Breast Cancer Research and Treatment

, Volume 123, Issue 3, pp 613–625 | Cite as

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

  • Anne M. Friel
  • Claire Corcoran
  • John Crown
  • Lorraine O’Driscoll
Review

Abstract

Early detection of cancer is vital to improved overall survival rates. At present, evidence is accumulating for the clinical value of detecting occult tumor cells in peripheral blood, plasma, and serum specimens from cancer patients. Both molecular and cellular approaches, which differ in sensitivity and specificity, have been used for such means. Circulating tumor cells and extracellular nucleic acids have been detected within blood, plasma, and sera of cancer patients. As the presence of malignant tumors are clinically determined and/or confirmed upon biopsy procurement—which in itself may have detrimental effects in terms of stimulating cancer progression/metastases—minimally invasive methods would be highly advantageous to the diagnosis and prognosis of breast cancer and the subsequent tailoring of targeted treatments for individuals, if reliable panels of biomarkers suitable for such an approach exist. Herein, we review the current advances made in the detection of such circulating tumor cells and nucleic acids, with particular emphasis on extracellular nucleic acids, specifically extracellular mRNAs and discuss their clinical relevance.

Keywords

Breast cancer Extracellular nucleic acids Circulating tumor cells Exosomes Cancer stem cells 

Notes

Acknowledgments

The authors wish to thank the Science Foundation Ireland, Strategic Research Cluster award to Molecular Therapeutics for Cancer Ireland (award 08/SRC/B1410) for funding associated with preparation of this review.

