Mammary Stem Cells pp 1-49

Part of the Methods in Molecular Biology book series (MIMB, volume 1293) | Cite as

Breast Cancer Stem Cells: Current Advances and Clinical Implications

  • Ming Luo
  • Shawn G. Clouthier
  • Yadwinder Deol
  • Suling Liu
  • Sunitha Nagrath
  • Ebrahim Azizi
  • Max S. Wicha

Abstract

There is substantial evidence that many cancers, including breast cancer, are driven by a population of cells that display stem cell properties. These cells, termed cancer stem cells (CSCs) or tumor initiating cells, not only drive tumor initiation and growth but also mediate tumor metastasis and therapeutic resistance. In this chapter, we summarize current advances in CSC research with a major focus on breast CSCs (BCSCs). We review the prevailing methods to isolate and characterize BCSCs and recent evidence documenting their cellular origins and phenotypic plasticity that enables them to transition between mesenchymal and epithelial-like states. We describe in vitro and clinical evidence that these cells mediate metastasis and treatment resistance in breast cancer, the development of novel strategies to isolate circulating tumor cells (CTCs) that contain CSCs and the use of patient-derived xenograft (PDX) models in preclinical breast cancer research. Lastly, we highlight several signaling pathways that regulate BCSC self-renewal and describe clinical implications of targeting these cells for breast cancer treatment. The development of strategies to effectively target BCSCs has the potential to significantly improve the outcomes for patients with breast cancer.

Key words

Cancer stem cells (CSCs) Breast cancer Circulating tumor cells (CTCs) Phenotypic plasticity Patient-derived xenograft (PDX) 

References

  1. 1.
    Sternlicht MD et al (2006) Hormonal and local control of mammary branching morphogenesis. Differentiation 74(7):365–381PubMedCentralPubMedGoogle Scholar
  2. 2.
    Hinck L, Silberstein GB (2005) Key stages in mammary gland development: the mammary end bud as a motile organ. Breast Cancer Res 7(6):245–251PubMedCentralPubMedGoogle Scholar
  3. 3.
    Hennighausen L, Robinson GW (2005) Information networks in the mammary gland. Nat Rev Mol Cell Biol 6(9):715–725PubMedGoogle Scholar
  4. 4.
    Smalley M, Ashworth A (2003) Stem cells and breast cancer: a field in transit. Nat Rev Cancer 3(11):832–844PubMedGoogle Scholar
  5. 5.
    Kordon EC, Smith GH (1998) An entire functional mammary gland may comprise the progeny from a single cell. Development 125(10):1921–1930PubMedGoogle Scholar
  6. 6.
    Smith GH (1996) Experimental mammary epithelial morphogenesis in an in vivo model: evidence for distinct cellular progenitors of the ductal and lobular phenotype. Breast Cancer Res Treat 39(1):21–31PubMedGoogle Scholar
  7. 7.
    Asselin-Labat ML et al (2007) Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 9(2):201–209PubMedGoogle Scholar
  8. 8.
    Stingl J et al (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439(7079):993–997PubMedGoogle Scholar
  9. 9.
    Shackleton M et al (2006) Generation of a functional mammary gland from a single stem cell. Nature 439(7072):84–88PubMedGoogle Scholar
  10. 10.
    Sleeman KE et al (2006) CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Res 8(1):R7PubMedCentralPubMedGoogle Scholar
  11. 11.
    Shipitsin M et al (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11(3):259–273PubMedGoogle Scholar
  12. 12.
    Villadsen R et al (2007) Evidence for a stem cell hierarchy in the adult human breast. J Cell Biol 177(1):87–101PubMedCentralPubMedGoogle Scholar
  13. 13.
    Lim E et al (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15(8):907–913PubMedGoogle Scholar
  14. 14.
    Eirew P et al (2008) A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability. Nat Med 14(12):1384–1389PubMedGoogle Scholar
  15. 15.
    Keller PJ et al (2011) Defining the cellular precursors to human breast cancer. Proc Natl Acad Sci U S A 109:2772–2777PubMedCentralPubMedGoogle Scholar
  16. 16.
    Visvader JE (2009) Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev 23(22):2563–2577PubMedCentralPubMedGoogle Scholar
  17. 17.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737PubMedGoogle Scholar
  18. 18.
    Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea—a paradigm shift. Cancer Res 66(4):1883–1890, discussion 1895-6PubMedGoogle Scholar
  19. 19.
    Liu S, Wicha MS (2010) Targeting breast cancer stem cells. J Clin Oncol 28(25):4006–4012PubMedGoogle Scholar
  20. 20.
    Charafe-Jauffret E et al (2008) Cancer stem cells in breast: current opinion and future challenges. Pathobiology 75(2):75–84PubMedCentralPubMedGoogle Scholar
  21. 21.
    Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988PubMedCentralPubMedGoogle Scholar
  22. 22.
    Ginestier C et al (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):555–567PubMedCentralPubMedGoogle Scholar
  23. 23.
    Liu S et al (2014) Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2(1):78–91PubMedCentralPubMedGoogle Scholar
  24. 24.
    Singh SK et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401PubMedGoogle Scholar
  25. 25.
    Collins AT et al (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65(23):10946–10951PubMedGoogle Scholar
  26. 26.
    Patrawala L et al (2006) Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25(12):1696–1708PubMedGoogle Scholar
  27. 27.
    O’Brien CA et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110PubMedGoogle Scholar
  28. 28.
    Ricci-Vitiani L et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115PubMedGoogle Scholar
  29. 29.
    Li C et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037PubMedGoogle Scholar
  30. 30.
