Breast Cancer

, Volume 25, Issue 6, pp 698–705 | Cite as

Clinicopathological significance of cancer stem cell markers CD44 and ALDH1 expression in breast cancer

  • Tahani LouhichiEmail author
  • Sonia Ziadi
  • Hanene Saad
  • Myriam Ben Dhiab
  • Sarra Mestiri
  • Mounir Trimeche
Original Article



CD44 and aldehyde dehydrogenase 1 (ALDH1) has been reputed to be cancer stem cell (CSC) markers in breast cancer. Yet, the clinicopathologic and prognostic significance of these markers remain unclear. In this study, we have investigated the expression of these markers and their relation with conventional clinicopathologic tumor characteristic including molecular subtype.


CD44 and ALDH1 expression were investigated by immunohistochemistry in a series of 157 formalin-fixed paraffin-embedded breast cancer tissues.


Overall, CD44 and ALDH1 are, respectively, detected in 33% (52 of 157) and 7% (10 of 157) of breast cancer cases. We also observed that CD44 expression was associated with histological grade (p = 0.005). For ALDH1, we found that its expression is more frequent with elderly women (> 50 years, p = 0.03). The investigation of relationship between the stem cell phenotype and breast cancer molecular subtype, revealed that CD44 and ALDH1 expression was more frequent in basal-like tumors (p = 0.005). Among the two cancer stem cell markers tested, ALDH1 showed a strong association with the basal marker EGFR (p = 0.05).


These findings suggest that CD44 and ALDH1 play a role in the clinical behavior in breast cancer and might be interesting biomarkers and therapeutic targets.


CD44 Aldehyde dehydrogenase 1 Cancer stem cell Breast cancer Basal-like 



The authors acknowledge Mr. Boukataya Samir (English teacher at the Faculty of Dental Medicine, Tunisia) for English editing.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.


