Medical Oncology

, Volume 28, Issue 3, pp 745–752

The CD44+/CD24− phenotype relates to ‘triple-negative’ state and unfavorable prognosis in breast cancer patients

  • Alexandra Giatromanolaki
  • Efthimios Sivridis
  • Aliki Fiska
  • Michael I. Koukourakis
Original Paper


Breast carcinomas have been reported to contain a subpopulation of CD44+/CD24− tumor cells with stem cell–like properties. This study investigates the significance of these two molecules in connection with tumor aggression and prognosis. The phenotypic profile of 139 breast carcinomas was investigated in paraffin sections using markers previously associated with stem cell–like properties (CD44, CD24), the “triple-state” (ER, PR, c-erb-B2), and angiogenesis (CD31). Tumors with >10% of CD44 and CD24 cancer cells were considered positive. The prevalence of CD44+ and CD24+ breast carcinomas in the series was 51.8% and 41.7%, respectively. Patients with the CD44(+)/CD24(−) phenotype had a 10-year lower median age at presentation and harbored tumors with a triple-negative state. They experienced an unfavorable prognosis. Lack of CD44 expression was associated with lymph node involvement, regardless of CD24 status, whereas the lack of both CD44 and CD24 was connected with high histologic grade and unfavorable prognosis which, notably, was the worse among all phenotypes. In multivariate analysis, the CD44(−)/CD24(−) phenotype, the nodal involvement, the vascular density and the ER-/PR-/c-erbB-2-profile were independent prognostic variables. It is concluded that assessment of the CD44/CD24 status may reveal distinct subgroups of breast cancer patients with different clinical behavior. The unsatisfactory response of the triple-negative tumors to current chemotherapy and their intimate link with the CD44(+)/CD24(−) phenotype, makes CD44 targeting an attractive therapeutic alternative for breast cancer patients. The strong association between the CD44(−)/CD24(−) phenotype and prognosis requires further investigation.


