Breast Cancer Research and Treatment

, Volume 156, Issue 2, pp 261–269 | Cite as

Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype

  • Kumiko Kida
  • Takashi IshikawaEmail author
  • Akimitsu Yamada
  • Kazuhiro Shimada
  • Kazutaka Narui
  • Sadatoshi Sugae
  • Daisuke Shimizu
  • Mikiko Tanabe
  • Takeshi Sasaki
  • Yasushi Ichikawa
  • Itaru Endo
Preclinical study


Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker, but its value as a predictor of prognosis and chemoresistance is controversial. This study investigated the effect of ALDH1 on prognosis and chemoresponse by breast cancer subtype. We immunohistochemically analyzed 653 invasive breast cancer specimens and evaluated correlations among clinicopathological factors, survival status, response to neoadjuvant chemotherapy, and ALDH1 expression. Of 653 specimens, 139 (21.3 %) expressed ALDH1 in tumor cells. ALDH1 expression was correlated significantly with larger tumor size, node metastasis, higher nuclear grade, and with HER2+ and progesterone/estrogen receptor (HR) subtypes. ALDH1 expression was significantly observed in HER2 type and triple-negative breast cancer (TNBC). Patients with ALDH1+ cancers had significantly shorter disease-free survival (P < 0001) and overall survival (P = 0.044). ALDH1 expression significantly affected prognosis of luminal types, but not TNBC and HER2-enriched types. For the 234 patients treated with neoadjuvant chemotherapy, pathological complete response (pCR) rate was significantly lower in ALDH1+ cases (13.5 vs. 30.3 %, P = 0.003). pCR and ALDH1 expression were significantly correlated in TNBC patients (P = 0.003). ALDH1+ breast cancers tended to be aggressive, with poor prognoses. Although ALDH1+ TNBC showed higher chemoresistance, ALDH1 had significant impact on prognosis in the luminal type but not in TNBC.


