J Breast Cancer.  2014 Mar;17(1):54-60.

The Expression of Aldehyde Dehydrogenase Family in Breast Cancer

• Qiu Y
• Pu T
• Li L
• Cheng F
• Lu C
• Sun L
• Teng X
• Ye F
• Bu H

Abstract

PURPOSE
It is widely accepted that aldehyde dehydrogenase (ALDH) activity is a signature of breast cancer stem cells, and high activity has been reported to be associated with poor clinical outcome. The aim of this study was to assess the expression of members of the ALDH family of isozymes in breast cancer tissues and to evaluate the implications of the results.
METHODS
We analyzed paraffin-embedded tumor tissue from 160 patients with breast cancer. Immunohistochemistry (IHC) staining was performed on the slides using antibodies against different ALDH family members. We collated the IHC results with patient clinical characteristics and determined their prognostic value. In addition, we analyzed normal, hyperplastic, and carcinomatous tissues in situ to check their ALDH distributions.
RESULTS
All the tested ALDH members were detected in the various tissue types, but at different levels. Only ALDH 1A3 was found to be significantly associated with distant metastasis (p=0.001), disease-free survival (p<0.001), and overall survival (p<0.001).
CONCLUSION
The level of ALDH 1A3 in breast cancer tissue is a predictive marker of a poor clinical outcome.

Keyword

Breast neoplasms; Metastasis; Neoplastic stem cells; Prognosis

MeSH Terms

Aldehyde Dehydrogenase*
Antibodies
Breast Neoplasms*
Breast*
Disease-Free Survival
Humans
Immunohistochemistry
Isoenzymes
Neoplasm Metastasis
Neoplastic Stem Cells
Prognosis
Stem Cells
Aldehyde Dehydrogenase
Antibodies
Isoenzymes

Figure

• 

  Figure 1 Typical images of immunihistochemistry (IHC) staining for aldehyde dehydrogenase (ALDH) 1A3 expression in invasive breast carcinoma (IHC stain for ALDH 1A3, ×400). (A) Absence of ALDH 1A3 expression in tumor (score=0). (B) Few ALDH 1A3 tumor cells with moderate staining intensity (score=1+2; P+I). (C) Abundant of ALDH 1A3 tumor cells with moderate staining intensity (score=2+4; P+I). (D) Abundant of ALDH 1A3 tumor cells with strong staining intensity (score=3+5; P+I).

• 

  Figure 2 The prevalence of aldehyde dehydrogenase (ALDH) 1A3 positive tumors cells with the clinical outcomes. Univariate survival analysis of ALDH 1A3 expression was performed in disease-free survival (A) and overall survival (B).

Reference

1. Badve S, Nakshatri H. Breast-cancer stem cells-beyond semantics. Lancet Oncol. 2012; 13:e43–e48.

2. Liu H, Patel MR, Prescher JA, Patsialou A, Qian D, Lin J, et al. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci U S A. 2010; 107:18115–18120.

3. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea: a paradigm shift. Cancer Res. 2006; 66:1883–1890.

4. Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest. 2011; 121:3804–3809.

5. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003; 100:3983–3988.

6. Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008; 10:R25.

7. Basak SK, Veena MS, Oh S, Huang G, Srivatsan E, Huang M, et al. The malignant pleural effusion as a model to investigate intratumoral heterogeneity in lung cancer. PLoS One. 2009; 4:e5884.

8. Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, et al. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res. 2008; 6:1146–1153.

9. Carpentino JE, Hynes MJ, Appelman HD, Zheng T, Steindler DA, Scott EW, et al. Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res. 2009; 69:8208–8215.

10. Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009; 69:3382–3389.

11. Rasper M, Schäfer A, Piontek G, Teufel J, Brockhoff G, Ringel F, et al. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity. Neuro Oncol. 2010; 12:1024–1033.

12. Todaro M, Iovino F, Eterno V, Cammareri P, Gambara G, Espina V, et al. Tumorigenic and metastatic activity of human thyroid cancer stem cells. Cancer Res. 2010; 70:8874–8885.

13. Wang L, Park P, Zhang H, La Marca F, Lin CY. Prospective identification of tumorigenic osteosarcoma cancer stem cells in OS99-1 cells based on high aldehyde dehydrogenase activity. Int J Cancer. 2011; 128:294–303.

14. Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, Murter C, et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst. 2010; 102:340–351.

15. Boonyaratanakornkit JB, Yue L, Strachan LR, Scalapino KJ, LeBoit PE, Lu Y, et al. Selection of tumorigenic melanoma cells using ALDH. J Invest Dermatol. 2010; 130:2799–2808.

16. Clay MR, Tabor M, Owen JH, Carey TE, Bradford CR, Wolf GT, et al. Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck. 2010; 32:1195–1201.

17. Li T, Su Y, Mei Y, Leng Q, Leng B, Liu Z, et al. ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients' outcome. Lab Invest. 2010; 90:234–244.

18. Su Y, Qiu Q, Zhang X, Jiang Z, Leng Q, Liu Z, et al. Aldehyde dehydrogenase 1 A1-positive cell population is enriched in tumor-initiating cells and associated with progression of bladder cancer. Cancer Epidemiol Biomarkers Prev. 2010; 19:327–337.

19. Deng S, Yang X, Lassus H, Liang S, Kaur S, Ye Q, et al. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS One. 2010; 5:e10277.

20. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007; 1:555–567.

21. Neumeister V, Rimm D. Is ALDH1 a good method for definition of breast cancer stem cells? Breast Cancer Res Treat. 2010; 123:109–111.

22. Resetkova E, Reis-Filho JS, Jain RK, Mehta R, Thorat MA, Nakshatri H, et al. Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment. Breast Cancer Res Treat. 2010; 123:97–108.

23. Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, et al. Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells. 2011; 29:32–45.

24. Currie MJ, Beardsley BE, Harris GC, Gunningham SP, Dachs GU, Dijkstra B, et al. Immunohistochemical analysis of cancer stem cell markers in invasive breast carcinoma and associated ductal carcinoma in situ: relationships with markers of tumor hypoxia and microvascularity. Hum Pathol. 2013; 44:402–411.

25. American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2012-2013. Atlanta: American Cancer Society;2012.

26. Rexer BN, Zheng WL, Ong DE. Retinoic acid biosynthesis by normal human breast epithelium is via aldehyde dehydrogenase 6, absent in MCF-7 cells. Cancer Res. 2001; 61:7065–7070.