In vivo amplification of the androgen receptor gene and progression of human prostate cancer

Abstract

Overexpression of amplified genes is often associated with the acquisition of resistance to cancer therapeutic agents in vitro. We have identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer which involves amplification of the androgen receptor (AR) gene. Comparative genomic hybridization shows that amplification of the Xq11–q13 region (the location), is common in tumours recurring during androgen deprivation therapy. We found high–level AR amplification in seven of 23 (30%) recurrent tumours, but in none of the specimens taken from the same patients prior to therapy. Our results suggest that AR amplification emerges during androgen deprivation therapy by facilitating tumour cell growth in low androgen concentrations.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Boring, C.C., Squires, T.S. & Tong, T. Cancer Statistics, 1993 CA. Cancer J. Clin. 43, 7–26 (1993).

    CAS  Article  Google Scholar 

  2. 2

    Gittes, R.F. Carcinoma of the prostate. New Engl. J. Med. 324, 236–245 (1991).

    CAS  Article  Google Scholar 

  3. 3

    Stearn, M.E. & McGarvey, T. Biology of disease. Prostate cancer: therapeutics, diagnostic, and basic studies. Lab. Invest. 67, 540–552 (1992).

    Google Scholar 

  4. 4

    Berges, R.R., Furuya, Y., Remington, L., English, H.F., Jacks, T. .& Isaacs, J.T. Cell proliferation, DNA repair, and p53 function are not required for programmed death of prostatic glandular cells induced by androgen ablation. Proc. natn. Acad. Sci. U.S.A. 90, 8910–8914 (1993).

    CAS  Article  Google Scholar 

  5. 5

    Labrie, F., Belanger, A., Dupont, A., Luu-The, V., Simard, J. & Labrie, C. Science behind total androgen blockade: from gene to combination therapy. Clin. Invest. Med. 16, 475–492 (1993).

    CAS  PubMed  Google Scholar 

  6. 6

    Culig, Z. et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Molec. Endocrinol. 7, 1541–1550 (1993).

    CAS  Google Scholar 

  7. 7

    Schoenberg, M.P. et al. Microsatelllte mutation (CAG24–18) in the androgen receptor gene In human prostate cancer. Biochem. Biophys. Res. Comm. 198, 74–80 (1994).

    CAS  Article  Google Scholar 

  8. 8

    Veldscholte, J. et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem. Biophys. Res. Commun. 173, 534–540 (1990).

    CAS  Article  Google Scholar 

  9. 9

    Thompson, T.C. Growth factors and oncogenes in prostate cancer. Cancer Cells 2, 345–354 (1990).

    CAS  PubMed  Google Scholar 

  10. 10

    Kallioniemi, A. et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumours. Science 258, 818–821 (1992).

    CAS  Article  Google Scholar 

  11. 11

    Kallioniemi, O.-P. et al. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumours. Genes Chrom. Cancer 10, 231–243 (1994).

    CAS  Article  Google Scholar 

  12. 12

    Lafreniere, R.G. et al. Physical mapping of 60 DNA markers in the p21.1–21.3 region of the human X chromosome. Genomics 11, 352–363 (1991).

    CAS  Article  Google Scholar 

  13. 13

    Gaddipati, J.P., McLeod, D.G. & Heidenberg, H.B. Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. Cancer Res. 54, 2861–2864 (1994).

    CAS  PubMed  Google Scholar 

  14. 14

    Kellens, R.E. Gene amplificatlon in mammalian cells. A comprehensive guide. (Marcel Dekker, Inc., New York, 1993).

    Google Scholar 

  15. 15

    Nowell, P.C. Mechanisms of tumour progression. Cancer Res. 46, 2203–2207 (1986).

    CAS  PubMed  Google Scholar 

  16. 16

    Dennis, L. Role of maximal androgen blockade in advanced prostate cancer. Prostate (suppl) 5, 17–22 (1994).

    Article  Google Scholar 

  17. 17

    Crawford, E.D. et al. A controlled trial of leuprolide with and without flutamlde in prostatic carcinoma. New Engl. J. Med. 321, 419–424 (1989).

    CAS  Article  Google Scholar 

  18. 18

    Corvi, R., Amler, L.C., Savelyeva, L., Gehring, M. & Schwab, M. MYCN is retained in single copy at chromosome 2 band p23–p24 during amplification in human neuroblastoma cells. Proc. natn. Acad. Sci. U.S.A. 91, 5523–5527 (1994).

    CAS  Article  Google Scholar 

  19. 19

    Visakorpi, T. et al. Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. Cancer Res. 55, 342–347 (1995).

    CAS  PubMed  Google Scholar 

  20. 20

    Cher, M.L., MacGrogan, D., Bookstein, R., Brown, J.A., Jenkins, R.B. & Jensen, R. Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer. Genes Chrom. Cancer 11, 153–162 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Tanner, M. et al. Increased copy number at 20q13 in breast cancer: defining the minimal region and exclusion of candidate genes. Cancer Res. 54, 2457–2460 (1994).

    Google Scholar 

  22. 22

    Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Habor Laboratory Press, Cold Spring Harbor, (1989).

    Google Scholar 

  23. 23

    Hyytinen, E., Visakorpi, T., Kallioniemi, A., Kallioniemi, O.-P. & Isola, J. Improved technique for analysis of formalin-fixed paraffin-embedded tumours by fluorescence in situ hybridization. Cytometry 16, 93–99 (1994).

    CAS  Article  Google Scholar 

  24. 24

    Kallioniemi, O.P. et al. ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization. Proc. natn. Acad. Sci. U.S.A. 88, 5321–5325 (1992).

    Article  Google Scholar 

  25. 25

    Ihalainen, J., Siitari, H., Laine, S., Syvänen, A.C. & Palotie, A. Towards automatic detection of point mutations: use of scintillating microplates in solid-phase minisequencing. Biotechniques 16, 938–943 (1994).

    CAS  PubMed  Google Scholar 

  26. 26

    Dixon, W.J. BMDP Statistical Software (University of California Press, Los Angeles, 1981).

    Google Scholar 

  27. 27

    Sandberg, A.A. Chromosomal abnormalities and related events in prostate cancer. Hum. Pathol. 23, 368–380 (1992).

    CAS  Article  Google Scholar 

  28. 28

    Rinker-Schaeffer, C.W. et al. Differential suppression of mammary and prostate cancer metastasis by human chromosomes 17 and 11. Cancer Res. 54, 6249–6256 (1994).

    CAS  PubMed  Google Scholar 

  29. 29

    Isaacs, W.B., Bova, G.S., Morton, R.A., Bussemakers, M.J.G., Brooks, J.D. & Ewing, C.M. Molecular biology of prostate cancer. Semin. Oncol. 21, 514–521 (1994).

    CAS  PubMed  Google Scholar 

  30. 30

    Macoska, J.A., Micale, M.A., Sakr, W.A., Benson, P.D. & Wolman, S.R. Extensive genetic alterations in prostate cancer revealed by dual PCR and FISH analysis. Genes Chrom. Cancer 8, 88–97 (1993).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Visakorpi, T., Hyytinen, E., Koivisto, P. et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9, 401–406 (1995). https://doi.org/10.1038/ng0495-401

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing