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CD133 as Biomarker in Breast Cancer

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Biomarkers in Cancer

Abstract

Breast cancer is one of the most common malignant diseases worldwide. Prognosis of breast cancer is still poor despite the diagnostic and therapeutic progress in recent years. In order to decrease breast cancer-related deaths, many studies are aimed at identifying novel screening- and prognosis-related biomarkers. Cancer stem cells (CSCs) are characterized by the capacity for self-renewal, tumorigenesis, and differentiation. Due to the role of cancer stem cells in tumor initiation and treatment failure, studies of CSC markers have been of great interest. CD133, five transmembrane single-chain glycoproteins, has been successfully used as a stem cell marker to identify and isolate CSCs in malignant tumors. CD133 can also be used to predict tumor metastasis, patient survival and resistance to therapy. This chapter provides an overview of the evidence regarding the existence and function of CD133 in breast cancers in the context of the experimental and clinical data. It also discusses CD133 as a possible target for breast cancer therapy.

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Abbreviations

ALDH:

Aldehyde Dehydrogenase

CSCs:

Cancer Stem Cells

DFS:

Disease-Free Survival

HIF:

Hypoxic Inducible Factor

NAC:

Neoadjuvant Therapy

OS:

Overall Survival

TGF-β:

Transforming Growth Factor-beta

TNBC:

Triple-Negative Breast Cancer

Wnt:

Wingless Related

References

  • Achuthan S, Santhoshkumar TR, Prabhakar J, et al. Drug-induced senescence generates chemoresistant stemlike cells with low reactive oxygen species. J Biol Chem. 2011;286:37813–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aomatsu N, Yashiro M, Kashiwagi S, et al. CD133 is a useful surrogate marker for predicting chemosensitivity to neoadjuvant chemotherapy in breast cancer. PLoS One. 2012;7:e45865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baba T, Convery PA, Matsumura N, et al. Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene. 2009;28:209–18.

    Article  CAS  PubMed  Google Scholar 

  • Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.

    Article  CAS  PubMed  Google Scholar 

  • Bauer KR, Brown M, Cress RD, et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 2007;109:1721–8.

    Article  PubMed  Google Scholar 

  • Bisson I, Prowse DM. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 2009;19:683–97.

    Article  CAS  PubMed  Google Scholar 

  • Bomken S, Fiser K, Heidenreich O, et al. Understanding the cancer stem cell. Br J Cancer. 2010;103:439–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chavez-MacGregor M, Gonzalez-Angulo AM. Breast cancer in 2012: new drugs, new knowledge, new targets. Nat Rev Clin Oncol. 2012;10:75–6.

    Article  Google Scholar 

  • Chen KL, Pan F, Jiang H, et al. Highly enriched CD133(+)CD44(+) stem-like cells with CD133(+)CD44(high) metastatic subset in HCT116 colon cancer cells. Clin Exp Metastasis. 2011;28:751–63.

    Article  CAS  PubMed  Google Scholar 

  • Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells–perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 2006;66:9339–44.

    Article  CAS  PubMed  Google Scholar 

  • Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51.

    Article  CAS  PubMed  Google Scholar 

  • Corbeil D, Fargeas CA, Huttner WB. Rat prominin, like its mouse and human orthologues, is a pentaspan membrane glycoprotein. Biochem Biophys Res Commun. 2001;285:939–44.

    Article  CAS  PubMed  Google Scholar 

  • Croker AK, Goodale D, Chu J, et al. High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med. 2009;13:2236–52.

    Article  PubMed  Google Scholar 

  • Currie MJ, Beardsley BE, Harris GC, 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;44:402–11.

    Article  CAS  PubMed  Google Scholar 

  • D’Anello L, Sansone P, Storci G, et al. Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells. Mol Cancer. 2010;9:300.

    Article  PubMed  PubMed Central  Google Scholar 

  • Damek-Poprawa M, Volgina A, Korostoff J, et al. Targeted inhibition of CD133+ cells in oral cancer cell lines. J Dent Res. 2011;90:638–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Bonito M, Cantile M, Collina F, et al. Overexpression of cell cycle progression inhibitor geminin is associated with tumor stem-like phenotype of triple-negative breast cancer. J Breast Cancer. 2012a;15:162–71.

