Molecular portraits of human breast tumours (original) (raw)

Nature volume 406, pages 747–752 (2000)Cite this article

Abstract

Human breast tumours are diverse in their natural history and in their responsiveness to treatments1. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Tavassoli, F. A. & Schnitt, S. J. Pathology of the Breast (Elsevier, New York, 1992).
    Google Scholar
  2. Eisen, M. B. & Brown, P. O. DNA arrays for analysis of gene expression. Methods Enzymol. 303, 179– 205 (1999).
    Article CAS Google Scholar
  3. Ross, D. T. et al. Systematic variation in gene expression patterns in human cancer cell lines. Nature Genet. 24, 227 –235 (2000).
    Article CAS Google Scholar
  4. Aas, T. et al. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nature Med. 2, 811–814 (1996).
    Article CAS Google Scholar
  5. Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863– 14868 (1998).
    Article ADS CAS Google Scholar
  6. Perou, C. M. et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc. Natl Acad. Sci. USA 96, 9212–9217 (1999).
    Article ADS CAS Google Scholar
  7. Yang, G. P., Ross, D. T., Kuang, W. W., Brown, P. O. & Weigel, R. J. Combining SSH and cDNA microarrays for rapid identification of differentially expressed genes. Nucleic Acids Res. 27, 1517–1523 (1999).
    Article CAS Google Scholar
  8. Hoch, R. V., Thompson, D. A., Baker, R. J. & Weigel, R. J. GATA-3 is expressed in association with estrogen receptor in breast cancer. Int. J. Cancer 84, 122– 128 (1999).
    Article CAS Google Scholar
  9. Pauletti, G., Godolphin, W., Press, M. F. & Slamon, D. J. Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene 13, 63–72 ( 1996).
    CAS PubMed Google Scholar
  10. Pollack, J. R. et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nature Genet. 23, 41– 46 (1999).
    Article CAS Google Scholar
  11. Ronnov-Jessen, L., Petersen, O. W. & Bissell, M. J. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol. Rev. 76, 69–125 ( 1996).
    Article CAS Google Scholar
  12. Taylor-Papadimitriou, J. et al. Keratin expression in human mammary epithelial cells cultured from normal and malignant tissue: relation to in vivo phenotypes and influence of medium. J. Cell Sci. 94, 403– 413 (1989).
    Article Google Scholar
  13. Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286 , 531–537 (1999).
    Article CAS Google Scholar
  14. Dairkee, S. H., Mayall, B. H., Smith, H. S. & Hackett, A. J. Monoclonal marker that predicts early recurrence of breast cancer. Lancet 1, 514 (1987).
    Article CAS Google Scholar
  15. Dairkee, S. H., Puett, L. & Hackett, A. J. Expression of basal and luminal epithelium-specific keratins in normal, benign, and malignant breast tissue. J. Natl Cancer Inst. 80, 691–695 (1988).
    Article CAS Google Scholar
  16. Malzahn, K., Mitze, M., Thoenes, M. & Moll, R. Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas. Virchows Arch. 433, 119 –129 (1998).
    Article CAS Google Scholar
  17. Guelstein, V. I. et al. Monoclonal antibody mapping of keratins 8 and 17 and of vimentin in normal human mammary gland, benign tumors, dysplasias and breast cancer. Int. J. Cancer 42, 147– 153 (1988).
    Article CAS Google Scholar
  18. Gusterson, B. A. et al. Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases. Cancer Res. 42, 4763–4770 (1982).
    CAS PubMed Google Scholar
  19. Nagle, R. B. et al. Characterization of breast carcinomas by two monoclonal antibodies distinguishing myoepithelial from luminal epithelial cells. J. Histochem. Cytochem. 34, 869–881 (1986).
    Article CAS Google Scholar
  20. Berns, E. M. et al. Prevalence of amplification of the oncogenes c-myc, HER2/neu, and int-2 in one thousand human breast tumors: correlation with steroid receptors. Eur. J. Cancer 28, 697– 700 (1992).
    Article CAS Google Scholar
  21. Heintz, N. H., Leslie, K. O., Rogers, L. A. & Howard, P. L. Amplification of the c-erb B-2 oncogene and prognosis of breast adenocarcinoma. Arch. Pathol. Lab. Med. 114, 160– 163 (1990).
    CAS PubMed Google Scholar
  22. DeRisi, J. L., Iyer, V. R. & Brown, P. O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278, 680–686 (1997).
    Article ADS CAS Google Scholar
  23. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

