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Chemokine receptor CXCR4 expression in breast cancer as a potential predictive marker of isolated tumor cells in bone marrow

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Abstract

Interactions between the CXCR4 chemokine receptor in breast cancer cells and the ligand CXCL12/SDF-1α are thought to play an important role in breast cancer metastases. In this pilot study, CXCR4 expression along with other biomarkers including HER2-neu and EGFR, were measured in primary tumor samples of patients with operable breast cancer to test whether any of these biomarkers alone and in combination could indicate breast cancer with high likelihood of metastasizing to bone marrow. Cytokeratin (CK) positive cells in bone marrow were identified by flow-cytometry following enrichment with CK 7/8 antibody-coupled magnetic beads. Primary tumors (n = 18) were stained with specific antibodies for CXCR4, HER2-neu, EGFR, and PCNA using an indirect avidin–biotin horseradish peroxidase method. The majority of the patients had T2/T3 tumors (72%), or lymph node involvement (67%) as pathologic characteristics that were more indicative of high-risk breast cancer. High CXCR4 cytoplasmic expression was found in 7 of 18 patients (39%), whereas 6 of 18 patients (33%) were found to have CK positivity in bone marrow. The median number of CK+ cells was 236 (range, 20–847) per 5 × 104 enriched BM cells. The presence of CK+ cells in bone marrow was found to be associated with increased expression of CXCR4 alone or in addition to EGFR and/or HER2-neu expression (P = 0.013, P = 0.005, and P = 0.025, respectively) in primary tumors. Furthermore, three patients with high CK positivity (>236 CK+ per 5 × 104 enriched bone marrow cells) in bone marrow exclusively expressed high levels of CXCR4 with EGFR/HER2-neu (P = 0.001). Our data suggest that high CXCR4 expression in breast cancer may be a potential marker in predicting isolated tumor cells in bone marrow. CXCR4 coexpression with EGFR/HER2-neu might further predict a particular subset of patients with high CK positivity in bone marrow.

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Abbreviations

BM:

bone marrow

CK:

cytokeratin

EGFR:

epidermal growth factor receptor

ER:

estrogen receptor

HG:

histologic grade

ITC:

isolated tumor cell

PBS:

phosphate buffered saline

PCNA:

proliferating cell nuclear antigen

PR:

progesteron receptor

TNM:

tumor node metastasis

References

  1. IJ Diel SD Costa R Holle et al. (1996) ArticleTitleMicrometastatic breast cancer cells in bone marrow at primary surgery: Prognostic value in comparison with nodal status J Natl Cancer Inst 88 1652–64

    Google Scholar 

  2. S Braun K Pantel P Müller et al. (2000) ArticleTitleCytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer N Engl J Med 343 IssueID4 525–33 Occurrence Handle10.1056/NEJM200002243420801

    Article  Google Scholar 

  3. EF Solomayer IJ Diel G Salanti et al. (2001) ArticleTitleTime independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patients Clin Cancer Res 7 4102–8

    Google Scholar 

  4. S Braun BS Cevatli C Assemi et al. (2001) ArticleTitleComparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy J Clin Oncol 19 IssueID5 1468–75 Occurrence Handle11230493

    PubMed  Google Scholar 

  5. B Gerber A Krause H Müller et al. (2001) ArticleTitleSimultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factors J Clin Oncol 19 IssueID4 960–71 Occurrence Handle11181658

    PubMed  Google Scholar 

  6. B Naume E Borgen G Kvalheim et al. (2001) ArticleTitleDetection of isolated tumor cells in bone marrow in early-stage breast carcinoma patients: comparison with preoperative clinical parameters and primary tumor characteristics Clin Cancer Res 7 IssueID12 4122–29 Occurrence Handle11751511

    PubMed  Google Scholar 

  7. S Menard P Squicciarini A Luini et al. (1994) ArticleTitleImmunodetection of bone marrow micrometastases in breast carcinoma patients and its correlation with primary tumour prognostic features Br J Cancer 69 IssueID6 1126–9 Occurrence Handle7911032

    PubMed  Google Scholar 

  8. C Schindlbeck W Janni N Shabani et al. (2004) ArticleTitleComparative analysis between the HER2 status primary breast cancer tissue and the detection of isolated tumor cells in the bone marrow Breast Cancer Res Treat 87 65–74 Occurrence Handle10.1023/B:BREA.0000041583.72269.e1 Occurrence Handle15377852

    Article  PubMed  Google Scholar 

  9. A Muller B Homey H Soto et al. (2001) ArticleTitleInvolvement of chemokine receptors in breast cancer metastases Nature 410 IssueID6824 50–6 Occurrence Handle10.1038/35065016 Occurrence Handle11242036