    Ma S et al (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132(7):2542–2556PubMedGoogle Scholar
  31. 31.
    Ma S et al (2010) MiR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 7(6):694–707PubMedGoogle Scholar
  32. 32.
    Kim CF et al (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121(6):823–835PubMedGoogle Scholar
  33. 33.
    Prince ME et al (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 104(3):973–978PubMedCentralPubMedGoogle Scholar
  34. 34.
    Mukherjee S (2010) The emperor of all maladies: a biography of cancer. 1st Scribner hardcover ed, vol 14. Scribner, New York, NY, p 571, 8 p. of platesGoogle Scholar
  35. 35.
    Huntly BJ, Gilliland DG (2005) Cancer biology: summing up cancer stem cells. Nature 435(7046):1169–1170PubMedGoogle Scholar
  36. 36.
    Sell S (2004) Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 51(1):1–28PubMedGoogle Scholar
  37. 37.
    Xu Q et al (2009) Isolation of tumour stem-like cells from benign tumours. Br J Cancer 101(2):303–311PubMedCentralPubMedGoogle Scholar
  38. 38.
    Clay MR et al (2010) Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck 32(9):1195–1201PubMedCentralPubMedGoogle Scholar
  39. 39.
    Silva IA et al (2011) Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res 71(11):3991–4001PubMedCentralPubMedGoogle Scholar
  40. 40.
    Krishnamurthy S et al (2010) Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Res 70(23):9969–9978PubMedCentralPubMedGoogle Scholar
  41. 41.
    Fang D et al (2005) A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65(20):9328–9337PubMedGoogle Scholar
  42. 42.
    Quintana E et al (2008) Efficient tumour formation by single human melanoma cells. Nature 456(7222):593–598PubMedCentralPubMedGoogle Scholar
  43. 43.
    Roesch A et al (2010) A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141(4):583–594PubMedCentralPubMedGoogle Scholar
  44. 44.
    Boiko AD et al (2010) Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466(7302):133–137PubMedCentralPubMedGoogle Scholar
  45. 45.
    Luo Y et al (2012) ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets. Stem Cells 30(10):2100–2113PubMedCentralPubMedGoogle Scholar
  46. 46.
    Kelly PN et al (2007) Tumor growth need not be driven by rare cancer stem cells. Science 317(5836):337PubMedGoogle Scholar
  47. 47.
    Charafe-Jauffret E et al (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69(4):1302–1313PubMedCentralPubMedGoogle Scholar
  48. 48.
    Charafe-Jauffret E et al (2013) ALDH1-positive cancer stem cells predict engraftment of primary breast tumors and are governed by a common stem cell program. Cancer Res 73(24):7290–7300PubMedGoogle Scholar
  49. 49.
    Pece S et al (2010) Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 140(1):62–73PubMedGoogle Scholar
  50. 50.
    Bunting KD (2002) ABC transporters as phenotypic markers and functional regulators of stem cells. Stem Cells 20(1):11–20PubMedGoogle Scholar
  51. 51.
    Hadnagy A et al (2006) SP analysis may be used to identify cancer stem cell populations. Exp Cell Res 312(19):3701–3710PubMedGoogle Scholar
  52. 52.
    Hirschmann-Jax C et al (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 101(39):14228–14233PubMedCentralPubMedGoogle Scholar
  53. 53.
    Kondo T, Setoguchi T, Taga T (2004) Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A 101(3):781–786PubMedCentralPubMedGoogle Scholar
  54. 54.
    Clarke RB et al (2005) A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev Biol 277(2):443–456PubMedGoogle Scholar
  55. 55.
    Alvi AJ et al (2003) Functional and molecular characterisation of mammary side population cells. Breast Cancer Res 5(1):R1–R8PubMedCentralPubMedGoogle Scholar
  56. 56.
    Clayton H, Titley I, Vivanco M (2004) Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Exp Cell Res 297(2):444–460PubMedGoogle Scholar
  57. 57.
    Welm BE et al (2002) Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 245(1):42–56PubMedGoogle Scholar
  58. 58.
    Patrawala L et al (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res 65(14):6207–6219PubMedGoogle Scholar
  59. 59.
    Britton KM et al (2012) Breast cancer, side population cells and ABCG2 expression. Cancer Lett 323(1):97–105PubMedGoogle Scholar
  60. 60.
    Nakanishi T et al (2010) Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling. Br J Cancer 102(5):815–826PubMedCentralPubMedGoogle Scholar
  61. 61.
    Mani SA et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715PubMedCentralPubMedGoogle Scholar
  62. 62.
    Marotta LL et al (2011) The JAK2/STAT3 signaling pathway is required for growth of CD44CD24 stem cell-like breast cancer cells in human tumors. J Clin Invest 121(7):2723–2735PubMedCentralPubMedGoogle Scholar
  63. 63.
    Honeth G et al (2008) The CD44+/CD24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res 10(3):R53PubMedCentralPubMedGoogle Scholar
  64. 64.
    Meyer MJ et al (2010) CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer. Cancer Res 70(11):4624–4633PubMedCentralPubMedGoogle Scholar
  65. 65.
    Friedrichs K et al (1995) High expression level of alpha 6 integrin in human breast carcinoma is correlated with reduced survival. Cancer Res 55(4):901–906PubMedGoogle Scholar
  66. 66.
    Lipscomb EA et al (2005) The alpha6beta4 integrin maintains the survival of human breast carcinoma cells in vivo. Cancer Res 65(23):10970–10976PubMedGoogle Scholar
  67. 67.
