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A CD44−/CD24+ phenotype is a poor prognostic marker in early invasive breast cancer

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Abstract

A CD44−/CD24+ phenotype is a poor prognostic marker in early invasive breast cancer. Breast cancer cells with high CD44 and low or absent CD24 (i.e. CD44+CD24−/low phenotype) are reported to have stem cell features. However, the clinical impact of CD24 and CD44 expression in tumours remains unclear. To explore the immunohistochemical expression of CD44 and CD24 (individually and combined) and their clinical value as prognostic and predictive markers. Immunohistochemical expression of CD24 and CD44 was studied in a large series of early primary invasive breast cancer tumours (n = 1036) prepared as a tissue microarray. Associations between the expression of each marker individually and in combination and clinico-pathological, molecular variables and patients’ outcome were investigated. CD24 cytoplasmic expression was significantly associated with poor prognostic variables including high tumour grade, ER−, PR−, HER2+, p53+ and triple negative (TN) phenotype; P < 0.05. However, CD24 expression was not significantly associated with patients’ outcome. Conversely, CD44 expression was associated with favourable prognostic criteria including lower Nottingham prognostic index, ER+, HER2− and luminal phenotype; P < 0.05. Moreover, CD44 expression was found to be an independent predictor of good prognosis. In combination, the CD44+/CD24− phenotype was associated with the most favourable outcome (84 and 80% 10 year breast cancer survival [BCSS] and metastasis free survival [MFS], respectively). Contrasting this, the CD44−/CD24+ phenotype was associated with the most dismal outcome (62 and 60% 10 years BCSS and MFS, respectively). CD24 and CD44 expression can individually yield prognostic data in breast cancer, but importantly, when both markers are considered; the CD44+/CD24− phenotype had the best prognosis, while the CD44−/CD24+ phenotype had the worst prognosis. This shows that the relationship between basic cell biology and clinical behaviour is not always straightforward and warrants further investigations of the true clinical impact of breast cancer stem cells.

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Abbreviations

AR:

Androgen receptor

BC:

Breast cancer

BCSS:

Breast cancer-specific survival

BLBC:

Basal-like breast cancer

CK:

Cytokeratin

CSC:

Cancer stem cells

DAB:

3,3′-Diaminobenzidine

EGFR:

Epidermal growth factor receptor

ECL:

Enhanced chemiluminescence

ER:

Oestrogen receptor

HER2:

Human epidermal growth factor receptor 2

HR:

Hazard ratio

IHC:

Immunohistochemistry

KD:

Kilodalton

LR:

Log rank

MFS:

Metastasis free survival

NPI:

Nottingham prognostic index

PBS:

Phosphate buffered saline

PR:

Progesterone receptor

REMARK:

Reporting recommendations for tumour marker prognostic studies

TBS:

Tris-buffered saline

TMA:

Tissue microarray

TN:

Triple negative

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107

    Article  PubMed  Google Scholar 

  2. Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284. doi:10.1146/annurev.med.58.062105.204854

    Article  PubMed  CAS  Google Scholar 

  3. Marx J (2003) Cancer research mutant stem cells may seed cancer. Science 301(5638):1308–1310. doi:10.1126/science.301.5638.1308

    Article  PubMed  CAS  Google Scholar 

  4. Li W, Liu F, Lei T, Xu X, Liu B, Cui L, Wei J, Guo X, Lang R, Fan Y, Gu F, Tang P, Zhang X, Fu L (2010) The clinicopathological significance of CD44+/CD24−/low and CD24+ tumor cells in invasive micropapillary carcinoma of the breast. Pathol Res Pract 206(12):828–834. doi:10.1016/j.prp.2010.09.008

    Article  PubMed  CAS  Google Scholar 

  5. Croker AK, Allan AL (2008) Cancer stem cells: implications for the progression and treatment of metastatic disease. J Cell Mol Med 12(2):374–390. doi:10.1111/j.1582-4934.2007.00211.x

    Article  PubMed  CAS  Google Scholar 

  6. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988. doi:10.1073/pnas.0530291100

    Article  PubMed  CAS  Google Scholar 

  7. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA, Daidone MG (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65(13):5506–5511. doi:10.1158/0008-5472.CAN-05-0626

    Article  PubMed  CAS  Google Scholar 

  8. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100(9):672–679. doi:10.1093/jnci/djn123

    Article  PubMed  CAS  Google Scholar 

  9. Mylona E, Giannopoulou I, Fasomytakis E, Nomikos A, Magkou C, Bakarakos P, Nakopoulou L (2008) The clinicopathologic and prognostic significance of CD44+/CD24(−/low) and CD44−/CD24+ tumor cells in invasive breast carcinomas. Hum Pathol 39(7):1096–1102. doi:10.1016/j.humpath.2007.12.003

    Article  PubMed  CAS  Google Scholar 

  10. Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H (2005) Prevalence of CD44+/CD24−/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 11(3):1154–1159

    PubMed  CAS  Google Scholar 

  11. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97(16):1180–1184

    Article  PubMed  CAS  Google Scholar 

  12. Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JFR, Macmillan D, Blamey RW, Ellis IO (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3):340–350

    Article  PubMed  CAS  Google Scholar 

  13. Rakha EA, Elsheikh SE, Aleskandarany MA, Habashi HO, Green AR, Powe DG, El-Sayed ME, Benhasouna A, Brunet JS, Akslen LA, Evans AJ, Blamey R, Reis-Filho JS, Foulkes WD, Ellis IO (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15(7):2302–2310. doi:10.1158/1078-0432.CCR-08-2132

