uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues

  1. Songdong Menga,
  2. Debu Tripathyb,
  3. Sanjay Shetec,
  4. Raheela Ashfaqd,
  5. Hossein Sabooriand,
  6. Barbara Haleyb,
  7. Eugene Frenkelb,
  8. David Euhuse,
  9. Marilyn Leitche,
  10. Cynthia Osbornef,
  11. Edward Cliffordg,
  12. Steve Perkinsh,
  13. Peter Beitschi,
  14. Amanullah Khanh,
  15. Larry Morrisonj,
  16. Dorothee Herlynk,
  17. Leon W. M. M. Terstappenl,
  18. Nancy Lanea,
  19. Jianqiang Wanga, and
  20. Jonathan Uhra,m
  1. aCancer Immunobiology Center,
  2. Departments of bInternal Medicine,
  3. dPathology, and
  4. eSurgery, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390;
  5. cDepartment of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
  6. fTexas Oncology Group, Dallas TX 75246;
  7. gSurgical Associates of Irving–Coppell, Irving, TX 75061;
  8. hSt. Paul University Hospital, Dallas, TX 75235;
  9. iDallas Surgical Group, Dallas, TX 75246;
  10. jAbbott Molecular, Inc., DesPlaines, IL 60018;
  11. kWistar Institute, Philadelphia, PA 19104; and
  12. lImmunicon Corporation, Huntingdon, PA 19006

  1. Contributed by Jonathan Uhr, September 18, 2006

Abstract

Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.

Footnotes

  • mTo whom correspondence should be addressed. E-mail: jonathan.uhr{at}utsouthwestern.edu

  • Author contributions: S.M., R.A., H.S., L.M., D.H., J.W., and J.U. performed research; D.T., B.H., E.F., D.E., M.L., C.O., E.C., and J.U. designed research; S.S., S.P., P.B., L.W.M.M.T., and J.U. analyzed data; and A.K., N.L., and J.U. wrote the paper.

  • Conflict of interest statement: J.U. holds stock in Immunicon Corporation.

  • See Commentary on page 17073.

  • Abbreviations:
    uPA,
    urokinase plasminogen activator;
    uPAR,
    uPA receptor;
    TC,
    tumor cell;
    CTC,
    circulating TC;
    IF,
    immunofluorescence;
    CI,
    confidence interval;
    TP,
    touch prep.
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  1. Published online before print November 1, 2006, doi: 10.1073/pnas.0608113103 PNAS November 14, 2006 vol. 103 no. 46 17361-17365
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