Age determines the prognostic role of the cancer stem cell marker aldehyde dehydrogenase-1 in breast cancer

BMC Cancer

J Sven D Mieog¹  Esther M de Kruijf¹  Esther Bastiaannet²  Peter JK Kuppen¹  Anita Sajet¹  Anton JM de Craen²  Vincent THBM Smit³  Cornelis JH van de Velde¹  Gerrit-Jan Liefers¹ 

[1] Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

[2] Department of Gerontology & Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

[3] Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

关键词: Prognostic factor Part of this work has been presented at the American Association for Cancer Research (AACR) Annual Meeting 2011;    ALDH1;    Age;    Breast cancer;   

Others  :  1080565
DOI  :  10.1186/1471-2407-12-42

 received in 2012-01-05, accepted in 2012-01-26,  发布年份 2012

【 摘 要 】

Background

The purpose of this study was to compare the expression and the prognostic effect of the breast cancer stem cell marker aldehyde dehydrogenase-1 (ALDH1) in young and elderly breast cancer patients.

Methods

The study population (N = 574) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Median follow-up was 17.9 years (range: 0.1 to 23.5). Tissue microarray slides were immunohistochemically stained for ALDH1 expression and quantified by two independent observers who were blinded to clinical outcome. Assessment of the prognostic effect of ALDH1 expression was stratified according to age and systemic treatment.

Results

Complete lack of expression of ALDH1 was found in 40% of tumors. With increasing age more tumors showed complete absence of ALDH1 expression (P < .001). In patients aged > 65 years, ALDH1 status was not associated with any clinical outcome. Conversely, in patients aged < 65 years, ALDH1 positivity was an independent risk factor of worse outcome for relapse free period (hazard ratio = 1.71 (95% CI, 1.09 to 2.68); P = .021) and relative survival (relative excess risks of death = 2.36 (95% CI, 1.22 to 3.68); P = .016). Ten-year relative survival risk was 57% in ALDH1-positive patients compared to 83% in ALDH1-negative patients.

Conclusion

ALDH1 expression and its prognostic effect are age-dependent. Our results support the hypothesis that breast cancer biology is different in elderly patients compared to their younger counterparts and emphasizes the importance of taking into consideration age-specific interactions in breast cancer research.

【 授权许可】

   
2012 Mieog et al; licensee BioMed Central Ltd

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Anders CK, Johnson R, Litton J, Phillips M, Bleyer A: Breast cancer before age 40 years. Semin Oncol 2009, 36(3):237-249.
• [2]Remvikos Y, Magdelenat H, Dutrillaux B: Genetic evolution of breast cancers. III: age-dependent variations in the correlations between biological indicators of prognosis. Breast Cancer Res Treat 1995, 34(1):25-33.
• [3]Diab SG, Elledge RM, Clark GM: Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000, 92(7):550-556.
• [4]Beadle BM, Woodward WA, Buchholz TA: The impact of age on outcome in early-stage breast cancer. Semin Radiat Oncol 2011, 21(1):26-34.
• [5]Anderson WF, Jatoi I, Sherman ME: Qualitative age interactions in breast cancer studies: mind the gap. J Clin Oncol 2009, 27(32):5308-5311.
• [6]Bastiaannet E, Liefers GJ, de Craen AJ, Kuppen PJ, van de Water W, Portielje JE, van der Geest LG, Janssen-Heijnen ML, Dekkers OM, van de Velde CJ, et al.: Breast cancer in elderly compared to younger patients in The Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients. Breast Cancer Res Treat 2010, 124(3):801-807.
• [7]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(7):3983-3988.
• [8]Cariati M, Naderi A, Brown JP, Smalley MJ, Pinder SE, Caldas C, Purushotham AD: Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int J Cancer 2008, 122(2):298-304.
• [9]Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, 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(5):555-567.
• [10]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(1):R10. BioMed Central Full Text
• [11]Resetkova E, Reis-Filho JS, Jain RK, Mehta R, Thorat MA, Nakshatri H, Badve S: Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment. Breast Cancer Res Treat 2010, 123(1):97-108.
• [12]Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, Tamaki Y, Noguchi S: 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 2009, 15(12):4234-4241.
• [13]Phillips TM, McBride WH, Pajonk F: The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 2006, 98(24):1777-1785.
• [14]Gong C, Yao H, Liu Q, Chen J, Shi J, Su F, Song E: Markers of tumor-initiating cells predict chemoresistance in breast cancer. PLoS One 2010, 5(12):e15630.
• [15]Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, Fields JZ, Wicha MS, Boman BM: 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(8):3382-3389.
• [16]Foulkes WD, Smith IE, Reis-Filho JS: Triple-negative breast cancer. N Engl J Med 2010, 363(20):1938-1948.
• [17]Nalwoga H, Arnes JB, Wabinga H, Akslen LA: Expression of aldehyde dehydrogenase 1 (ALDH1) is associated with basal-like markers and features of aggressive tumours in African breast cancer. Br J Cancer 2010, 102(2):369-375.
• [18]Zhou L, Jiang Y, Yan T, Di G, Shen Z, Shao Z, Lu J: The prognostic role of cancer stem cells in breast cancer: a meta-analysis of published literatures. Breast Cancer Res Treat 2010, 122(3):795-801.
• [19]van Nes JG, de Kruijf EM, Faratian D, van de Velde CJ, Putter H, Falconer C, Smit VT, Kay C, van de Vijver MJ, Kuppen PJ, et al.: COX2 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients. Breast Cancer Res Treat 2011, 125(3):671-685.
• [20]Putter H, Fiocco M, Geskus RB: Tutorial in biostatistics: competing risks and multi-state models. Stat Med 2007, 26(11):2389-2430.
• [21]Anderson WF, Jatoi I, Devesa SS: Distinct breast cancer incidence and prognostic patterns in the NCI's SEER program: suggesting a possible link between etiology and outcome. Breast Cancer Res Treat 2005, 90(2):127-137.
• [22]Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999, 341(27):2061-2067.
• [23]Anderson WF, Matsuno R: Breast cancer heterogeneity: a mixture of at least two main types? J Natl Cancer Inst 2006, 98(14):948-951.
• [24]Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, Campan M, Noushmehr H, Bell CG, Maxwell AP, et al.: Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res 2010, 20(4):440-446.
• [25]Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, Helyer L, Pan L, Leidal A, Gujar S, 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(1):32-45.
• [26]Marcato P, Dean CA, Giacomantonio CA, Lee PW: Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle 2011, 10(9):1378-1384.