Skip to main content

Advertisement

Log in

Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  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

    Article  Google Scholar 

  2. Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL (1997) Identification of a lineage of multipotent hematopoietic progenitors. Development 124:1929–1939

    CAS  PubMed  Google Scholar 

  3. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  CAS  PubMed  Google Scholar 

  4. Molofsky AV, Pardal R, Morrison SJ (2004) Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 16:700–707

    Article  CAS  PubMed  Google Scholar 

  5. Ward RJ, Dirks PB (2007) Cancer stem cells: at the headwaters of tumor development. Annu Rev Pathol 2:175–189

    Article  CAS  PubMed  Google Scholar 

  6. Polyak K, Hahn WC (2006) Roots and stems: stem cells in cancer. Nat Med 12:296–300

    Article  CAS  PubMed  Google Scholar 

  7. Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–1012

    Article  CAS  PubMed  Google Scholar 

  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 30:314–325

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 12:42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 123:97–108

    Article  PubMed  Google Scholar 

  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 58:608–616

    Article  PubMed  Google Scholar 

  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 14:444

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284

    Article  CAS  PubMed  Google Scholar 

  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 100:672–679

    Article  CAS  PubMed  Google Scholar 

  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 15:4234–4241

    Article  CAS  PubMed  Google Scholar 

  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 5:67

    Article  PubMed  PubMed Central  Google Scholar 

  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 25:1645–1653

    Article  CAS  PubMed  Google Scholar 

  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 10:25

    Article  Google Scholar 

  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 15:4234–4241

    Article  CAS  PubMed  Google Scholar 

  26. Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 15:2483–2493

    CAS  PubMed  Google Scholar 

  29. Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–1012

    Article  CAS  PubMed  Google Scholar 

  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 30:314–325

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  36. Paik S, Kim C, Wolmark N (2008) HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 358:1409–1411

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Takashi Ishikawa.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kida, K., Ishikawa, T., Yamada, A. et al. Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype. Breast Cancer Res Treat 156, 261–269 (2016). https://doi.org/10.1007/s10549-016-3738-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-016-3738-7

Keywords

Navigation