    Article  PubMed  Google Scholar 

  10. MCP Smith KE Luker JR Garbow et al. (2004) ArticleTitleCXCR4 regulates growth of both primary and metastatic breast cancer Cancer Res 64 8604–12 Occurrence Handle15574767

    PubMed  Google Scholar 

  11. H Geminder O Sagi-Assif L Goldberg et al. (2001) ArticleTitleA possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma J Immunol 167 IssueID8 4747–57 Occurrence Handle11591806

    PubMed  Google Scholar 

  12. HV Russell J Hicks MF Okcu JG Nuchtern (2004) ArticleTitleCXCR4 expression in neuroblastoma primary tumors is associated with clinical presentation of bone and bone marrow metastases J Pediatr Surg 39 IssueID10 1506–11 Occurrence Handle10.1016/j.jpedsurg.2004.06.019 Occurrence Handle15486895

    Article  PubMed  Google Scholar 

  13. W Shen LJ Bendall DJ Gottlieb K Bradstock (2001) ArticleTitleThe chemokine receptor CXCR4 enhances integrin-mediated in vitro adhesion and facilitates engraftment of leukemic precursor-B cells in the bone marrow Exp Hematol 29 IssueID12 1439–47 Occurrence Handle10.1016/S0301-472X(01)00741-X Occurrence Handle11750103

    Article  PubMed  Google Scholar 

  14. RS Taichman C Cooper ET Keller et al. (2002) ArticleTitleUse of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone Cancer Res 62 IssueID6 1832–7 Occurrence Handle11912162

    PubMed  Google Scholar 

  15. S Braun G Schlimock I Heumos et al. (2001) ArticleTitleErb2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I-III breast cancer patients Cancer Res 61 IssueID5 1890–5 Occurrence Handle11280743

    PubMed  Google Scholar 

  16. Cabioglu N, Miller C, Parikh N et al. Crosstalk between CXCR4 and HER2-neu in breast cancer: transactivation of HER2-neu by stromal derived factor-1 alpha through Src kinase activation. Proceedings of 95th American Association for Cancer Research, 95th Annual Meeting, 2004; p. 907.

  17. HJG Bloom WW Richardson (1957) ArticleTitleHistologic grading and prognosis in breast cancer Br J Cancer 11 IssueID3 359–77 Occurrence Handle13499785

    PubMed  Google Scholar 

  18. VM Martin C Siewert A Scharl et al. (1998) ArticleTitleImmunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS Exp Hematol 26 IssueID3 252–64 Occurrence Handle9502622

    PubMed  Google Scholar 

  19. N Cabioglu A Igci EO Yildirim et al. (2002) ArticleTitleAn ultrasensitive tumor enriched flow-cytometric assay for detection of isolated tumor cells in bone marrow of patients with breast cancer Am J Surg 184 414–7 Occurrence Handle10.1016/S0002-9610(02)01015-2 Occurrence Handle12433604

    Article  PubMed  Google Scholar 

  20. Cabioglu N, Yazici MS, Arun BK et al. Expression of CXCR4 predicts lymph node metastasis in early breast cancer. Annual Meeting Proceedings; the 40th Annual Meeting of the American Society of Clinical Oncology, 2004, p. 9525.

  21. B Chen MWM Brekel Particlevan den W Buschers et al. (2003) ArticleTitleValidation of tissue array technology in head and neck squamous cell carcinoma Head Neck 25 922–30 Occurrence Handle10.1002/hed.10308 Occurrence Handle14603452

    Article  PubMed  Google Scholar 

  22. Y Niu X Fu A Lv et al. (2002) ArticleTitlePotential markers predicting distant metastasis in axillary node-negative breast carcinoma Int J Cancer 98 IssueID5 754–60 Occurrence Handle10.1002/ijc.10136 Occurrence Handle11920647

    Article  PubMed  Google Scholar 

  23. Z Suo B Risberg MG Kalsson et al. (2002) ArticleTitleEGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival J Pathol 196 IssueID1 17–25 Occurrence Handle10.1002/path.1003 Occurrence Handle11748637

    Article  PubMed  Google Scholar 

  24. S Tsutsui S Ohno S Murakami et al. (2003) ArticleTitlePrognostic value of the combination of epidermal growth factor receptor and c-erbB-2 in breast cancer Surgery 133 IssueID2 219–21 Occurrence Handle10.1067/msy.2003.32 Occurrence Handle12605184

    Article  PubMed  Google Scholar 

  25. YM Li Y Pan Y Wei et al. (2004) ArticleTitleUpregulation of CXCR4 is essential for HER2-mediated tumor metastasis Cancer Cell 6 459–69 Occurrence Handle10.1016/j.ccr.2004.09.027 Occurrence Handle15542430