    Chute JP et al (2006) Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci U S A 103(31):11707–11712PubMedCentralPubMedGoogle Scholar
  68. 68.
    Storms RW et al (1999) Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc Natl Acad Sci U S A 96(16):9118–9123PubMedCentralPubMedGoogle Scholar
  69. 69.
    Ludeman SM (1999) The chemistry of the metabolites of cyclophosphamide. Curr Pharm Des 5(8):627–643PubMedGoogle Scholar
  70. 70.
    Cheung AM et al (2007) Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential. Leukemia 21(7):1423–1430PubMedGoogle Scholar
  71. 71.
    Sullivan JP et al (2010) Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Res 70(23):9937–9948PubMedCentralPubMedGoogle Scholar
  72. 72.
    Huang EH et al (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69(8):3382–3389PubMedCentralPubMedGoogle Scholar
  73. 73.
    Carpentino JE et al (2009) Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res 69(20):8208–8215PubMedCentralPubMedGoogle Scholar
  74. 74.
    van den Hoogen C et al (2010) High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res 70(12):5163–5173PubMedGoogle Scholar
  75. 75.
    Dontu G et al (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17(10):1253–1270PubMedCentralPubMedGoogle Scholar
  76. 76.
    D’Angelo RC, Wicha MS (2010) Stem cells in normal development and cancer. Prog Mol Biol Transl Sci 95:113–158PubMedGoogle Scholar
  77. 77.
    Kusumbe AP, Bapat SA (2009) Cancer stem cells and aneuploid populations within developing tumors are the major determinants of tumor dormancy. Cancer Res 69(24):9245–9253PubMedGoogle Scholar
  78. 78.
    Hendrikx PJ et al (1996) Homing of fluorescently labeled murine hematopoietic stem cells. Exp Hematol 24(2):129–140PubMedGoogle Scholar
  79. 79.
    Lanzkron SM, Collector MI, Sharkis SJ (1999) Homing of long-term and short-term engrafting cells in vivo. Ann N Y Acad Sci 872:48–54, discussion 54-6PubMedGoogle Scholar
  80. 80.
    Askenasy N, Farkas DL (2002) Optical imaging of PKH-labeled hematopoietic cells in recipient bone marrow in vivo. Stem Cells 20(6):501–513PubMedGoogle Scholar
  81. 81.
    Cicalese A et al (2009) The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138(6):1083–1095PubMedGoogle Scholar
  82. 82.
    Lassailly F, Griessinger E, Bonnet D (2010) “Microenvironmental contaminations” induced by fluorescent lipophilic dyes used for noninvasive in vitro and in vivo cell tracking. Blood 115(26):5347–5354PubMedGoogle Scholar
  83. 83.
    Liu S, Clouthier SG, Wicha MS (2012) Role of microRNAs in the regulation of breast cancer stem cells. J Mammary Gland Biol Neoplasia 17(1):15–21PubMedCentralPubMedGoogle Scholar
  84. 84.
    Liu S et al (2012) MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genet 8(6):e1002751PubMedCentralPubMedGoogle Scholar
  85. 85.
    Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15(6):740–746PubMedGoogle Scholar
  86. 86.
    Yang J et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939PubMedGoogle Scholar
  87. 87.
    Wu Y et al (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15(5):416–428PubMedCentralPubMedGoogle Scholar
  88. 88.
    Yang MH et al (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10(3):295–305PubMedGoogle Scholar
  89. 89.
    Samavarchi-Tehrani P et al (2010) Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7(1):64–77PubMedGoogle Scholar
  90. 90.
    Brabletz T (2012) To differentiate or not: routes towards metastasis. Nat Rev Cancer 12(6):425–436PubMedGoogle Scholar
  91. 91.
    Tsai JH et al (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22(6):725–736PubMedCentralPubMedGoogle Scholar
  92. 92.
    Ocana OH et al (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22(6):709–724PubMedGoogle Scholar
  93. 93.
    Malanchi I et al (2012) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481(7379):85–89Google Scholar
  94. 94.
    Korpal M et al (2011) Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 17(9):1101–1108PubMedCentralPubMedGoogle Scholar
  95. 95.
    Stankic M et al (2013) TGF-beta-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep 5(5):1228–1242PubMedCentralPubMedGoogle Scholar
  96. 96.
    Herschkowitz JI et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76PubMedCentralPubMedGoogle Scholar
  97. 97.
    Perou CM et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752PubMedGoogle Scholar
  98. 98.
    Sorlie T et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98(19):10869–10874PubMedCentralPubMedGoogle Scholar
  99. 99.
    Sotiriou C et al (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 100(18):10393–10398PubMedCentralPubMedGoogle Scholar
  100. 100.
    Chang JC et al (2005) Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. J Clin Oncol 23(6):1169–1177PubMedGoogle Scholar
  101. 101.
    Creighton CJ et al (2009) Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A 106(33):13820–13825PubMedCentralPubMedGoogle Scholar
  102. 102.
    Molyneux G et al (2010) BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7(3):403–417PubMedGoogle Scholar
  103. 103.
    Proia TA et al (2011) Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem Cell 8(2):149–163PubMedCentralPubMedGoogle Scholar
  104. 104.
    Keller PJ et al (2012) Defining the cellular precursors to human breast cancer. Proc Natl Acad Sci U S A 109(8):2772–2777PubMedCentralPubMedGoogle Scholar
  105. 105.
    Van Keymeulen A et al (2011) Distinct stem cells contribute to mammary gland development and maintenance. Nature 479(7372):189–193PubMedGoogle Scholar
  106. 106.