  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; E359–E386.CrossRefPubMedGoogle Scholar
  2. 2.
    Campbell LL, Polyak K. Breast tumors heterogeneity: cancer stem cells or clonal evolution. Cell Cycle. 2007;2332:6–8.Google Scholar
  3. 3.
    Honeth G, Bendahl PO, Ringner M, Saal LH, Gruvberger-Saal SK, Lovgren K, et al. The CD44+/CD24− phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10:R53.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lawson JC, Blatch GL, Edkins AL. Cancer stem cells in Breast cancer and metastases. Breast Cancer Res. 2009;118:241 – 54.CrossRefGoogle Scholar
  5. 5.
    Ricardo S, Vieira AF, Gerhard R, Leitao D, Pinto R, Cameselle-Teijeiro JF, et al. Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol. 2011;64:937 – 46.CrossRefPubMedGoogle Scholar
  6. 6.
    Orian-Rousseau V. CD44, a therapeutic target for metastasin tumors. Eur J Cancer. 2010;46:1271–77.CrossRefPubMedGoogle Scholar
  7. 7.
    Bourguignon LYW, Wong G, Earle C, Krueger K, Spevak CC. Hyaluronan–CD44 interaction promotes c-Src-mediated twist signaling, microRNA-10b expression, and RhoA/RhoC up-regulation, leading to Rho-kinase-associated cytoskeleton activation and breast tumor cell invasion. J Biol Chem. 2010;285:36721–35.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial–mesenchymal transition and breast cancer progression. J Clin Invest. 2011;121:1064–74.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zucchi I, Sanzone S, Astigiano S, Pelucchi P, Scotti M, Valsecchi V, et al. The properties of a mammary gland cancer stem cell. Proc Natl Acad Sci. 2007;104:10476–81.CrossRefPubMedGoogle Scholar
  10. 10.
    Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ, et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci. 2006;103:11707–12.CrossRefPubMedGoogle Scholar
  11. 11.
    Povsic TJ, Zavodni KL, Kelly FL, Zhu S, Goldschmidt-Clermont PJ, Dong C, et al. Circulating progenitor cells can be reliably identified on the basis of aldehyde dehydrogenase activity. J Am Coll Cardiol. 2007;50:2243–48.CrossRefPubMedGoogle Scholar
  12. 12.
    Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, et al. Breast cancer cells lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 2009;69:1302–13.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mylona E, Giannopoulou I, Fasomytakis E, Nomikos A, Magkou C, Bakarakos P, et al. The clinicopathologic and prognostic significance of CD44+/CD24–/low and CD44–/CD24 + tumor cells in invasive breast carcinomas. Hum Pathol. 2008;39:1096–102.CrossRefPubMedGoogle Scholar
  15. 15.
    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;11:1154–59.PubMedGoogle Scholar
  16. 16.
    Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann Oncol. 2013;24:2206 – 223.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tan EY, Thike AA, Tan PH. ALDH1 expression is enriched in breast cancers arising in young women but does not predict outcome. Br J Cancer. 2013;109:109–13.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Neumeister V, Agarwal S, Bordeaux J, Camp RL, Rimm DL. In situ identification of putative cancer stem cells by multiplexing ALDH1, CD44, and cytokeratin identifies breast cancer patients with poor prognosis. Am J Pathol. 2010;176:2131–38.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nogami T, Shien T, Tanaka T, Nishiyama K, Mizoo T, Iwamto T, et al. Expression of ALDH1 in axillary lymph node metastases is a prognostic factor of poor clinical outcome in breast cancer patients with 1–3 lymph node metastases. Breast Cancer. 2012;21:58–65.CrossRefPubMedGoogle Scholar
  20. 20.
    Sakakibara M, Fujimori T, Miyoshi T, Nagashima T, Fujimoto H, Suzuki HT, et al. Aldehyde dehydrogenase 1-positive cells in axillary lymph node metastases after chemotherapy as a prognostic factor in patients with lymph node-positive breast cancer. Cancer. 2012;118:3899–910.CrossRefPubMedGoogle Scholar
  21. 21.
    Dong Y, Bi LR, Xu N, Yang HM, Zhang HT, Ding Y, et al. The expression of aldehyde dehydrogenase 1 in invasive primary breast tumors and axillary lymph node metastases is associated with poor clinical prognosis. Pathol Res Pract. 2013;209:555–61.CrossRefPubMedGoogle Scholar
  22. 22.
    Morimoto K, Kim SJ, Tanei T, Shimazu K, Tanji Y, Taguchi T, et al. Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor positive human epidermal growth factor receptor type 2, and high Ki67 expression. Cancer Sci. 2009;100:1062–68.CrossRefPubMedGoogle Scholar
  23. 23.
    Kapucuoglu N, Bozkurt KK, Baspınar S, Kocer M, Eroglu HE, Akdeniz R, et al. The clinicopathological and prognostic significance of CD24, CD44, CD133, ALDH1 expressions in invasive ductal carcinoma of the breast CD44/CD24 expression in breast cancer. Pathol Res Pract. 2015;211:740–47.CrossRefPubMedGoogle Scholar
  24. 24.
    Tsang JYS, Huang YH, Luo MH, Ni YB, Chan SK, Lui PCW, et al. Cancer stem cell markers are associated with adverse biomarker profiles and molecular subtypes of breast cancer. Breast Cancer Res Treat. 2012;136:407–17.CrossRefPubMedGoogle Scholar
  25. 25.
    Chekhun SV, Zadvorny TV, Tymovska YO, Anikusko MF, Novak OE, Polishchuk LZ. CD44+/CD24− markers of cancer stem cells in patients with Breast cancer of different molecular subtypes. Exp Oncol. 2015;37:58–63.PubMedGoogle Scholar
  26. 26.
    Uchoa DM, Graudenz MS, Callegari-Jacques SM, Hartmann CR, Ferreira BP, Fitarelli-Kiehl M, et al. Expression of cancer stem cell markers in basal and penta-negative breast carcinomas—a study of a series of triple-negative tumors. Pathol Res Pract. 2014;210:432 – 39.CrossRefGoogle Scholar
  27. 27.
    Yan Y, Zuo X, Wei D. Concise review: emerging role of CD44 in cancer stem cells: a promising biomarker and therapeutic target. Stem Cells Transl Med. 2015;4(9):1033–43.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Makki J, Myint O, Wynn AA, Samsudin AT, John DV. Expression distribution of cancer stem cells, epithelial to mesenchymal transition, and telomerase activity in breast cancer and their association with clinicopathologic characteristics. Clin Med Insights Pathol. 2015;8:1–16.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Kim YS, Jung MJ, Ryu DW, Lee CH. Clinicopathologic characteristics of breast cancer stem cells identified on the basis of aldehyde dehydrogenase 1 expression. J Breast Cancer. 2014;17:121 – 28.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Idowu MO, Kimeciak M, Dumu C, Burton RS, Grimes MM, Powers CN, et al. CD44+/CD24− cancer stem: progenitor cells are more abundant in triple-negative invasisve breast carcinoma phenotype and are associated with poor outcome. Hum Pathol. 2012;43:364 – 73.CrossRefPubMedGoogle Scholar
  31. 31.
    De Beça FF, Caetano P, Gerhard R, Alvarenga CA, Gomes M, Paredes J, et al. Cancer stem cells markers CD44, CD24 and ALDH1 in breast cancer special histological types. J Clin Pathol. 2013;66:187 – 91.CrossRefPubMedGoogle Scholar
  32. 32.
    Dontu G, El-Ashry D, Wisha MS. Breast cancer stem:progenitor cells and estrogen receptor. Trends Endocrinol Metab. 2004;15:193 – 97.CrossRefPubMedGoogle Scholar
  33. 33.
    Liu S, Ginestier C, Charafe-Jauffret E, Focco H, Kleer CG, Merajver SD, et al. BRCA1 regulates human mammary stem:progenitor cell fate. Proc Natl Acad Sci USA. 2008;105:1680–85.CrossRefPubMedGoogle Scholar
  34. 34.
    Turner N, Tutt A, Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer. 2004;4:814–19.CrossRefPubMedGoogle Scholar
  35. 35.
    Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14:43–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Sahin IH, Klostergaard J. CD44 as a drug delivery target in human cancers: where are we now? Expert Opin Ther Targets. 2015;16:1–5.Google Scholar

Copyright information

© The Japanese Breast Cancer Society 2018

Authors and Affiliations

  • Tahani Louhichi
    • 1
    Email author
  • Sonia Ziadi
    • 1
  • Hanene Saad
    • 1
  • Myriam Ben Dhiab
    • 1
  • Sarra Mestiri
    • 1
  • Mounir Trimeche
    • 1
  1. 1.Department of PathologyFarhat-Hached HospitalSousseTunisia

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