Breast Cancer Stem Cells and Cellomics

  • Esin Demir
  • Bilge Atar
  • Dipali Dhawan
  • Debmalya Barh
  • Mehmet Gunduz
  • Esra Gunduz
Chapter

Abstract

“Omics” technologies are powerful high-throughput analytic tools to get inside whole-system level alterations of cancer cells. Since cancer stem cells are groups of vital cells in heterogeneous tumor populations, their omics analysis will enable better understanding in most controversial issues. These issues are mostly treatment resistance and metastatic ability of tumors. The relation between breast cancer patients’ survival rates and stem cells in breast tumor has revealed the significance of breast cancer stem cells. The high tumor-forming capacity of these stem cells makes it necessary to get more comprehensive insight about their biology. Genomics, proteomics, and epigenomics are helpful tools for this purpose. The general step of these high-throughput methods is the isolation of breast cancer stem cells based on specific markers. Another shared feature of these omics approaches is to use a large set of interested genes, transcripts, or proteins. In addition to these two common key features, the remaining experimental setups may change from one to another omics analysis. The outcome of these approaches can yield some signatures, which will be mostly critical for later therapeutic strategies. Taken altogether, omics approaches not only reveal comprehensive understanding about breast cancer stem cells but also open the doors to more effective targeted therapies.