    Jeselsohn R et al (2010) Cyclin D1 kinase activity is required for the self-renewal of mammary stem and progenitor cells that are targets of MMTV-ErbB2 tumorigenesis. Cancer Cell 17(1):65–76PubMedCentralPubMedGoogle Scholar
  107. 107.
    Liu S et al (2008) BRCA1 regulates human mammary stem/progenitor cell fate. Proc Natl Acad Sci U S A 105(5):1680–1685PubMedCentralPubMedGoogle Scholar
  108. 108.
    Lagadec C et al (2010) Survival and self-renewing capacity of breast cancer initiating cells during fractionated radiation treatment. Breast Cancer Res 12(1):R13PubMedCentralPubMedGoogle Scholar
  109. 109.
    Phillips TM, McBride WH, Pajonk F (2006) The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98(24):1777–1785PubMedGoogle Scholar
  110. 110.
    Karimi-Busheri F et al (2010) Senescence evasion by MCF-7 human breast tumor-initiating cells. Breast Cancer Res 12(3):R31PubMedCentralPubMedGoogle Scholar
  111. 111.
    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(2):R25PubMedCentralPubMedGoogle Scholar
  112. 112.
    Shafee N et al (2008) Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. Cancer Res 68(9):3243–3250PubMedCentralPubMedGoogle Scholar
  113. 113.
    Woodward WA et al (2007) WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci U S A 104(2):618–623PubMedCentralPubMedGoogle Scholar
  114. 114.
    Diehn M et al (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239):780–783PubMedCentralPubMedGoogle Scholar
  115. 115.
    Yu F et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131(6):1109–23PubMedGoogle Scholar
  116. 116.
    Zielske SP et al (2011) Ablation of breast cancer stem cells with radiation. Transl Oncol 4(4):227–233PubMedCentralPubMedGoogle Scholar
  117. 117.
    Li X et al (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100(9):672–679PubMedGoogle Scholar
  118. 118.
    Korkaya H et al (2008) HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 27(47):6120–6130PubMedCentralPubMedGoogle Scholar
  119. 119.
    Tanei T et al (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(12):4234–4241PubMedGoogle Scholar
  120. 120.
    Behbod F et al (2006) Transcriptional profiling of mammary gland side population cells. Stem Cells 24(4):1065–1074PubMedGoogle Scholar
  121. 121.
    Ithimakin S et al (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res 73(5):1635–1646PubMedCentralPubMedGoogle Scholar
  122. 122.
    Sladek NE (2003) Human aldehyde dehydrogenases: potential pathological, pharmacological, and toxicological impact. J Biochem Mol Toxicol 17(1):7–23PubMedGoogle Scholar
  123. 123.
    Su Y et al (2010) Aldehyde dehydrogenase 1 A1-positive cell population is enriched in tumor-initiating cells and associated with progression of bladder cancer. Cancer Epidemiol Biomarkers Prev 19(2):327–337PubMedCentralPubMedGoogle Scholar
  124. 124.
    Kim MP et al (2011) ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PLoS One 6(6):e20636PubMedCentralPubMedGoogle Scholar
  125. 125.
    Landen CN Jr et al (2010) Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Mol Cancer Ther 9(12):3186–3199PubMedCentralPubMedGoogle Scholar
  126. 126.
    Magni M et al (1996) Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood 87(3):1097–1103PubMedGoogle Scholar
  127. 127.
    Moreb J et al (1996) Overexpression of the human aldehyde dehydrogenase class I results in increased resistance to 4-hydroperoxycyclophosphamide. Cancer Gene Ther 3(1):24–30PubMedGoogle Scholar
  128. 128.
    Moreb JS et al (2000) Expression of antisense RNA to aldehyde dehydrogenase class-1 sensitizes tumor cells to 4-hydroperoxycyclophosphamide in vitro. J Pharmacol Exp Ther 293(2):390–396PubMedGoogle Scholar
  129. 129.
    Sun QL et al (2011) Comparative proteomic analysis of paclitaxel sensitive A549 lung adenocarcinoma cell line and its resistant counterpart A549-Taxol. J Cancer Res Clin Oncol 137(3):521–532PubMedGoogle Scholar
  130. 130.
    Sladek NE et al (2002) Cellular levels of aldehyde dehydrogenases (ALDH1A1 and ALDH3A1) as predictors of therapeutic responses to cyclophosphamide-based chemotherapy of breast cancer: a retrospective study. Rational individualization of oxazaphosphorine-based cancer chemotherapeutic regimens. Cancer Chemother Pharmacol 49(4):309–321PubMedGoogle Scholar
  131. 131.
    Croker AK, Allan AL (2012) Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44(+) human breast cancer cells. Breast Cancer Res Treat 133(1):75–87PubMedGoogle Scholar
  132. 132.
    Ward JF (1985) Biochemistry of DNA lesions. Radiat Res Suppl 8:S103–S111PubMedGoogle Scholar
  133. 133.
    Powell S, McMillan TJ (1990) DNA damage and repair following treatment with ionizing radiation. Radiother Oncol 19(2):95–108PubMedGoogle Scholar
  134. 134.
    Kryston TB et al (2011) Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res 711(1–2):193–201PubMedGoogle Scholar
  135. 135.
    Smith J et al (2000) Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci U S A 97(18):10032–10037PubMedCentralPubMedGoogle Scholar
  136. 136.
    Ito K et al (2004) Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431(7011):997–1002PubMedGoogle Scholar
  137. 137.
    Ito K et al (2006) Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12(4):446–451PubMedGoogle Scholar
  138. 138.
    Tothova Z et al (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128(2):325–339PubMedGoogle Scholar
  139. 139.