References

  1. 1.
    Jemal A et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96PubMedCrossRefGoogle Scholar
  2. 2.
    Perou C et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752PubMedCrossRefGoogle Scholar
  3. 3.
    Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360(8):790–800PubMedCrossRefGoogle Scholar
  4. 4.
    Jiang WG et al (2002) Molecular detection of micro-metastasis in breast cancer. Crit Rev Oncol Hematol 43(1):13–31PubMedCrossRefGoogle Scholar
  5. 5.
    Gilbey AM et al (2004) The detection of circulating breast cancer cells in blood. J Clin Pathol 57(9):903–911PubMedCrossRefGoogle Scholar
  6. 6.
    Pantel K, Brakenhoff R (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4(6):448–456PubMedCrossRefGoogle Scholar
  7. 7.
    Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988PubMedCrossRefGoogle Scholar
  8. 8.
    Zhang S et al (2008) Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 68(11):4311–4320PubMedCrossRefGoogle Scholar
  9. 9.
    Baba T et al (2009) Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 28(2):209–218PubMedCrossRefGoogle Scholar
  10. 10.
    Curley M et al (2009) CD133 Expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells 27(12):2875–2883PubMedGoogle Scholar
  11. 11.
    Rutella S et al (2009) Cells with characteristics of cancer stem/progenitor cells express the CD133 antigen in human endometrial tumors. Clin Cancer Res 15(13):4299–4311PubMedCrossRefGoogle Scholar
  12. 12.
    Ashworth T (1869) A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust Med J 14:146–147Google Scholar
  13. 13.
    Allan AL, Keeney M (2010) Circulating tumor cell analysis: technical and statistical considerations for application to the clinic. J Oncol 2010:426218PubMedGoogle Scholar
  14. 14.
    Liu M et al (2009) Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J Clin Oncol 27(31):5153–5159PubMedCrossRefGoogle Scholar
  15. 15.
    Cristofanilli M et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791PubMedCrossRefGoogle Scholar
  16. 16.
    Budd G et al (2006) Circulating tumor cells versus imaging–predicting overall survival in metastatic breast cancer. Clin Cancer Res 12(21):6403–6409PubMedCrossRefGoogle Scholar
  17. 17.
    Hayes D et al (2006) Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12(141):4218–4224PubMedCrossRefGoogle Scholar
  18. 18.
    Pierga J et al (2008) Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res 14(21):7004–7010PubMedCrossRefGoogle Scholar
  19. 19.
    Harris L et al (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33):5287–5312PubMedCrossRefGoogle Scholar
  20. 20.
    Nagrath S et al (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173):1235–1239PubMedCrossRefGoogle Scholar
  21. 21.
    Tewes M et al (2009) Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies. Breast Cancer Res Treat 115(3):581–590PubMedCrossRefGoogle Scholar
  22. 22.
    Alix-Panabières C et al (2005) Characterization and enumeration of cells secreting tumor markers in the peripheral blood of breast cancer patients. J Immunol Methods 299(1–2):177–188PubMedCrossRefGoogle Scholar
  23. 23.
    Alix-Panabières C et al (2007) Detection and characterization of putative metastatic precursor cells in cancer patients. Clin Chem 53(3):537–539PubMedCrossRefGoogle Scholar
  24. 24.
    Fehm T et al (2009) Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Res 11(4):R59PubMedCrossRefGoogle Scholar
  25. 25.
    Fehm T et al (2007) Determination of HER2 status using both serum HER2 levels and circulating tumor cells in patients with recurrent breast cancer whose primary tumor was HER2 negative or of unknown HER2 status. Breast Cancer Res 9(5):R74PubMedCrossRefGoogle Scholar
  26. 26.
    Alunni-Fabbroni M, Sandri M (2010) Circulating tumour cells in clinical practice: methods of detection and possible characterization. Methods 50(4):289–297PubMedCrossRefGoogle Scholar
  27. 27.
    Vona G et al (2000) Isolation by size of epithelial tumor cells: a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol 156(1):57–63PubMedGoogle Scholar
  28. 28.
    Gertler R et al (2003) Detection of circulating tumor cells in blood using an optimized density gradient centrifugation. Recent Results Cancer Res 162:149–155PubMedGoogle Scholar
  29. 29.
    Müller V et al (2005) Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 11(10):3678–3685PubMedCrossRefGoogle Scholar
  30. 30.
    Naume B et al (2004) Detection of isolated tumor cells in peripheral blood and in BM: evaluation of a new enrichment method. Cytotherapy 6(3):244–252PubMedCrossRefGoogle Scholar
  31. 31.
    Hayes G et al (2010) Isolation of malignant B cells from patients with chronic lymphocytic leukemia (CLL) for analysis of cell proliferation: validation of a simplified method suitable for multi-center clinical studies. Leuk Res 34(6):809–815Google Scholar
  32. 32.