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Bonito M, Collina F, Cantile M, et al. Aberrant expression of cancer stem cells marker prominin-1 in low-grade tubulolobular breast carcinoma: a correlative study between qRT-PCR, flow-cytometric and immunohistochemistry analysis [corrected]. J Breast Cancer. 2012b;15:15–23.

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Cosimo S, Baselga J. Management of breast cancer with targeted agents: importance of heterogeneity. [corrected]. Nat Rev Clin Oncol. 2010;7:139–47.

    Article  PubMed  Google Scholar 

  • Giebel B, Corbeil D, Beckmann J, et al. Segregation of lipid raft markers including CD133 in polarized human hematopoietic stem and progenitor cells. Blood. 2004;104:2332–8.

    Article  CAS  PubMed  Google Scholar 

  • Ginestier C, Hur MH, Charafe-Jauffret E, 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;1:555–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giordano A, Gao H, Anfossi S, et al. Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Mol Cancer Ther. 2012;11:2526–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giuffre G, Adamo V, Ieni A, et al. Hematopoietic progenitor cells (HPCs) in node-negative invasive breast carcinomas: immunohistochemical analysis and clinico-pathological correlations. Pathol Res Pract. 2011;207:487–91.

    Article  CAS  PubMed  Google Scholar 

  • Guo L, Fan D, Zhang F, et al. Selection of brain metastasis-initiating breast cancer cells determined by growth on hard agar. Am J Pathol. 2011;178:2357–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.

    Article  CAS  PubMed  Google Scholar 

  • Hibi K, Sakata M, Kitamura YH, et al. Demethylation of the CD133 gene is frequently detected in advanced colorectal cancer. Anticancer Res. 2009;29:2235–7.

    CAS  PubMed  Google Scholar 

  • Hibi K, Sakata M, Kitamura YH, et al. Demethylation of the CD133 gene is frequently detected in early gastric carcinoma. Anticancer Res. 2010;30:1201–3.

    CAS  PubMed  Google Scholar 

  • Huang EH, Hynes MJ, Zhang T, 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;69:3382–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ieni A, Giuffre G, Adamo V, et al. Prognostic impact of CD133 immunoexpression in node-negative invasive breast carcinomas. Anticancer Res. 2011;31:1315–20.

    CAS  PubMed  Google Scholar 

  • Irollo E, Pirozzi G. CD133: to be or not to be, is this the real question? Am J Transl Res. 2013;5:563–81.

    PubMed  PubMed Central  Google Scholar 

  • Kagara N, Huynh KT, Kuo C, et al. Epigenetic regulation of cancer stem cell genes in triple-negative breast cancer. Am J Pathol. 2012;181:257–67.

    Article  CAS  PubMed  Google Scholar 

  • Kawamoto H, Yuasa T, Kubota Y, et al. Characteristics of CD133(+) human colon cancer SW620 cells. Cell Transplant. 2010;19:857–64.

    Article  PubMed  Google Scholar 

  • Kemper K, Versloot M, Cameron K, et al. Mutations in the Ras-Raf Axis underlie the prognostic value of CD133 in colorectal cancer. Clin Cancer Res. 2012;18:3132–41.

    Article  CAS  PubMed  Google Scholar 

  • Koshio J, Kagamu H, Nozaki K, et al. DEAD/H (Asp–Glu–Ala–Asp/His) box polypeptide 3, X-linked is an immunogenic target of cancer stem cells. Cancer Immunol Immunother. 2013;62:1619–28.