Keywords

“Omics” Genomics Proteomics Epigenomics Gene signature Breast cancer stem cell 

References

  1. 1.
    Wicha M, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res. 2006;66(4):1883–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Regenbrecht CR, Lehrach H, Adjaye J. Stemming cancer: functional genomics of cancer stem cells in solid tumors. Stem Cell Rev. 2008;4:319–28.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Spillane JB, Henderson MA. Cancer stem cells: a review. ANZ J Surg. 2007;77:464–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nat Rev Cancer. 2006;6:425–36.PubMedCrossRefGoogle Scholar
  5. 5.
    Rahman R, Heath R, Grundy R. Cellular immortality in brain tumours: an integration of the cancer stem cell paradigm. Biochim Biophys Acta. 2009;1792(4):280–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Stupp R, Hegi ME. Targeting brain-tumor stem cells. Nat Biotechnol. 2007;25(2):193–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Morrison BJ, Schmidt CW, Lakhani SR, Reynolds BA, Lopez JA. Breast cancer stem cells: implications for therapy of breast cancer. Breast Cancer Res. 2008;10(4):210.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    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(7):3983–8.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Vargo-Gogola T, Rosen JM. Modelling breast cancer: one size does not fit all. Nat Rev Cancer. 2007;7(9):659–72.PubMedCrossRefGoogle Scholar
  10. 10.
    Charafe-Jauffret E, Ginestier C, Birnbaum D. Breast cancer stem cells: tools and models to rely on. BMC Cancer. 2009;9:202.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Cariati M, Naderi A, Brown JP, Smalley MJ, Pinder SE, Caldas C, et al. 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;122:298–304.PubMedCrossRefGoogle Scholar
  12. 12.
    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(5):555–67.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Ali HR, Dawson SJ, Blows FM, Provenzano E, Pharoah PD, Caldas C. Cancer stem cell markers in breast cancer: pathological, clinical and prognostic significance. Breast Cancer Res. 2011;13(6):R118.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Dontu G. Breast cancer stem cell markers—the rocky road to clinical applications. Breast Cancer Res. 2008;10:110. doi:10.1186/bcr2130.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Lehmann C, Jobs G, Thomas M, Burtscher H, Kubbies M. Established breast cancer stem cell markers do not correlate with in vivo tumorigenicity of tumor-initiating cells. Int J Oncol. 2012;41(6):1932–42. doi:10.3892/ijo.2012.1654.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Croker AK, Goodale D, Chu J, Postenka C, Hedley BD, Hess DA, 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(8B):2236–52.PubMedCrossRefGoogle Scholar
  17. 17.
    Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65:5506–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, Giulini B, et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2009;13(6):1083–95.CrossRefGoogle Scholar
  19. 19.
    Sajithlal GB, Rothermund K, Zhang F, Dabbs DJ, Latimer JJ, Grant SG, et al. Permanently blocked stem cells derived from breast cancer cell lines. Stem Cells. 2010;28(6):1008–18.PubMedCrossRefGoogle Scholar
  20. 20.
    Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell. 2010;140(1):62–73.PubMedCrossRefGoogle Scholar
  21. 21.
    Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Hardt O, Wild S, Oerlecke I, Hofmann K, Luo S, Wiencek Y, et al. Highly sensitive profiling of CD44+/CD24- breast cancer stem cells by combining global mRNA amplification and next generation sequencing: evidence for a hyperactive PI3K pathway. Cancer Lett. 2012;325(2):165–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Wend P, Holland J, Ziebold U, Birchmeier W. Wnt signaling in stem and cancer stem cells. Semin Cell Dev Biol. 2010;8:855–63.CrossRefGoogle Scholar
  24. 24.
    Guo S, Liu M, Gonzalez-Perez RR. Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim Biophys Acta. 2011;5(2):197–213.Google Scholar
  25. 25.
    Miller T, Rexer B, Garrett J, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Vollan HK, Caldas C. The breast cancer genome—a key for better oncology. BMC Cancer. 2011;11:501.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Miller LD, Liu ET. Expression genomics in breast cancer research: microarrays at the crossroads of biology and medicine. Breast Cancer Res. 2007;9(2):206.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Budczies J, Weichert W, Noske A, Müller BM, Weller C, Wittenberger T, et al. Genome-wide gene expression profiling of formalin-fixed paraffin-embedded breast cancer core biopsies using microarrays. J Histochem Cytochem. 2011;59(2):146–57.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12(4):395–402.PubMedCrossRefGoogle Scholar
  30. 30.
    Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007;129(6):1065–79.PubMedCrossRefGoogle Scholar
  31. 31.
    Velculescu VE, Zhang L, Vogelstein B, Kinzler KW. Serial analysis of gene expression. Science. 1995;270(5235):484–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29(2):117–29.PubMedCrossRefGoogle Scholar
  33. 33.
    Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009;19(1):103–15.PubMedCrossRefGoogle Scholar
  34. 34.
    Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med. 2007;356(3):217–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Leth-Larsen R, Terp MG, Christensen AG, Elias D, Kühlwein T, Jensen ON, et al. Functional heterogeneity within the CD44 high human breast cancer stem cell-like compartment reveals a gene signature predictive of distant metastasis. Mol Med. 2012;18:1109–21. doi:10.2119/molmed.2012.00091.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Laronga C, Drake RR. Proteomic approach to breast cancer. Cancer Control. 2007;14(4):360–8.PubMedGoogle Scholar
  37. 37.
    Kanojia D, Zhou W, Zhang J, Jie C, Lo PK, Wang Q, et al. Proteomic profiling of cancer stem cells derived from primary tumors of HER2/Neu transgenic mice. Proteomics. 2012. doi:10.1002/pmic.201200103.PubMedGoogle Scholar
  38. 38.
    Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27(47):6120–30.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Cadenas C, Franckenstein D, Schmidt M, Gehrmann M, Hermes M, Geppert B, et al. Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer. Breast Cancer Res. 2010;12(3):R44.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF, et al. Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol. 2004;203(2):661–71.PubMedCrossRefGoogle Scholar