    Mostert B et al (2009) Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. Cancer Treat Rev 35(5):463–474PubMedCrossRefGoogle Scholar
  33. 33.
    Cristofanilli M, Braun S (2010) Circulating tumor cells revisited. JAMA 303(11):1092–1093PubMedCrossRefGoogle Scholar
  34. 34.
    Fehm T et al (2005) Methods for isolating circulating epithelial cells and criteria for their classification as carcinoma cells. Cytotherapy 7(2):171–185PubMedCrossRefGoogle Scholar
  35. 35.
    Austrup F et al (2000) Prognostic value of genomic alterations in minimal residual cancer cells purified from the blood of breast cancer patients. Br J Cancer 83(12):1664–1673PubMedCrossRefGoogle Scholar
  36. 36.
    Fehm T et al (2002) Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 8(7):2073–2084PubMedGoogle Scholar
  37. 37.
    Meng S et al (2006) uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues. Proc Natl Acad Sci USA 103(46):17361–17365PubMedCrossRefGoogle Scholar
  38. 38.
    Meng S et al (2004) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 101(25):9393–9398PubMedCrossRefGoogle Scholar
  39. 39.
    Pantel K et al (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8(5):329–340PubMedCrossRefGoogle Scholar
  40. 40.
    Braun S et al (2009) The prognostic impact of bone marrow micrometastases in women with breast cancer. Cancer Invest 27(6):598–603PubMedCrossRefGoogle Scholar
  41. 41.
    Braun S et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802PubMedCrossRefGoogle Scholar
  42. 42.
    Janni W et al (2005) The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer 103(5):884–891PubMedCrossRefGoogle Scholar
  43. 43.
    Krawczyk N et al (2009) HER2 status on persistent disseminated tumor cells after adjuvant therapy may differ from initial HER2 status on primary tumor. Anticancer Res 29(10):4019–4024PubMedGoogle Scholar
  44. 44.
    Mandel P, Metais P (1948) Les acides nucleiques du plasma sanguine chez l’homme (in French). C R Seances Soc Biol Fil 142(3–4):241–243PubMedGoogle Scholar
  45. 45.
    Tan EM et al (1966) Deoxybonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J Clin Invest 45(11):1732–1740PubMedCrossRefGoogle Scholar
  46. 46.
    Koffler D et al (1973) The occurrence of single-stranded DNA in the serum of patients with systemic lupus erythematosus and other diseases. J Clin Invest 52(1):198–204PubMedCrossRefGoogle Scholar
  47. 47.
    Leon S et al (1977) Free DNA in the serum of rheumatoid arthritis patients. J Rheumatol 4(2):139–143PubMedGoogle Scholar
  48. 48.
    Leon S et al (1977) Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 37(3):646–650PubMedGoogle Scholar
  49. 49.
    Stroun M et al (1989) Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology 46(5):318–322PubMedCrossRefGoogle Scholar
  50. 50.
    Sorenson G et al (1994) Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol Biomarkers Prev 3(1):67–71Google Scholar
  51. 51.
    Vasioukhin V et al (1994) Point mutations of the N-ras gene in the blood plasma DNA of patients with myelodysplastic syndrome or acute myelogenous leukaemia. Br J Haematol 86(4):774–779PubMedCrossRefGoogle Scholar
  52. 52.
    Kohler C et al (2009) Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors. Mol Cancer 8:105PubMedCrossRefGoogle Scholar
  53. 53.
    Divella R et al (2009) Circulating hTERT DNA in early breast cancer. Anticancer Res 29(7):2845–2849PubMedGoogle Scholar
  54. 54.
    Van der Auwera I et al (2009) The presence of circulating total DNA and methylated genes is associated with circulating tumour cells in blood from breast cancer patients. Br J Cancer 100(8):1277–1286PubMedCrossRefGoogle Scholar
  55. 55.
    van der Drift M et al (2010) Circulating DNA is a non-invasive prognostic factor for survival in non-small cell lung cancer. Lung Cancer 68(2):283–287PubMedCrossRefGoogle Scholar
  56. 56.
    Yoon K et al (2009) Comparison of circulating plasma DNA levels between lung cancer patients and healthy controls. J Mol Diagn 11(3):182–185PubMedCrossRefGoogle Scholar
  57. 57.
    Yen L et al (2009) Detection of KRAS oncogene in peripheral blood as a predictor of the response to cetuximab plus chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res 15(13):4508–4513PubMedCrossRefGoogle Scholar
  58. 58.
    Ellinger J et al (2009) CpG island hypermethylation of cell-free circulating serum DNA in patients with testicular cancer. J Urol 182(1):324–329PubMedCrossRefGoogle Scholar
  59. 59.
    Board R et al (2009) Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study. Br J Cancer 101(10):1724–1730PubMedCrossRefGoogle Scholar
  60. 60.
    Chuang T et al (2010) Detectable BRAF mutation in serum DNA samples from patients with papillary thyroid carcinomas. Head Neck 32(2):229–234PubMedGoogle Scholar
  61. 61.
    Schwarzenbach H et al (2009) Comparative evaluation of cell-free tumor DNA in blood and disseminated tumor cells in bone marrow of patients with primary breast cancer. Breast Cancer Res 11(5):R71PubMedCrossRefGoogle Scholar
