12.
    Young CYF, Montgomery BT, Andrews PE, Qui SD, Bilhartz DL, Tindall DJ: Hormonal regulation of prostate specific antigen messenger RNA in human prostate adenocarcinoma cell line LNCaP. Cancer Res 51: 3748–3752, 1991Google Scholar
  13. 13.
    Riegman PHJ, Vlietstra RJ, van der Korput JAGM, Brinkman AO, Trapman J: The promoter of the prostate specific antigen contains a functional androgen responsive element. Mol Endocrinol 5: 1921–1930, 1991Google Scholar
  14. 14.
    Zarghami N, Grass L, Diamandis EP. Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer. Br J Cancer 75: 579–588, 1997Google Scholar
  15. 15.
    Cleutjens KBJM, van Eekelen CCEM, van der Korput HAGM, Brinkmann AO, Trapman J: Two androgen response regions cooperate in steroid hormone regulated activity of the prostatespecific antigen promoter. J Biol Chem 271: 6379–6388, 1996Google Scholar
  16. 16.
    Cleutjens KBJM, van der Korput HAGM, van Eekelen CCCM, van Riooji HCJ, Faber PW, Trapman J: An androgen responsive element in a far upstream enhancer region is essential for high androgen-regulated activity of the prostate specific antigen promoters. Mol Endocrinol 11: 148–1461, 1997Google Scholar
  17. 17.
    Pang S, Taneja S, Dardashti K, Cohan P, Kaboo R, Sokoloff M, Tso CL, DeKernion JB, Belldegrun AS: Prostate tissue specificity of prostate-specific antigen promoter isolated from a patient with prostate cancer. Human Gene Therapy 6: 1417–1426, 1995Google Scholar
  18. 18.
    Lundwall A: Characterization of the gene for prostate-specific antigen, a human glandular kallikrein. Biochem Biophys Res Commun 161: 1151–1159, 1989Google Scholar
  19. 19.
    Klobeck HG, Combriato G, Schultz P, Arbusow V, Fittler F: Genomic sequence of human prostate specific antigen (PSA). Nucleic Acids Res 17: 3981, 1987Google Scholar
  20. 20.
    Majumdar S, Diamandis EP: The promoter of the enhancer region of the KLK 3 (prostate specific antigen) gene is frequently mutated in breast tumors and breast carcinoma cell lines. Br J Cancer 79: 1594–1602, 1999Google Scholar
  21. 21.
    Spiessl B, Beahrs OH, Hermanek P, Hutter RVP, Scheibe O, Sobin LH, Wagner G: Illustrated guide to the TNM/pTNM classification of malignant tumors. TNM atlas, 3rd edn Springer-Verlag, Berlin, New York, 1989, p. 343Google Scholar
  22. 22.
    Bloom HJG, Richardson WW: Histological grading and prognosis in breast cancer. Br J Cancer 11: 359–377, 1957Google Scholar
  23. 23.
    Schuur ER, Henderson GA, Kmetec LA, Miller JD, Lamparski HG, Henderson DR: Prostate-specific antigen expression is regulated by an upstream enhancer. J Biol Chem 271: 7043–7051, 1996Google Scholar
  24. 24.
    Bharaj BS, Angelopoulou K, Diamandis EP: Rapid sequencing of the p53 gene with a new automated sequencer. Clin Chem 44: 1397–1403, 1998Google Scholar
  25. 25.
    Dressler LG, Seamer LC, Owens MA, Clark GM, McGuire WL: DNA flow cytometry and prognostic factors in 1131 frozen breast cancer specimens. Cancer 61: 420–427, 1988Google Scholar
  26. 26.
    Scatchard G: The attraction of proteins for small molecules and ions. Ann NY Acad Sci 51: 660–672, 1949Google Scholar
  27. 27.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with folin- phenol reagent. J Biol Chem 193: 265–275, 1951Google Scholar
  28. 28.
    Alexiera-Figusch J, van Putten WLS, Blankestein MA, Blonk-Van Der wijst J, Klijn JGM: The prognostic value and relationships of patient characteristics, estrogen and progestin receptors and site of relapse in primary breast cancer. Cancer 61: 758–768, 1988Google Scholar
  29. 29.
    Reiher A, Kolb R, Reiner G, Jakesz R, Schemper M, Spona J: Prognostic significance of steroid hormone receptor and histopathological characterization of human breast cancer. J Cancer Res Clin Oncol 113: 285–290, 1987Google Scholar
  30. 30.
    Ferguson RA, Yu H, Kalyvas M, Zammit S, Diamandis EP: Ultrasensitive detection of prostate specific antigen by a new time-resolved immunofluorometric assay and the Immulite immunochemiluminescent third generation assay: potential applications in prostate and breast cancers. Clin Chem 42: 675–684, 1996Google Scholar
  31. 31.
    Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958Google Scholar
  32. 32.
    Cox DR: Regression models and life tables. R Stat Soc B 34: 187–202, 1972Google Scholar
  33. 33.
    Tsuyuki D, Grass L, Diamandis EP: Frequent detection of mutations in the 5'flanking region of the prostate-specific antigen gene in female breast cancer. Eur J Cancer 33: 1853–1856, 1997Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Bhupinder Bharaj
    • 1
    • 2
  • Andreas Scorilas
    • 1
    • 2
  • Eleftherios P. Diamandis
    • 1
    • 2
  • Maurizia Giai
    • 3
  • Michael A. Levesque
    • 1
    • 2
  • Donald J.A. Sutherland
    • 4
    • 5
  • Barry R. Hoffman
    • 1
    • 2
  1. 1.Department of Pathology and Laboratory MedicineMount Sinai HospitalTorontoCanada
  2. 2.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  3. 3.Department of Gynecologic Oncology, Institute of Obstetrics and GynecologyUniversity of TurinTurinItaly
  4. 4.Toronto-Sunnybrook Regional Cancer CentreSunnybrook and Women's College Health Sciences CentreTorontoCanada
  5. 5.Department of MedicineUniversity of TorontoTorontoCanada

Personalised recommendations