    Article  CAS  PubMed  Google Scholar 

  • Lehmann C, Jobs G, Thomas M, et al. Established breast cancer stem cell markers do not correlate with in vivo tumorigenicity of tumor-initiating cells. Int J Oncol. 2012;41:1932–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li CY, Li BX, Liang Y, et al. Higher percentage of CD133+ cells is associated with poor prognosis in colon carcinoma patients with stage IIIB. J Transl Med. 2009;7:56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao Y, Hu X, Huang X, et al. Quantitative analyses of CD133 expression facilitate researches on tumor stem cells. Biol Pharm Bull. 2010;33:738–42.

    Article  CAS  PubMed  Google Scholar 

  • Lin L, Liu Y, Li H, et al. Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030. Br J Cancer. 2011;105:212–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 2006;5:67.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu Q, Li JG, Zheng XY, et al. Expression of CD133, PAX2, ESA, and GPR30 in invasive ductal breast carcinomas. Chin Med J (Engl). 2009;122:2763–9.

    Google Scholar 

  • Liu TJ, Sun BC, Zhao XL, et al. CD133+ cells with cancer stem cell characteristics associates with vasculogenic mimicry in triple-negative breast cancer. Oncogene. 2013;32:544–53.

    Article  CAS  PubMed  Google Scholar 

  • Ma S, Tang KH, Chan YP, et al. miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell. 2010;7:694–707.

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto K, Arao T, Tanaka K, et al. mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells. Cancer Res. 2009;69:7160–4.

    Article  CAS  PubMed  Google Scholar 

  • Meng X, Li M, Wang X, et al. Both CD133+ and CD133− subpopulations of A549 and H446 cells contain cancer-initiating cells. Cancer Sci. 2009;100:1040–6.

    Article  CAS  PubMed  Google Scholar 

  • Meyer MJ, Fleming JM, Lin AF, et al. CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer. Cancer Res. 2010;70:4624–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mine T, Matsueda S, Li Y, et al. Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells. Cancer Immunol Immunother. 2009;58:1185–94.

    Article  CAS  PubMed  Google Scholar 

  • Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell. 2010;7:150–61.

    Article  CAS  PubMed  Google Scholar 

  • Nadal R, Ortega FG, Salido M, et al. CD133 expression in circulating tumor cells from breast cancer patients: Potential role in resistance to chemotherapy. Int J Cancer. 2013;133:2398–407.

    Article  CAS  PubMed  Google Scholar 

  • Nikolova T, Wu M, Brumbarov K, et al. WNT-conditioned media differentially affect the proliferation and differentiation of cord blood-derived CD133+ cells in vitro. Differentiation. 2007;75:100–11.

    Article  CAS  PubMed  Google Scholar 

  • Ong CW, Kim LG, Kong HH, et al. CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol. 2010;23:450–7.

    Article  CAS  PubMed  Google Scholar 

  • Park SY, Lee HE, Li H, et al. Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin Cancer Res. 2010;16:876–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Platet N, Liu SY, Atifi ME, et al. Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Lett. 2007;258:286–90.

    Article  CAS  PubMed  Google Scholar 

  • Rappa G, Fodstad O, Lorico A. The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells. 2008;26:3008–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.

    Article  CAS  PubMed  Google Scholar 

  • Roy S, Majumdar AP. Signaling in colon cancer stem cells. J Mol Signal. 2012;7:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwab LP, Peacock DL, Majumdar D, et al. Hypoxia-inducible factor 1alpha promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res. 2012;14:R6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi L, Wan Y, Sun G, et al. Functional differences of miR-125b on the invasion of primary glioblastoma CD133-negative cells and CD133-positive cells. Neuromolecular Med. 2012;14:303–16.

    Article  CAS  PubMed  Google Scholar 

  • Shmelkov SV, Meeus S, Moussazadeh N, et al. Cytokine preconditioning promotes codifferentiation of human fetal liver CD133+ stem cells into angiomyogenic tissue. Circulation. 2005;111:1175–83.

    Article  CAS  PubMed  Google Scholar 

  • Shmelkov SV, Butler JM, Hooper AT, et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133− metastatic colon cancer cells initiate tumors. J Clin Invest. 2008;118:2111–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.