CD44−/CD24− phenotype Triple-negative state Prognosis Breast cancer 


  1. 1.
    Thorne RF, Legg JW, Isacke CM. The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events. J Cell Sci. 2004;117(Pt 3):373–80.PubMedGoogle Scholar
  2. 2.
    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.PubMedCrossRefGoogle Scholar
  3. 3.
    Lopez JI, Camenisch TD, Stevens MV, Sands BJ, McDonald J, Schroeder JA. CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res. 2005;65:6755–63.PubMedCrossRefGoogle Scholar
  4. 5.
    Bourguignon LY, Peyrollier K, Xia W, Gilad E. Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem. 2008;283:17635–51.PubMedCrossRefGoogle Scholar
  5. 6.
    Afify A, Purnell P, Nguyen L. Role of CD44s and CD44v6 on human breast cancer cell adhesion, migration, and invasion. Exp Mol Pathol. 2009;86:95–100.PubMedCrossRefGoogle Scholar
  6. 7.
    Klingbeil P, Natrajan R, Everitt G, Vatcheva R, Marchio C, Palacios J, Buerger H, Reis-Filho JS, Isacke CM. CD44 is overexpressed in basal-like breast cancers but is not a driver of 11p13 amplification. Breast Cancer Res Treat. 2010;120:95–109.PubMedCrossRefGoogle Scholar
  7. 8.
    Kim HJ, Kim JB, Lee KM, Shin I, Han W, Ko E, Bae JY, Noh DY. Isolation of CD24(high) and CD24(low/-) cells from MCF-7: CD24 expression is positively related with proliferation, adhesion and invasion in MCF-7. Cancer Lett. 2007;258:98–108.PubMedCrossRefGoogle Scholar
  8. 9.
    Bauerschmitz GJ, Ranki T, Kangasniemi L, Ribacka C, Eriksson M, Porten M, Herrmann I, Ristimäki A, Virkkunen P, Tarkkanen M, Hakkarainen T, Kanerva A, Rein D, Pesonen S, Hemminki A. Tissue-specific promoters active in CD44+ CD24−/low breast cancer cells. Cancer Res. 2008;68:5533–9.PubMedCrossRefGoogle Scholar
  9. 10.
    Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J, Liu A, Miu K, Watnick RS, Reinhardt F, McAllister SS, Jacks T, Weinberg RA. Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell. 2008;134:62–73.PubMedCrossRefGoogle Scholar
  10. 11.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.PubMedCrossRefGoogle Scholar
  11. 12.
    Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA, Daidone MG. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65:5506–11.PubMedCrossRefGoogle Scholar
  12. 13.
    Dontu G, Liu S, Wicha MS. Stem cells in mammary development and carcinogenesis: implications for prevention and treatment. Stem Cell Rev. 2005;1:207–13.PubMedCrossRefGoogle Scholar
  13. 14.
    Hough M, Rosten PM, Sexton TL, Kay R, Humphries RK. Mapping of CD24 and homologous sequences to multiple chromosomal loci. Genomics. 1994;22:154–61.PubMedCrossRefGoogle Scholar
  14. 15.
    Fischer GF, Majdic O, Gadd S, Knapp W. Signal transduction in lymphocytic and myeloid cells via CD24, a new member of phosphoinositol-anchored membrane molecules. J Immun. 1990;144:638–41.PubMedGoogle Scholar
  15. 16.
    Lim SC. CD24 and human carcinoma: tumor biological aspects. Biomed Pharmacother. 2005;59(Suppl 2):S351–4.PubMedCrossRefGoogle Scholar
  16. 17.
    Aigner S, Sthoeger ZM, Fogel M, Weber E, Zarn J, Ruppert M, Zeller Y, Vestweber D, Stahel R, Sammar M, Altevogt P. CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood. 1997;89:3385–95.PubMedGoogle Scholar
  17. 18.
    Senner V, Sturm A, Baur I, Schrell UH, Distel L, Paulus W. CD24 promotes invasion of glioma cells in vivo. Neuropathol Exp Neurol. 1999;58:795–802.CrossRefGoogle Scholar
  18. 19.
    Baumann P, Cremers N, Kroese F, Orend G, Chiquet-Ehrismann R, Uede T, Yagita H, Sleeman JP. CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res. 2005;65:10783–93.PubMedCrossRefGoogle Scholar
  19. 20.
    Runz S, Mierke CT, Joumaa S, Behrens J, Fabry B, Altevogt P. CD24 induces localization of beta1 integrin to lipid raft domains. Biochem Biophys Res Commun. 2008;365:35–41.PubMedCrossRefGoogle Scholar
  20. 21.
    Sagiv E, Starr A, Rozovski U, Khosravi R, Altevogt P, Wang T, Arber N. Targeting CD24 for treatment of colorectal and pancreatic cancer by monoclonal antibodies or small interfering RNA. Cancer Res. 2008;68:2803–12.PubMedCrossRefGoogle Scholar
  21. 22.
    Schabath H, Runz S, Joumaa S, Altevogt P. CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells. J Cell Sci. 2006;119(Pt 2):314–25.PubMedCrossRefGoogle Scholar
  22. 23.
    Honeth G, Bendahl PO, Ringnér M, Saal LH, Gruvberger-Saal SK, Lövgren K, Grabau D, Fernö M, Borg A, Hegardt C. The CD44+/CD24− phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10:R53.PubMedCrossRefGoogle Scholar
  23. 24.
    Pandit TS, Kennette W, Mackenzie L, Zhang G, Al-Katib W, Andrews J, Vantyghem SA, Ormond DG, Allan AL, Rodenhiser DI, Chambers AF, Tuck AB. Lymphatic metastasis of breast cancer cells is associated with differential gene expression profiles that predict cancer stem cell-like properties and the ability to survive, establish and grow in a foreign environment. Int J Oncol. 2009;35:297–308.PubMedGoogle Scholar
  24. 25.
    Sivridis E, Stamos C, Fiska A, Nikolettos N, Koukourakis MI, Giatromanolaki A. c-erbB-2 and the “triple-state” in early breast carcinomas. Med Oncol. 2009. doi:10.1007/s12032-009-9252-6.
  25. 26.
    Giatromanolaki A, Sivridis E, Brekken R, Thorpe PE, Anastasiadis P, Gatter KC, Harris AL. Koukourakis MI; The angiogenic “vascular endothelial growth factor/flk-1(KDR) receptor” pathway in patients with endometrial carcinoma: prognostic and therapeutic implications. Cancer. 2001;92:2569–77.PubMedCrossRefGoogle Scholar
  26. 27.
    Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. 1994;330:1260–6.PubMedCrossRefGoogle Scholar