    Article  PubMed  CAS  Google Scholar 

  14. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374

    Article  PubMed  CAS  Google Scholar 

  15. Ahmed MA, Jackson D, Seth R, Robins A, Lobo DN, Tomlinson IP, Ilyas M (2010) CD24 is upregulated in inflammatory bowel disease and stimulates cell motility and colony formation. Inflamm Bowel Dis 16(5):795–803. doi:10.1002/ibd.21134

    Article  PubMed  Google Scholar 

  16. Kristiansen G, Machado E, Bretz N, Rupp C, Winzer KJ, Konig AK, Moldenhauer G, Marme F, Costa J, Altevogt P (2010) Molecular and clinical dissection of CD24 antibody specificity by a comprehensive comparative analysis. Lab Invest 90(7):1102–1116. doi:10.1038/labinvest.2010.70

    Article  PubMed  CAS  Google Scholar 

  17. McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr (1985) Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109(8):716–721

    PubMed  Google Scholar 

  18. Rakha EA, El-Sayed ME, Green AR, Paish EC, Powe DG, Gee J, Nicholson RI, Lee AH, Robertson JF, Ellis IO (2007) Biologic and clinical characteristics of breast cancer with single hormone receptor positive phenotype. J Clin Oncol 25(30):4772–4778

    Article  PubMed  Google Scholar 

  19. Camp RL, Dolled-Filhart M, Rimm DL (2004) X-Tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10:7252–7259. doi:10.1158/1078-0432.ccr-04-0713

    Google Scholar 

  20. Ahmed MA, Al-Attar A, Kim J, Watson NF, Scholefield JH, Durrant LG, Ilyas M (2009) CD24 shows early upregulation and nuclear expression but is not a prognostic marker in colorectal cancer. J Clin Pathol 62(12):1117–1122. doi:10.1136/jcp.2009.069310

    Article  PubMed  CAS  Google Scholar 

  21. Bernard-Marty C, Cardoso F, Piccart MJ (2004) Facts and controversies in systemic treatment of metastatic breast cancer. Oncologist 9(6):617–632. doi:10.1634/theoncologist.9-6-617

    Article  PubMed  Google Scholar 

  22. Roche H, Vahdat LT (2011) Treatment of metastatic breast cancer: second line and beyond. Ann Oncol 22(5):1000–1010. doi:10.1093/annonc/mdq429

    Article  PubMed  CAS  Google Scholar 

  23. Kristiansen G, Winzer KJ, Mayordomo E, Bellach J, Schluns K, Denkert C, Dahl E, Pilarsky C, Altevogt P, Guski H, Dietel M (2003) CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res 9(13):4906–4913

    PubMed  CAS  Google Scholar 

  24. Lopez JI, Camenisch TD, Stevens MV, Sands BJ, McDonald J, Schroeder JA (2005) CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res 65(15):6755–6763. doi:10.1158/0008-5472.CAN-05-0863

    Article  PubMed  CAS  Google Scholar 

  25. Diaz LK, Zhou X, Wright ET, Cristofanilli M, Smith T, Yang Y, Sneige N, Sahin A, Gilcrease MZ (2005) CD44 expression is associated with increased survival in node-negative invasive breast carcinoma. Clin Cancer Res 11(9):3309–3314. doi:10.1158/1078-0432.CCR-04-2184

    Article  PubMed  CAS  Google Scholar 

  26. Bankfalvi A, Terpe HJ, Breukelmann D, Bier B, Rempe D, Pschadka G, Krech R, Bocker W (1998) Gains and losses of CD44 expression during breast carcinogenesis and tumour progression. Histopathology 33(2):107–116

    Article  PubMed  CAS  Google Scholar 

  27. Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K, Clarke MF (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356(3):217–226. doi:10.1056/NEJMoa063994

    Article  PubMed  CAS  Google Scholar 

  28. Alison MR, Lim SM, Nicholson LJ (2011) Cancer stem cells: problems for therapy? J Pathol 223(2):147–161. doi:10.1002/path.2793

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Professor Peter Altvoget for the generous gift of anti-CD24 (SWA11) antibody. We also thank the Ministry of Higher Education (Egypt) for funding Mohamed Ahmed and M. Aleskandarany.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK

    Mohamed A. H. Ahmed, Mohammed A. Aleskandarany, Emad A. Rakha, Ahmed Benhasouna, Christopher Nolan, Andrew R. Green, Mohammad Ilyas & Ian O. Ellis

  2. Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Mohamed A. H. Ahmed

  3. Pathology Department, Menoufyia University, Shibin el Kom, Egypt

    Mohammed A. Aleskandarany

  4. Department of Histopathology, Nottingham City Hospital NHS Trust, Hucknall Road, Nottingham, NG5 1PB, UK

    Emad A. Rakha, Mohammad Ilyas & Ian O. Ellis

  5. Egyptian Ministry of Health, Ismailia, Egypt

    Radwa Z. A. Moustafa

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  1. Mohamed A. H. Ahmed
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  2. Mohammed A. Aleskandarany
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Corresponding author

Correspondence to Ian O. Ellis.

Electronic supplementary material

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10549_2011_1865_MOESM1_ESM.tif

Supplementary Fig. 1: CD24 Nuclear expression. TMA core showing nuclear immunohistochemical expression of CD24; (A): X100, and (B): ×200. (C) and (D): Kaplan–Meier survival plot for patients’ BCSS and MFS for nuclear expression of CD24. Supplementary material 1 (EPS 2849 kb)

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Supplementary material 3 (DOC 96 kb)

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Ahmed, M.A.H., Aleskandarany, M.A., Rakha, E.A. et al. A CD44−/CD24+ phenotype is a poor prognostic marker in early invasive breast cancer. Breast Cancer Res Treat 133, 979–995 (2012). https://doi.org/10.1007/s10549-011-1865-8

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  • DOI: https://doi.org/10.1007/s10549-011-1865-8

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