    Miyamoto K et al (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1(1):101–112PubMedGoogle Scholar
  140. 140.
    Guzman ML et al (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105(11):4163–4169PubMedCentralPubMedGoogle Scholar
  141. 141.
    Bao S et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760PubMedGoogle Scholar
  142. 142.
    Yin H, Glass J (2011) The phenotypic radiation resistance of CD44+/CD24(-or low) breast cancer cells is mediated through the enhanced activation of ATM signaling. PLoS One 6(9):e24080PubMedCentralPubMedGoogle Scholar
  143. 143.
    Zhang M, Atkinson RL, Rosen JM (2010) Selective targeting of radiation-resistant tumor-initiating cells. Proc Natl Acad Sci U S A 107(8):3522–3527PubMedCentralPubMedGoogle Scholar
  144. 144.
    Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4(1):33–45PubMedGoogle Scholar
  145. 145.
    Cheng C, Yaffe MB, Sharp PA (2006) A positive feedback loop couples Ras activation and CD44 alternative splicing. Genes Dev 20(13):1715–1720PubMedCentralPubMedGoogle Scholar
  146. 146.
    Orian-Rousseau V et al (2002) CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16(23):3074–3086PubMedCentralPubMedGoogle Scholar
  147. 147.
    Sherman LS et al (2000) CD44 enhances neuregulin signaling by Schwann cells. J Cell Biol 150(5):1071–1084PubMedCentralPubMedGoogle Scholar
  148. 148.
    Bourguignon LY et al (1997) Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation. J Biol Chem 272(44):27913–27918PubMedGoogle Scholar
  149. 149.
    Draffin JE et al (2004) CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res 64(16):5702–5711PubMedGoogle Scholar
  150. 150.
    Hiraga T, Ito S, Nakamura H (2013) Cancer stem-like cell marker CD44 promotes bone metastases by enhancing tumorigenicity, cell motility, and hyaluronan production. Cancer Res 73(13):4112–4122PubMedGoogle Scholar
  151. 151.
    Brown RL et al (2011) CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest 121(3):1064–1074PubMedCentralPubMedGoogle Scholar
  152. 152.
    Kouros-Mehr H et al (2008) GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13(2):141–152PubMedCentralPubMedGoogle Scholar
  153. 153.
    Schabath H et al (2006) CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells. J Cell Sci 119(Pt 2):314–325PubMedGoogle Scholar
  154. 154.
    Cojoc M et al (2013) Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther 6:1347–1361PubMedCentralPubMedGoogle Scholar
  155. 155.
    Sheridan C et al (2006) CD44+/CD24− breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 8(5):R59PubMedCentralPubMedGoogle Scholar
  156. 156.
    Liu R et al (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356(3):217–226PubMedGoogle Scholar
  157. 157.
    Balic M et al (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12(19):5615–5621PubMedGoogle Scholar
  158. 158.
    Liu H et al (2010) Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci U S A 107(42):18115–18120PubMedCentralPubMedGoogle Scholar
  159. 159.
    Theodoropoulos PA et al (2010) Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. Cancer Lett 288(1):99–106PubMedGoogle Scholar
  160. 160.
    Charafe-Jauffret E et al (2010) Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res 16(1):45–55PubMedCentralPubMedGoogle Scholar
  161. 161.
    Liu S et al (2011) Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 71(2):614–624PubMedCentralPubMedGoogle Scholar
  162. 162.
    Lianidou ES, Markou A (2011) Circulating tumor cells in breast cancer: detection systems, molecular characterization, and future challenges. Clin Chem 57(9):1242–1255PubMedGoogle Scholar
  163. 163.
    Murray NP et al (2012) Redefining micrometastasis in prostate cancer: a comparison of circulating prostate cells, bone marrow disseminated tumor cells and micrometastasis—implications in determining local or systemic treatment for biochemical failure after radical prostatectomy. Int J Mol Med 30(4):896–904PubMedGoogle Scholar
  164. 164.
    Cristofanilli M et al (2005) Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23(7):1420–1430PubMedGoogle Scholar
  165. 165.
    Joosse SA, Pantel K (2013) Biologic challenges in the detection of circulating tumor cells. Cancer Res 73(1):8–11PubMedGoogle Scholar
  166. 166.
    Maheswaran S et al (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359(4):366–377PubMedCentralPubMedGoogle Scholar
  167. 167.
    Nagrath S et al (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173):1235–1239PubMedCentralPubMedGoogle Scholar
  168. 168.
    Baccelli I et al (2013) Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31(6):539–544PubMedGoogle Scholar
  169. 169.
    Zhang L et al (2013) The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med 5(180):180ra48PubMedGoogle Scholar
  170. 170.
    Yu M et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584PubMedCentralPubMedGoogle Scholar
  171. 171.
    Pestrin M et al (2012) Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study. Breast Cancer Res Treat 134(1):283–289PubMedGoogle Scholar
  172. 172.
    Giordano A et al (2011) Artificial neural network analysis of circulating tumor cells in metastatic breast cancer patients. Breast Cancer Res Treat 129(2):451–458PubMedGoogle Scholar
  173. 173.
    Cohen SJ et al (2009) Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 20(7):1223–1229PubMedGoogle Scholar
  174. 174.
    Olmos D et al (2009) Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience. Ann Oncol 20(1):27–33PubMedGoogle Scholar
  175. 175.
    Allard WJ et al (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10(20):6897–6904PubMedGoogle Scholar
  176. 176.
    Whitesides GM (2006) The origins and the future of microfluidics. Nature 442(7101):368–373PubMedGoogle Scholar
  177. 177.