Download references

Acknowledgements

We thank W. Gerald and L. Norton for the three New York tumour specimens; M. Stampfer and P. Yaswen for the 184 sample mRNAs; and members of the P. O. Brown, D. Botstein and A.-L. Børresen-Dale labs for discussions. We are grateful to the NCI and the Howard Hughes Medical Institute who provided support for this research. C.M.P. is a SmithKline Beecham Pharmaceuticals Fellow of the Life Sciences Research Foundation. T.S. is a research fellow of the Norwegian Cancer Society. M.B.E. is an Alfred P. Sloan Foundation Postdoctoral Fellow in Computational Molecular Biology. D.T.R. is a Walter and Idun Berry Fellow. P.O.B. is an Associate Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Charles M. Perou, Therese Sørlie and Patrick O. Brown: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Genetics, Stanford University School of Medicine, Stanford, 94305, California, USA
    Charles M. Perou, Michael B. Eisen, Christian A. Rees, Alexander Pergamenschikov, Cheryl Williams & David Botstein
  2. Department of Genetics, The Norwegian Radium Hospital, Montebello Oslo, N-0310, Norway
    Therese Sørlie, Hilde Johnsen & Anne-Lise Børresen-Dale
  3. Department of Pathology, Stanford University School of Medicine, Stanford, 94305, USA, California
    Matt van de Rijn & Shirley X. Zhu
  4. Department of Surgery, Stanford University School of Medicine, Stanford, 94305 , California, USA
    Stefanie S. Jeffrey
  5. Department of Biochemistry, Stanford University School of Medicine, Stanford, 94305, California, USA
    Jonathan R. Pollack, Douglas T. Ross & Patrick O. Brown
  6. Department of Pathology, The Gade Institute Haukeland University Hospital, Bergen, N-5021, Norway
    Lars A. Akslen
  7. Department of Molecular Biology, University of Bergen, Bergen, N-5020, Norway
    Øystein Fluge
  8. Department of Oncology, Haukeland University Hospital, Bergen, N-5021, Norway
    Per E. Lønning
  9. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, 94305, California , USA
    Patrick O. Brown

Authors

  1. Charles M. Perou
    You can also search for this author inPubMed Google Scholar
  2. Therese Sørlie
    You can also search for this author inPubMed Google Scholar
  3. Michael B. Eisen
    You can also search for this author inPubMed Google Scholar
  4. Matt van de Rijn
    You can also search for this author inPubMed Google Scholar
  5. Stefanie S. Jeffrey
    You can also search for this author inPubMed Google Scholar
  6. Christian A. Rees
    You can also search for this author inPubMed Google Scholar
  7. Jonathan R. Pollack
    You can also search for this author inPubMed Google Scholar
  8. Douglas T. Ross
    You can also search for this author inPubMed Google Scholar
  9. Hilde Johnsen
    You can also search for this author inPubMed Google Scholar
  10. Lars A. Akslen
    You can also search for this author inPubMed Google Scholar
  11. Øystein Fluge
    You can also search for this author inPubMed Google Scholar
  12. Alexander Pergamenschikov
    You can also search for this author inPubMed Google Scholar
  13. Cheryl Williams
    You can also search for this author inPubMed Google Scholar
  14. Shirley X. Zhu
    You can also search for this author inPubMed Google Scholar
  15. Per E. Lønning
    You can also search for this author inPubMed Google Scholar
  16. Anne-Lise Børresen-Dale
    You can also search for this author inPubMed Google Scholar
  17. Patrick O. Brown
    You can also search for this author inPubMed Google Scholar
  18. David Botstein
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toDavid Botstein.

Supplementary information

Rights and permissions

About this article

Cite this article

Perou, C., Sørlie, T., Eisen, M. et al. Molecular portraits of human breast tumours.Nature 406, 747–752 (2000). https://doi.org/10.1038/35021093

Download citation

This article is cited by