  41. 41.
    Holmes MD, Chen WY, Schnitt SJ, Collins L, Colditz GA, Hankinson SE, et al. COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin. Breast Cancer Res Treat. 2011;130(2):657–62.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, et al. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell. 2004;119(4):529–42.PubMedCrossRefGoogle Scholar
  43. 43.
    Lo PK, Sukumar S. Epigenomics and breast cancer. Pharmacogenomics. 2008. doi:10.2217/14622416.9.12.1879.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8(4):286–98.PubMedCrossRefGoogle Scholar
  45. 45.
    Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, Lambert MP, McKay-Chopin S, Tavtigian SV, et al. Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. Epigenetics. 2011;6(4):428–39.PubMedCrossRefGoogle Scholar
  46. 46.
    Niwa H, Burdon T, Chambers I, Smith A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 1998;12(13):2048–60.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Kiger AA, Jones DL, Schulz C, et al. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science. 2001;294(5551):2542–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Blick T, Widodo E, Hugo H, Waltham M, Lenburg ME, Neve RM, et al. Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis. 2008;25(6):629–42. doi:10.1007/s10585-008-9170-6.PubMedCrossRefGoogle Scholar
  49. 49.
    Trimboli AJ, Fukino K, de Bruin A, Wei G, Shen L, Tanner SM, et al. Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res. 2008;68(3):937–45. doi:10.1158/0008-5472.PubMedCrossRefGoogle Scholar
  50. 50.
    Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3(3):155–66.PubMedCrossRefGoogle Scholar
  51. 51.
    Hartwell KA, Muir B, Reinhardt F, Carpenter AE, Sgroi DC, Weinberg RA. The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc Natl Acad Sci U S A. 2006;103(50):18969–74.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39.PubMedCrossRefGoogle Scholar
  53. 53.
    Hollier BG, Evans K, Mani SA. The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia. 2009;14(1):29–43.PubMedCrossRefGoogle Scholar
  54. 54.
    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Nicolini A, Ferrari P, Fini M, Borsari V, Fallahi P, Antonelli A, et al. Stem cells: their role in breast cancer development and resistance to treatment. Curr Pharm Biotechnol. 2011;12(2):196–205.PubMedCrossRefGoogle Scholar
  57. 57.
    Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 2007;67(5):1979–87.PubMedCrossRefGoogle Scholar
  58. 58.
    Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol. 2004;24(17):7559–66.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Stathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Kouroussis C, Apostolaki S, et al. Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. J Clin Oncol. 2002;20(16):3404–12.PubMedCrossRefGoogle Scholar
  60. 60.
    Xenidis N, Vlachonikolis I, Mavroudis D, Perraki M, Stathopoulou A, Malamos N, et al. Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer. Ann Oncol. 2003;14:849–55.PubMedCrossRefGoogle Scholar
  61. 61.
    Xenidis N, Perraki M, Kafousi M, Apostolaki S, Bolonaki I, Stathopoulou A, et al. Predictive and prognostic value of peripheral blood cytokeratin-19 mRNA-positive cells detected by real-time polymerase chain reaction in node-negative breast cancer patients. J Clin Oncol. 2006;24:3756–62.PubMedCrossRefGoogle Scholar
  62. 62.
    Ignatiadis M, Kallergi G, Ntoulia M, Perraki M, Apostolaki S, Kafousi M, et al. Prognostic value of the molecular detection of circulating tumor cells using a multimarker reverse transcription-PCR assay for cytokeratin 19, mammoglobin A, and HER2 in early breast cancer. Clin Cancer Res. 2008;14(9):2593–600.PubMedCrossRefGoogle Scholar
  63. 63.
    Ignatiadis M, Xenidis N, Perraki M, Apostolaki S, Politaki E, Kafousi M, et al. Different prognostic value of cytokeratin-19 mRNA–positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol. 2007;25(33):5194–202.PubMedCrossRefGoogle Scholar
  64. 64.
    Xenidis N, Ignatiadis M, Apostolaki S, Perraki M, Kalbakis K, Agelaki S, et al. Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol. 2009;27(13):2177–84.PubMedCrossRefGoogle Scholar
  65. 65.
    Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91.PubMedCrossRefGoogle Scholar
  66. 66.
    Mostert B, Sleijfer S, Foekens JA, Gratama JW. Circulating tumor cells (CTCs): detection methods and heir clinical relevance in breast cancer. Cancer Treat Rev. 2009;35:463–74.PubMedCrossRefGoogle Scholar
  67. 67.
    Bonnomet A, Brysse A, Tachsidis A, Waltham M, Thompson EW, Polette M, et al. Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia. 2010;15(2):261–73.PubMedCrossRefGoogle Scholar
  68. 68.
    Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res. 2006;12(19):5615–21.PubMedCrossRefGoogle Scholar
  69. 69.
    Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009;11(4):R46.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Theodoropoulos PA, Polioudaki H, Agelaki S, Kallergi G, Saridaki Z, Mavroudis D, et al. Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. Cancer Lett. 2010;288(1):99–106.PubMedCrossRefGoogle Scholar
  71. 71.
    Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007;131(6):1109–23.PubMedCrossRefGoogle Scholar
  72. 72.
    Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 2009;138(3):592–603.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.PubMedCrossRefGoogle Scholar
  74. 74.
    Yu F, Jiao Y, Zhu Y, Wang Y, Zhu J, Cui X, et al. MicroRNA 34c gene down-regulation via DNA methylation promotes self-renewal and epithelial-mesenchymal transition in breast tumor-initiating cells. J Biol Chem. 2012;287(1):465–73.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Zhu Y, Yu F, Jiao Y, Feng J, Tang W, Yao H, et al. Reduced miR-128 in breast tumor-initiating cells induces chemotherapeutic resistance via Bmi-1 and ABCC5. Clin Cancer Res. 2011;17(22):7105–15.PubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  • Esin Demir
    • 1
  • Bilge Atar
    • 1
  • Dipali Dhawan
    • 2
  • Debmalya Barh
    • 3
  • Mehmet Gunduz
    • 1
  • Esra Gunduz
    • 1
  1. 1.Department of Medical GeneticsTurgut Özal University Medical SchoolAnkaraTurkey
  2. 2.Institute of Life Sciences, Ahmedabad UniversityAhmedabadIndia
  3. 3.Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB)Nonakuri, Purba MedinipurIndia

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