    Khandurina J et al (2000) Integrated system for rapid PCR-based DNA analysis in microfluidic devices. Anal Chem 72(13):2995–3000PubMedGoogle Scholar
  178. 178.
    Erickson D et al (2004) Electrokinetically controlled DNA hybridization microfluidic chip enabling rapid target analysis. Anal Chem 76(24):7269–7277PubMedGoogle Scholar
  179. 179.
    Haeberle S, Zengerle R (2007) Microfluidic platforms for lab-on-a-chip applications. Lab Chip 7(9):1094–1110PubMedGoogle Scholar
  180. 180.
    Gleghorn JP et al (2010) Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. Lab Chip 10(1):27–29PubMedCentralPubMedGoogle Scholar
  181. 181.
    Adams AA et al (2008) Highly efficient circulating tumor cell isolation from whole blood and label-free enumeration using polymer-based microfluidics with an integrated conductivity sensor. J Am Chem Soc 130(27):8633–8641PubMedCentralPubMedGoogle Scholar
  182. 182.
    Stott SL et al (2010) Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci U S A 107(43):18392–18397PubMedCentralPubMedGoogle Scholar
  183. 183.
    Yoon HJ et al (2013) Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets. Nat Nanotechnol 8(10):735–741PubMedCentralPubMedGoogle Scholar
  184. 184.
    Lin HK et al (2010) Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin Cancer Res 16(20):5011–5018PubMedCentralPubMedGoogle Scholar
  185. 185.
    Vona G et al (2004) Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology 39(3):792–797PubMedGoogle Scholar
  186. 186.
    Zheng S et al (2007) Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells. J Chromatogr A 1162(2):154–161PubMedGoogle Scholar
  187. 187.
    Zheng S et al (2011) 3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood. Biomed Microdevices 13(1):203–213PubMedGoogle Scholar
  188. 188.
    Kuo JS et al (2010) Deformability considerations in filtration of biological cells. Lab Chip 10(7):837–842PubMedGoogle Scholar
  189. 189.
    Zhou J, Papautsky I (2013) Fundamentals of inertial focusing in microchannels. Lab Chip 13(6):1121–1132PubMedGoogle Scholar
  190. 190.
    Bhagat AA, Kuntaegowdanahalli SS, Papautsky I (2008) Continuous particle separation in spiral microchannels using Dean flows and differential migration. Lab Chip 8(11):1906–1914PubMedGoogle Scholar
  191. 191.
    Hou HW et al (2013) Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci Rep 3:1259PubMedCentralPubMedGoogle Scholar
  192. 192.
    Ozkumur E et al (2013) Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl Med 5(179):179ra47PubMedCentralPubMedGoogle Scholar
  193. 193.
    Zhang W et al (2012) Microfluidics separation reveals the stem-cell-like deformability of tumor-initiating cells. Proc Natl Acad Sci U S A 109(46):18707–18712PubMedCentralPubMedGoogle Scholar
  194. 194.
    Kuperwasser C et al (2004) Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci U S A 101(14):4966–4971PubMedCentralPubMedGoogle Scholar
  195. 195.
    DeRose YS et al (2011) Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med 17(11):1514–1520PubMedCentralPubMedGoogle Scholar
  196. 196.
    Zhang X et al (2013) A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res 73(15):4885–4897PubMedCentralPubMedGoogle Scholar
  197. 197.
    Marangoni E et al (2007) A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res 13(13):3989–3998PubMedGoogle Scholar
  198. 198.
    Beckhove P et al (2003) Efficient engraftment of human primary breast cancer transplants in nonconditioned NOD/Scid mice. Int J Cancer 105(4):444–453PubMedGoogle Scholar
  199. 199.
    Bergamaschi A et al (2009) Molecular profiling and characterization of luminal-like and basal-like in vivo breast cancer xenograft models. Mol Oncol 3(5–6):469–482PubMedGoogle Scholar
  200. 200.
    du Manoir S et al (2013) Breast tumor PDXs are genetically plastic and correspond to a subset of aggressive cancers prone to relapse. Mol Oncol 8:431–43PubMedGoogle Scholar
  201. 201.
    Clarke R et al (2001) Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev 53(1):25–71PubMedGoogle Scholar
  202. 202.
    Cottu P et al (2012) Modeling of response to endocrine therapy in a panel of human luminal breast cancer xenografts. Breast Cancer Res Treat 133(2):595–606PubMedGoogle Scholar
  203. 203.
    Kabos P et al (2012) Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures. Breast Cancer Res Treat 135(2):415–432PubMedGoogle Scholar
  204. 204.
    Ginestier C et al (2010) CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 120(2):485–497PubMedCentralPubMedGoogle Scholar
  205. 205.
    Turkson J, Jove R (2000) STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19(56):6613–6626PubMedGoogle Scholar
  206. 206.
    Redell MS, Tweardy DJ (2005) Targeting transcription factors for cancer therapy. Curr Pharm Des 11(22):2873–2887PubMedGoogle Scholar
  207. 207.
    Chen Z, Han ZC (2008) STAT3: a critical transcription activator in angiogenesis. Med Res Rev 28(2):185–200PubMedGoogle Scholar
  208. 208.
    Dave B et al (2012) Selective small molecule Stat3 inhibitor reduces breast cancer tumor-initiating cells and improves recurrence free survival in a human-xenograft model. PLoS One 7(8):e30207PubMedCentralPubMedGoogle Scholar
  209. 209.
    Noguera-Troise I et al (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444(7122):1032–1037PubMedGoogle Scholar
  210. 210.
    Ridgway J et al (2006) Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444(7122):1083–1087PubMedGoogle Scholar
  211. 211.