    Article  PubMed  Google Scholar 

  26. S Braun F Hepp HL Sommer K Pantel (1999) ArticleTitleTumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease Int J Cancer (Pred Oncol) 84 1–5 Occurrence Handle10.1002/(SICI)1097-0215(19990219)84:1<1::AID-IJC1>3.0.CO;2-A

    Article  Google Scholar 

  27. A Forus HK Høifødt GET Øverli et al. (1999) ArticleTitleSensitive fluorescent in situ hybridisation method for the characterisation of breast cancer cells in bone marrow aspirates J Clin Pathol Mol Pathol 52 68–74

    Google Scholar 

  28. G Schlimock G Riethmuller (1990) ArticleTitleDetection, characterization and tumorigenicity of disseminated tumor cells in human bone marrow Semin Cancer Biol 1 207–15 Occurrence Handle2103496

    PubMed  Google Scholar 

  29. G Schlimock I Funke B Bock et al. (1990) ArticleTitleEpithelial tumor cells in bone marrow of patients with colorectal cancer: Immunocytochemical detection, phenotypic characterization, and prognostic significance J Clin Oncol 8 831–7 Occurrence Handle1692090

    PubMed  Google Scholar 

  30. IS Zeelenberg L Ruuls-Van Stalle E Roos (2003) ArticleTitleThe chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases Cancer Res 63 IssueID13 3833–9 Occurrence Handle12839981

    PubMed  Google Scholar 

  31. W Janni S Gastroph F Hepp et al. (2000) ArticleTitlePrognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma Cancer 88 2252–9 Occurrence Handle10.1002/(SICI)1097-0142(20000515)88:10<2252::AID-CNCR8>3.0.CO;2-Q Occurrence Handle10820346

    Article  PubMed  Google Scholar 

  32. B Naume E Boregen JM Nesland et al. (1998) ArticleTitleIncreased sensitivity for detection of micrometastases in bone-marrow/peripheral-blood stem-cell products from breast-cancer patients by negative immunomagnetic seperation Int J Cancer 78 556–60 Occurrence Handle10.1002/(SICI)1097-0215(19981123)78:5<556::AID-IJC5>3.0.CO;2-G Occurrence Handle9808522

    Article  PubMed  Google Scholar 

  33. S Kasimir-Bauer C Oberhoff K Sliwinska et al. (2001) ArticleTitleEvaluation of different methods for the detection of minimal residual disease in blood and bone marrow of patients with primary breast cancer: importance for clinical use? Breast Cancer Res Treat 69 123–32 Occurrence Handle10.1023/A:1012288201969 Occurrence Handle11759818

    Article  PubMed  Google Scholar 

  34. E Racilla D Euhus AJ Weiss et al. (1998) ArticleTitleDetection and characterization of carcinoma cells in the blood Proc Natl Acad Sci USA 95 4589–94 Occurrence Handle10.1073/pnas.95.8.4589 Occurrence Handle9539782

    Article  PubMed  Google Scholar 

  35. B Molnar A Ladanyi L Tanko et al. (2001) ArticleTitleCorrespondence re: circulating tumor cell clusters in the peripheral blood of colorectal cancer patients Clin Cancer Res 7 4080–5 Occurrence Handle11751505

    PubMed  Google Scholar 

  36. MR Weihrauch E Skibowski A Draube et al. (2002) ArticleTitleImmunomagnetic enrichment and detection of isolated tumor cells in bone marrow of patients with epithelial malignancies Clin Exp Metast 19 617–21 Occurrence Handle10.1023/A:1020988227349

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 85, 77030, Houston, TX, USA

    Neslihan Cabioglu, Michele Doucet & Janet E. Price

  2. Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Aysegul Sahin

  3. Department of Pathology, Istanbul Faculty of Medicine, Istanbul, Turkey

    Ekrem Yavuz

  4. Department of General Surgery, Istanbul Faculty of Medicine, Istanbul, Turkey

    Abdullah Igci

  5. Institute of Experimental Medical Research, Instanbul University, Istanbul, Turkey

    Engin O.Yildirim, Esin Aktas, Sema Bilgic, Bayram Kiran & Gunnur Deniz

Authors
  1. Neslihan Cabioglu
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  2. Aysegul Sahin
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  3. Michele Doucet
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  4. Ekrem Yavuz
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  5. Abdullah Igci
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  6. Engin O.Yildirim
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  7. Esin Aktas
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  8. Sema Bilgic
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  9. Bayram Kiran
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  10. Gunnur Deniz
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  11. Janet E. Price
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Correspondence to Neslihan Cabioglu.

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Cabioglu, N., Sahin, A., Doucet, M. et al. Chemokine receptor CXCR4 expression in breast cancer as a potential predictive marker of isolated tumor cells in bone marrow. Clin Exp Metastasis 22, 39–46 (2005). https://doi.org/10.1007/s10585-005-3222-y

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  • DOI: https://doi.org/10.1007/s10585-005-3222-y

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