  27. 28.
    Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H. Prevalence of CD44+/CD24−/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res. 2005;11:1154–9.PubMedGoogle Scholar
  28. 29.
    Grimshaw MJ, Cooper L, Papazisis K, Coleman JA, Bohnenkamp HR, Chiapero-Stanke L, Taylor-Papadimitriou J, Burchell JM. Mammosphere culture of metastatic breast cancer cells enriches for tumorigenic breast cancer cells. Breast Cancer Res. 2008;10:R52.PubMedCrossRefGoogle Scholar
  29. 30.
    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. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672–9.PubMedCrossRefGoogle Scholar
  30. 31.
    Mylona E, Giannopoulou I, Fasomytakis E, Nomikos A, Magkou C, Bakarakos P, Nakopoulou L. The clinicopathologic and prognostic significance of CD44+/CD24(−/low) and CD44−/CD24+ tumor cells in invasive breast carcinomas. Hum Pathol. 2008;39:1096–102.PubMedCrossRefGoogle Scholar
  31. 32.
    Dey D, Saxena M, Paranjape AN, Krishnan V, Giraddi R, Kumar MV, Mukherjee G, Rangarajan A. Phenotypic and functional characterization of human mammary stem/progenitor cells in long term culture. PLoS One. 2009;4:e5329.PubMedCrossRefGoogle Scholar
  32. 33.
    Phillips TM, McBride WH, Pajonk F. The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 2006;98:1777–85.PubMedCrossRefGoogle Scholar
  33. 34.
    Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, Goulet R Jr, Badve S, Nakshatri H. CD44+/CD24− breast cancer cells exhibit enhanced invasive properties an early step necessary for metastasis. Breast Cancer Res. 2006;8:R59.PubMedCrossRefGoogle Scholar
  34. 35.
    Hughes L, Malone C, Chumsri S, Burger AM, McDonnell S. Characterisation of breast cancer cell lines and establishment of a novel isogenic subclone to study migration, invasion and tumourigenicity. Clin Exp Metastasis. 2008;25:549–57.PubMedCrossRefGoogle Scholar
  35. 36.
    Kaipparettu BA, Malik S, Konduri SD, Liu W, Rokavec M, van der Kuip H, Hoppe R, Hammerich-Hille S, Fritz P, Schroth W, Abele I, Das GM, Oesterreich S, Brauch H. Estrogen-mediated downregulation of CD24 in breast cancer cells. Int J Cancer. 2008;123:66–72.PubMedCrossRefGoogle Scholar
  36. 37.
    Meyer MJ, Fleming JM, Ali MA, Pesesky MW, Ginsburg E, Vonderhaar BK. Dynamic regulation of CD24 and the invasive, CD44posCD24neg phenotype in breast cancer cell lines. Breast Cancer Res. 2009;11:R82.PubMedCrossRefGoogle Scholar
  37. 38.
    Gong JF, Yuan YH, Song GH, Yu J, Han Y, Jia J, Ren J. Pilot study on the correlation between high incidence of CD44+/CD24−/low/ABCG2- cells and poor prognosis in breast cancer. Beijing Da Xue Xue Bao. 2008;40:465–70.PubMedGoogle Scholar
  38. 39.
    Buess M, Rajski M, Vogel-Durrer BM, Herrmann R, Rochlitz C. Tumor-endothelial interaction links the CD44(+)/CD24(−) phenotype with poor prognosis in early-stage breast cancer. Neoplasia. 2009;11:987–1002.PubMedGoogle Scholar
  39. 40.
    Bourguignon LY. CD44-mediated oncogenic signaling and cytoskeleton activation during mammary tumor progression. J Mammary Gland Biol Neoplasia. 2001;6:287–97.PubMedCrossRefGoogle Scholar
  40. 41.
    Hill A, McFarlane S, Mulligan K, Gillespie H, Draffin JE, Trimble A, Ouhtit A, Johnston PG, Harkin DP, McCormick D, Waugh DJ. Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells. Oncogene. 2006;25:6079–91.PubMedCrossRefGoogle Scholar
  41. 42.
    Subramaniam V, Vincent IR, Gilakjan M, Jothy S. Suppression of human colon cancer tumors in nude mice by siRNA CD44 gene therapy. Exp Mol Pathol. 2007;83:332–40.PubMedCrossRefGoogle Scholar
  42. 43.
    Du L, Wang H, He L, Zhang J, Ni B, Wang X, Jin H, Cahuzac N, Mehrpour M, Lu Y, Chen Q. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008;14:6751–60.PubMedCrossRefGoogle Scholar
  43. 44.
    Diaz LK, Zhou X, Wright ET, Cristofanilli M, Smith T, Yang Y, Sneige N, Sahin A, Gilcrease MZ. CD44 expression is associated with increased survival in node negative invasive breast carcinoma. Clin Cancer Res. 2005;11:3309–14.PubMedCrossRefGoogle Scholar
  44. 45.
    Lee JH, Kim SH, Lee ES, Kim YS. CD24 overexpression in cancer development and progression: a meta-analysis. Oncol Rep. 2009;22:1149–56.PubMedGoogle Scholar
  45. 46.
    Athanassiadou P, Grapsa D, Gonidi M, Athanassiadou AM, Tsipis A, Patsouris E. CD24 expression has a prognostic impact in breast carcinoma. Pathol Res Pract. 2009;205:524–33.PubMedCrossRefGoogle Scholar
  46. 47.
    Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L. Brca1 breast tumors contain distinct CD44+/CD24− and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res. 2008;10:R10.PubMedCrossRefGoogle Scholar
  47. 48.
    Kurebayashi J. Possible treatment strategies for triple-negative breast cancer on the basis of molecular characteristics. Breast Cancer. 2009;16:275–80.PubMedCrossRefGoogle Scholar
  48. 49.
    Platt VM, Szoka FC Jr. Anticancer therapeutics: targeting macromolecules and nanocarriers to hyaluronan or CD44, a hyaluronan receptor. Mol Pharm. 2008;5:474–86.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Alexandra Giatromanolaki
    • 1
  • Efthimios Sivridis
    • 1
  • Aliki Fiska
    • 1
  • Michael I. Koukourakis
    • 2
  1. 1.Department of PathologyDemocritus University of Thrace Medical School, and University General Hospital of AlexandroupolisAlexandroupolisGreece
  2. 2.Department of Radiotherapy/OncologyDemocritus University of Thrace, and University General Hospital of AlexandroupolisAlexandroupolisGreece

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