    Scehnet JS et al (2007) Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109(11):4753–4760PubMedCentralPubMedGoogle Scholar
  212. 212.
    Hoey T et al (2009) DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5(2):168–177PubMedGoogle Scholar
  213. 213.
    Schott AF et al (2013) Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res 19(6):1512–1524PubMedCentralPubMedGoogle Scholar
  214. 214.
    Todaro M et al (2013) Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy. Cancer Res 73(21):6393–6400PubMedGoogle Scholar
  215. 215.
    Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15(23):3059–3087PubMedGoogle Scholar
  216. 216.
    Liu S et al (2006) Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66(12):6063–6071PubMedCentralPubMedGoogle Scholar
  217. 217.
    Kubo M et al (2004) Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 64(17):6071–6074PubMedGoogle Scholar
  218. 218.
    Tremblay MR et al (2008) Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists. J Med Chem 51(21):6646–6649PubMedGoogle Scholar
  219. 219.
    Robarge KD et al (2009) GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett 19(19):5576–5581PubMedGoogle Scholar
  220. 220.
    Olive KP et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461PubMedCentralPubMedGoogle Scholar
  221. 221.
    Chiba S (2006) Notch signaling in stem cell systems. Stem Cells 24(11):2437–2447PubMedGoogle Scholar
  222. 222.
    Roy M, Pear WS, Aster JC (2007) The multifaceted role of Notch in cancer. Curr Opin Genet Dev 17(1):52–59PubMedGoogle Scholar
  223. 223.
    Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3(10):756–767PubMedGoogle Scholar
  224. 224.
    Jhappan C et al (1992) Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev 6(3):345–355PubMedGoogle Scholar
  225. 225.
    Bouras T et al (2008) Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell 3(4):429–441PubMedGoogle Scholar
  226. 226.
    Reedijk M et al (2005) High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 65(18):8530–8537PubMedGoogle Scholar
  227. 227.
    Harrison H et al (2010) Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 70(2):709–718PubMedCentralPubMedGoogle Scholar
  228. 228.
    Zang S et al (2010) RNAi-mediated knockdown of Notch-1 leads to cell growth inhibition and enhanced chemosensitivity in human breast cancer. Oncol Rep 23(4):893–899PubMedGoogle Scholar
  229. 229.
    Olsauskas-Kuprys R, Zlobin A, Osipo C (2013) Gamma secretase inhibitors of Notch signaling. Onco Targets Ther 6:943–955PubMedCentralPubMedGoogle Scholar
  230. 230.
    Lindsay J et al (2008) ErbB2 induces Notch1 activity and function in breast cancer cells. Clin Transl Sci 1(2):107–115PubMedCentralPubMedGoogle Scholar
  231. 231.
    Farnie G et al (2013) Combined inhibition of ErbB1/2 and Notch receptors effectively targets breast ductal carcinoma in situ (DCIS) stem/progenitor cell activity regardless of ErbB2 status. PLoS One 8(2):e56840PubMedCentralPubMedGoogle Scholar
  232. 232.
    Osipo C et al (2008) ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene 27(37):5019–5032PubMedGoogle Scholar
  233. 233.
    Won HY et al (2012) Loss of Mel-18 enhances breast cancer stem cell activity and tumorigenicity through activating Notch signaling mediated by the Wnt/TCF pathway. FASEB J 26(12):5002–5013PubMedGoogle Scholar
  234. 234.
    Rexer BN, Arteaga CL (2013) Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications. Cancer Res 73(13):3817–3820PubMedCentralPubMedGoogle Scholar
  235. 235.
    Nagata Y et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127PubMedGoogle Scholar
  236. 236.
    Korkaya H et al (2009) Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol 7(6):e1000121PubMedCentralPubMedGoogle Scholar
  237. 237.
    Junttila TT et al (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15(5):429–440PubMedGoogle Scholar
  238. 238.
    Serra V et al (2008) NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68(19):8022–8030PubMedGoogle Scholar
  239. 239.
    Andre F et al (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28(34):5110–5115PubMedGoogle Scholar
  240. 240.
    Chakrabarty A et al (2013) Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. Cancer Res 73(3):1190–1200PubMedCentralPubMedGoogle Scholar
  241. 241.
    Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8(5):387–398PubMedGoogle Scholar
  242. 242.
    Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810PubMedGoogle Scholar
  243. 243.
    Badders NM et al (2009) The Wnt receptor, Lrp5, is expressed by mouse mammary stem cells and is required to maintain the basal lineage. PLoS One 4(8):e6594PubMedCentralPubMedGoogle Scholar
  244. 244.
    Bafico A et al (2004) An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 6(5):497–506PubMedGoogle Scholar
  245. 245.
    Klopocki E et al (2004) Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors. Int J Oncol 25(3):641–649PubMedGoogle Scholar
  246. 246.
    Nagahata T et al (2003) Amplification, up-regulation and over-expression of DVL-1, the human counterpart of the Drosophila disheveled gene, in primary breast cancers. Cancer Sci 94(6):515–518PubMedGoogle Scholar
  247. 247.
    Nakopoulou L et al (2006) Study of phospho-beta-catenin subcellular distribution in invasive breast carcinomas in relation to their phenotype and the clinical outcome. Mod Pathol 19(4):556–563PubMedGoogle Scholar
  248. 248.
    Piva et al (2014) Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med 6:66–79Google Scholar
  249. 249.
    Li Y et al (2003) Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A 100(26):15853–15858PubMedCentralPubMedGoogle Scholar
  250. 250.