Breast cancer Stem cell ALDH1 Prognosis Chemoresistance Subtype 


Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Ginester C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567. doi: 10.1016/j.stem.2007.08.014 CrossRefGoogle Scholar
  2. 2.
    Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL (1997) Identification of a lineage of multipotent hematopoietic progenitors. Development 124:1929–1939PubMedGoogle Scholar
  3. 3.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111CrossRefPubMedGoogle Scholar
  4. 4.
    Molofsky AV, Pardal R, Morrison SJ (2004) Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 16:700–707CrossRefPubMedGoogle Scholar
  5. 5.
    Ward RJ, Dirks PB (2007) Cancer stem cells: at the headwaters of tumor development. Annu Rev Pathol 2:175–189CrossRefPubMedGoogle Scholar
  6. 6.
    Polyak K, Hahn WC (2006) Roots and stems: stem cells in cancer. Nat Med 12:296–300CrossRefPubMedGoogle Scholar
  7. 7.
    Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–1012CrossRefPubMedGoogle Scholar
  8. 8.
    Zhao D, Najbauer J, Annala AJ, Garcia E, Mets MZ, Gutova M, Polewski MD, Gilchrist M, Glackin CA, Kim SU, Aboody KS (2012) Human neural stem cell tropism to metastatic breast cancer. Stem Cells 30:314–325CrossRefPubMedGoogle Scholar
  9. 9.
    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 100:3983–3988. doi: 10.1073/pnas.05302911000530291100 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mieog JS, de Kruijf EM, Bastiaannet E, Kuppen PJ, Sajet A, de Craen AJ, Smit VT, van de Velde CJ, Liefers GJ (2012) Age determines the prognostic role of the cancer stem cell marker aldehyde dehydrogenase-1 in breast cancer. BMC Cancer 12:42CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Resetkova E, Reis-Filho JS, Jain RK, Mehta R, Thorat MA, Nakshatri H, Badve S (2010) Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment. Breast Cancer Res Treat 123:97–108CrossRefPubMedGoogle Scholar
  12. 12.
    Yoshioka T, Umekita Y, Ohi Y, Souda M, Sagara Y, Rai Y, Tanimoto A (2011) Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study. Histopathology 58:608–616CrossRefPubMedGoogle Scholar
  13. 13.
    Liu Y, Lv D, Duan J, Xu S, Zhang J, Yang X, Zhang X, Cui Y, Bian X, Yu S (2014) ALDH1A1 expression correlates with clinicopathologic features and poor prognosis of breast cancer patients: a systematic review and meta-analysis. BMC Cancer 14:444CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Morimoto K, Kim SJ, Tanei T, Shimazu K, Tanji Y, Taguchi T, Tamaki Y, Terada N, Noguchi S (2009) 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 100:1062–1068. doi: 10.1111/j.1349-7006.2009.01151.x CrossRefPubMedGoogle Scholar
  15. 15.
    Neumeister V, Agarwal S, Bordeaux J, Camp RL, Rimm DL (2010) In situ identification of putative cancer stem cells by multiplexing ALDH1, CD44, and cytokeratin identifies breast cancer patients with poor prognosis. Am J Pathol 176:2131–2138. doi: 10.2353/ajpath.2010.090712 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhou L, Jiang Y, Yan T, Di G, Shen Z, Shao Z, Lu J (2010) The prognostic role of cancer stem cells in breast cancer: a meta-analysis of published literatures. Breast Cancer Res Treat 122:795–801. doi: 10.1007/s10549-010-0999-4 CrossRefPubMedGoogle Scholar
  17. 17.
    Ricardo S, Vieira AF, Gerhard R, Leitão D, Pinto R, Cameselle-Teijeiro JF, Milanezi F, Schmitt F, Paredes J (2011) Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol 64:937–946. doi: 10.1136/jcp.2011.090456 CrossRefPubMedGoogle Scholar
  18. 18.
    Kakarala M, Wicha MS (2008) Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26:2813–2820. doi: 10.1200/JCO.2008.16.3931 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284CrossRefPubMedGoogle Scholar
  20. 20.
    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 100:672–679CrossRefPubMedGoogle Scholar
  21. 21.
    Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, Tamaki Y, Noguchi S (2009) Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 15:4234–4241CrossRefPubMedGoogle Scholar
  22. 22.
    Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ghods AJ, Irvin D, Liu G, Yuan X, Abdulkadir IR, Tunici P, Konda B, Wachsmann-Hogiu S, Black KL, Yu JS (2007) Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells 25:1645–1653CrossRefPubMedGoogle Scholar
  24. 24.
    Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10:25CrossRefGoogle Scholar
  25. 25.
    Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, Tamaki Y, Noguchi S (2009) Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 15:4234–4241CrossRefPubMedGoogle Scholar
  26. 26.
    Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168PubMedGoogle Scholar
  27. 27.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical Oncology; College of American Pathologists (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013. doi: 10.1200/JCO.2013.50.9984 CrossRefPubMedGoogle Scholar
  28. 28.
    Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV (1997) Effect of preoperative chemotherapy on local- regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15:2483–2493PubMedGoogle Scholar
  29. 29.
    Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–1012CrossRefPubMedGoogle Scholar
  30. 30.
    Zhao D, Najbauer J, Annala AJ, Garcia E, Metz MZ, Gutova M, Polewski MD, Gilchrist M, Glackin CA, Kim SU, Aboody KS (2012) Human neural stem cell tropism to metastatic breast cancer. Stem Cells 30:314–325CrossRefPubMedGoogle Scholar
  31. 31.
    Kim YS, Jung MJ, Ryu DW, Lee CH (2014) Clinicopathologic characteristics of breast cancer stem cells identified on the basis of aldehyde dehydrogenase 1 expression. J Breast Cancer 17:121–128. doi: 10.4048/jbc.2014.17.2.121 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hashimoto K, Shimizu C, Tsuda H, Saji S, Osaki A, Shigekawa T, Aogi K (2012) Immunohistochemical detection of breast cancer stem cells in hormone receptor-positive breast cancer and their role in response to endocrine therapy and clinical outcome. Oncology 82:168–174. doi: 10.1159/000336078 CrossRefPubMedGoogle Scholar
  33. 33.
    Ohi Y, Umekita Y, Yoshioka T, Souda M, Rai Y, Sagara Y, Sagara Y, Sagara Y, Tanimoto A (2011) Aldehyde dehydrogenase 1 expression predicts poor prognosis in triple-negative breast cancer. Histopathology 59:776–780. doi: 10.1111/j.1365-2559.2011.03884.x CrossRefPubMedGoogle Scholar
  34. 34.
    Zhou L, Li K, Luo Y, Tian L, Wang M, Li C, Huang Q (2013) Novel prognostic markers for patients with triple-negative breast cancer. Hum Pathol 44:2180–2187. doi: 10.1016/j.humpath.2013.03.021 CrossRefPubMedGoogle Scholar
  35. 35.
    De Brot M, Rocha RM, Soares FA, Gobbi H (2012) Prognostic impact of the cancer stem cell related markers ALDH1 and EZH2 in triple-negative and basal-like breast cancers. Pathology 44:303–312. doi: 10.1097/PAT.0b013e3283534bcb CrossRefPubMedGoogle Scholar
  36. 36.
    Paik S, Kim C, Wolmark N (2008) HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 358:1409–1411CrossRefPubMedGoogle Scholar
  37. 37.
    Korkaya H, Wicha M (2013) HER2 and breast cancer stem cells: more than meets the eye. Cancer Res 73:3489–3493. doi: 10.1158/0008-5472.CAN-13-0260 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Korkaya H, Paulson A, Iovino F, Wicha MS (2008) HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 27:6120–6130. doi: 10.1038/onc.2008.207 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ithimakin S, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF, Quraishi AA, Ignatoski KW, Daignault S, Davis A, Hall CL, Palanisamy N, Heath AN, Tawakkol N, Luther TK, Clouthier SG, Chadwick WA, Day ML, Kleer CG, Thomas DG, Hayes DF, Korkaya H, Wicha MS (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res 7:1635–1646. doi: 10.1158/0008-5472.CAN-12-3349 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Kumiko Kida
    • 1
  • Takashi Ishikawa
    • 4
    Email author
  • Akimitsu Yamada
    • 2
  • Kazuhiro Shimada
    • 1
  • Kazutaka Narui
    • 2
  • Sadatoshi Sugae
    • 1
  • Daisuke Shimizu
    • 1
  • Mikiko Tanabe
    • 3
  • Takeshi Sasaki
    • 3
  • Yasushi Ichikawa
    • 1
  • Itaru Endo
    • 1
  1. 1.Department of Gastroenterological Surgery and Surgical OncologyYokohama City University Graduate School of MedicineYokohamaJapan
  2. 2.Department of Breast and Thyroid SurgeryYokohama City University Medical CenterYokohamaJapan
  3. 3.Department of PathologyYokohama City University Medical CenterYokohamaJapan
  4. 4.Department of Breast SurgeryTokyo Medical UniversityTokyoJapan

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