    Article  CAS  PubMed  Google Scholar 

  • Smith LM, Nesterova A, Ryan MC, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer. 2008;99:100–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Storci G, Sansone P, Trere D, et al. The basal-like breast carcinoma phenotype is regulated by SLUG gene expression. J Pathol. 2008;214:25–37.

    Article  CAS  PubMed  Google Scholar 

  • Suetsugu A, Nagaki M, Aoki H, et al. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun. 2006;351:820–4.

    Article  CAS  PubMed  Google Scholar 

  • Sun B, Liu R, Xiao ZD, et al. c-MET protects breast cancer cells from apoptosis induced by sodium butyrate. PLoS One. 2012a;7:e30143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun J, Zhang C, Liu G, et al. A novel mouse CD133 binding-peptide screened by phage display inhibits cancer cell motility in vitro. Clin Exp Metastasis. 2012b;29:185–96.

    Article  PubMed  Google Scholar 

  • Swaminathan SK, Roger E, Toti U, et al. CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer. J Control Release. 2013;171:280–7.

    Article  CAS  PubMed  Google Scholar 

  • Tabu K, Sasai K, Kimura T, et al. Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Res. 2008;18:1037–46.

    Article  CAS  PubMed  Google Scholar 

  • Tentes IK, Schmidt WM, Krupitza G, et al. Long-term persistence of acquired resistance to 5-fluorouracil in the colon cancer cell line SW620. Exp Cell Res. 2010;316:3172–81.

    Article  CAS  PubMed  Google Scholar 

  • Tirino V, Desiderio V, d’Aquino R, et al. Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS One. 2008;3:e3469.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tirino V, Camerlingo R, Franco R, et al. The role of CD133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer. Eur J Cardiothorac Surg. 2009;36:446–53.

    Article  PubMed  Google Scholar 

  • Vermeulen L, Todaro M, de Sousa MF, et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A. 2008;105:13427–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.

    Article  CAS  PubMed  Google Scholar 

  • Wang YK, Zhu YL, Qiu FM, et al. Activation of Akt and MAPK pathways enhances the tumorigenicity of CD133+ primary colon cancer cells. Carcinogenesis. 2010;31:1376–80.

    Article  CAS  PubMed  Google Scholar 

  • Wang CH, Chiou SH, Chou CP, et al. Photothermolysis of glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody. Nanomedicine. 2011;7:69–79.

    CAS  PubMed  Google Scholar 

  • Wang J, Sakariassen PØ, Tsinkalovsky O, et al. CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 2008;122:761–8.

    Article  CAS  PubMed  Google Scholar 

  • Wright MH, Calcagno AM, Salcido CD, et al. Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res. 2008;10:R10.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xiao Y, Ye Y, Yearsley K, et al. The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype. Am J Pathol. 2008;173:561–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan X, Ma L, Yi D, et al. A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations. Proc Natl Acad Sci U S A. 2011;108:1591–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin AH, Miraglia S, Zanjani ED, et al. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 1997;90:5002–12.

    CAS  PubMed  Google Scholar 

  • You H, Ding W, Rountree CB. Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. Hepatology. 2010;51:1635–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao P, Lu Y, Jiang X, et al. Clinicopathological significance and prognostic value of CD133 expression in triple-negative breast carcinoma. Cancer Sci. 2011;102:1107–11.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study is partially funded by KAKENHI (Grant-in-Aid for Scientific Research, Nos. 23390329).

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Authors and Affiliations

  1. Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Tasuku Matsuoka & Masakazu Yashiro

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  1. Tasuku Matsuoka
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  2. Masakazu Yashiro
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Correspondence to Masakazu Yashiro .

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Editors and Affiliations

  1. Faculty of Life Sciences & Medicine King’s College London, Department of Nutrition and Dietetics Division of Diabetes & Nutritional Scien, London, United Kingdom

    Victor R. Preedy

  2. Faculty of Science & Technology, Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

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Matsuoka, T., Yashiro, M. (2015). CD133 as Biomarker in Breast Cancer. In: Preedy, V., Patel, V. (eds) Biomarkers in Cancer. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7681-4_24

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