    Liu BY et al (2004) The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci U S A 101(12):4158–4163PubMedCentralPubMedGoogle Scholar
  251. 251.
    Conley SJ et al (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109(8):2784–2789PubMedCentralPubMedGoogle Scholar
  252. 252.
    Yang ZQ et al (2009) Methylation-associated silencing of SFRP1 with an 8p11-12 amplification inhibits canonical and non-canonical WNT pathways in breast cancers. Int J Cancer 125(7):1613–1621PubMedCentralPubMedGoogle Scholar
  253. 253.
    He B et al (2004) A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia 6(1):7–14PubMedCentralPubMedGoogle Scholar
  254. 254.
    DeAlmeida VI et al (2007) The soluble wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res 67(11):5371–5379PubMedGoogle Scholar
  255. 255.
    Albini A, Sporn MB (2007) The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7(2):139–147PubMedGoogle Scholar
  256. 256.
    Karnoub AE et al (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563PubMedGoogle Scholar
  257. 257.
    Asselin-Labat ML et al (2010) Control of mammary stem cell function by steroid hormone signalling. Nature 465(7299):798–802PubMedGoogle Scholar
  258. 258.
    Fillmore CM et al (2010) Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci U S A 107(50):21737–21742PubMedCentralPubMedGoogle Scholar
  259. 259.
    Pierce BL et al (2009) Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol 27(21):3437–3444PubMedCentralPubMedGoogle Scholar
  260. 260.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867PubMedCentralPubMedGoogle Scholar
  261. 261.
    Sansone P et al (2007) IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117(12):3988–4002PubMedCentralPubMedGoogle Scholar
  262. 262.
    Conze D et al (2001) Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res 61(24):8851–8858PubMedGoogle Scholar
  263. 263.
    Iliopoulos D, Hirsch HA, Struhl K (2009) An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139(4):693–706PubMedCentralPubMedGoogle Scholar
  264. 264.
    Korkaya H et al (2012) Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell 47(4):570–584PubMedCentralPubMedGoogle Scholar
  265. 265.
    Germain D, Frank DA (2007) Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 13(19):5665–5669PubMedGoogle Scholar
  266. 266.
    Lin L et al (2013) Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24− subpopulations of breast cancer cells. PLoS One 8(12):e82821PubMedCentralPubMedGoogle Scholar
  267. 267.
    Yu F et al (2010) Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene 29(29):4194–4204PubMedGoogle Scholar
  268. 268.
    Shimono Y et al (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138(3):592–603PubMedCentralPubMedGoogle Scholar
  269. 269.
    World Health Organization (2012) Cancer Fact Sheet N297. http://publications.cancerresearchuk.org/downloads/product/CS_REPORT_WORLD.pdf
  270. 270.
    Phend C (2011) Breast cervical cancer kill 625,000 women each year. (3/25/12). http://abcnews.go.com/Health/breast-cervical-cancers-rise-globally/story?id=14529241
  271. 271.
    National Cancer Institute. Surveillance epidemiology and end results: SEER stat fact sheets. Accessed 31 Mar 12. http://seer.cancer.gov/
  272. 272.
    American Cancer Society. Cancer facts and figures 2012. Accessed 31 Mar 12. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2012/
  273. 273.
    Perez EA et al (2010) HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol 28(28):4307–4315PubMedCentralPubMedGoogle Scholar
  274. 274.
    Recht A et al (1996) The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334(21):1356–1361PubMedGoogle Scholar
  275. 275.
    Slamon DJ et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792PubMedGoogle Scholar
  276. 276.
    Hedge SR, Sun W, Lynch JP (2008) Systemic and targeted therapy for advanced colon cancer. Expert Rev Gastroenterol Hepatol 2(1):135–149Google Scholar
  277. 277.
    Silvestri GA, Rivera MP (2005) Targeted therapy for the treatment of advanced non-small cell lung cancer: a review of the epidermal growth factor receptor antagonists. Chest 128(6):3975–3984PubMedGoogle Scholar
  278. 278.
    Sherbenou DW, Druker BJ (2007) Applying the discovery of the Philadelphia chromosome. J Clin Invest 117(8):2067–2074PubMedCentralPubMedGoogle Scholar
  279. 279.
    Sakariassen PO, Immervoll H, Chekenya M (2007) Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies. Neoplasia 9(11):882–892PubMedCentralPubMedGoogle Scholar
  280. 280.
    Brekelmans CT et al (2007) Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer 43(5):867–876PubMedGoogle Scholar
  281. 281.
    Korkaya H, Wicha MS (2007) Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs 21(5):299–310PubMedGoogle Scholar
  282. 282.
    Houston S (2011) Stemming the tide. ChemistryWorld.org. http://www.rsc.org/chemistryworld/restricted/2011/September/StemmingTheTide.asp
  283. 283.
    Markey K (2009) Firms seek to prove cancer stem cell hypothesis. Bio Market Trends. 29(18). http://www.genengnews.com/gen-articles/firms-seek-to-prove-cancer-stem-cell-hypothesis/3066/

Copyright information

© Springer Science+Business Media LLC New York 2015

Authors and Affiliations

  • Ming Luo
    • 1
  • Shawn G. Clouthier
    • 1
  • Yadwinder Deol
    • 1
  • Suling Liu
    • 2
  • Sunitha Nagrath
    • 3
  • Ebrahim Azizi
    • 1
  • Max S. Wicha
    • 1
  1. 1.Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  2. 2.School of Life SciencesUniversity of Science and Technology of ChinaHefeiChina
  3. 3.Department of Chemical EngineeringUniversity of MichiganAnn ArborUSA

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