  62. 62.
    Marrakchi R et al (2008) Detection of cytokeratin 19 mRNA and CYFRA 21-1 (cytokeratin 19 fragments) in blood of Tunisian women with breast cancer. Int J Biol Markers 23(4):238–243Google Scholar
  63. 63.
    García V et al (2008) Free circulating mRNA in plasma from breast cancer patients and clinical outcome. Cancer Lett 263(2):312–320PubMedCrossRefGoogle Scholar
  64. 64.
    O’Driscoll L et al (2008) Feasibility and relevance of global expression profiling of gene transcripts in serum from breast cancer patients using whole genome microarrays and quantitative RT-PCR. Cancer Genomics Proteomics 5(2):94–104PubMedGoogle Scholar
  65. 65.
    Terrin L et al (2008) Relationship between tumor and plasma levels of hTERT mRNA in patients with colorectal cancer: implications for monitoring of neoplastic disease. Clin Cancer Res 14(22):7444–7451PubMedCrossRefGoogle Scholar
  66. 66.
    Vrieling A et al (2009) Expression of insulin-like growth factor system components in colorectal tissue and its relation with serum IGF levels. Growth Horm IGF Res 19(2):126–135PubMedCrossRefGoogle Scholar
  67. 67.
    Fleischhacker M, Schmidt B (2007) Circulating nucleic acids (CNAs) and cancer—a survey. Biochim Biophys Acta 1775(1):181–232PubMedGoogle Scholar
  68. 68.
    Rieber M, Bacalao J (1974) An “external” RNA removable from mammalian cells by mild proteolysis. Proc Natl Acad Sci USA 71(12):4960–4964PubMedCrossRefGoogle Scholar
  69. 69.
    Laktionov PP et al (2004) Cell-surface-bound nucleic acids: free and cell-surface-bound nucleic acids in blood of healthy donors and breast cancer patients. Ann NY Acad Sci 1022:221–227PubMedCrossRefGoogle Scholar
  70. 70.
    Chelobanov BP et al (2004) Isolation of nucleic acid binding proteins: an approach for isolation of cell surface, nucleic acid binding proteins. Ann NY Acad Sci 1022:239–243PubMedCrossRefGoogle Scholar
  71. 71.
    Wieczorek AJ, Rhyner K (1989) A gene probe test for serum RNA proteolipid in neoplasia. Schweiz Med Wochenschr 119(39):1342–1343PubMedGoogle Scholar
  72. 72.
    Wieczorek AJ et al (1985) Isolation and characterization of an RNA–proteolipid complex associated with the malignant state in humans. Proc Natl Acad Sci USA 82(10):3455–3459PubMedCrossRefGoogle Scholar
  73. 73.
    Hasselmann DO et al (2001) Extracellular tyrosinase mRNA within apoptotic bodies is protected from degradation in human serum. Clin Chem 47(8):1488–1489PubMedGoogle Scholar
  74. 74.
    Stroun M et al (1978) Presence of RNA in the nucleoprotein complex spontaneously released by human lymphocytes and frog auricles in culture. Cancer Res 38(10):3546–3554PubMedGoogle Scholar
  75. 75.
    Jachertz D et al (1979) Information carried by the DNA released by antigen-stimulated lymphocytes. Immunology 37(4):753–763PubMedGoogle Scholar
  76. 76.
    Anker P et al (1999) Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients. Cancer Metastasis Rev 18(1):65–73PubMedCrossRefGoogle Scholar
  77. 77.
    Jahr JS et al (2001) A novel approach to measuring circulating blood volume: the use of a hemoglobin-based oxygen carrier in a rabbit model. Anesth Analg 92(3):609–614PubMedCrossRefGoogle Scholar
  78. 78.
    Skog J et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476PubMedCrossRefGoogle Scholar
  79. 79.
    Wright LC et al (1986) A proteolipid in cancer cells is the origin of their high-resolution NMR spectrum. FEBS Lett 203(2):164–168PubMedCrossRefGoogle Scholar
  80. 80.
    Rosi A et al (1988) RNA–lipid complexes released from the plasma membrane of human colon carcinoma cells. Cancer Lett 39(2):153–160PubMedCrossRefGoogle Scholar
  81. 81.
    Ceccarini M et al (1989) Biochemical and NMR studies on structure and release conditions of RNA-containing vesicles shed by human colon adenocarcinoma cells. Int J Cancer 44(4):714–721PubMedCrossRefGoogle Scholar
  82. 82.
    Ratajczak J et al (2006) Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20(9):1487–1495PubMedCrossRefGoogle Scholar
  83. 83.
    Graner MW et al (2009) Proteomic and immunologic analyses of brain tumor exosomes. FASEB J 23(5):1541–1557PubMedCrossRefGoogle Scholar
  84. 84.
    Thery C et al (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2(8):569–579PubMedGoogle Scholar
  85. 85.
    Keller S et al (2006) Exosomes: from biogenesis and secretion to biological function. Immunol Lett 107(2):102–108PubMedCrossRefGoogle Scholar
  86. 86.
    Calzolari A et al (2006) TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J Cell Sci 119(Pt 21):4486–4498PubMedCrossRefGoogle Scholar
  87. 87.
    Valadi H et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659PubMedCrossRefGoogle Scholar
  88. 88.
    Safaei R et al (2005) Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther 4(10):1595–1604PubMedCrossRefGoogle Scholar
  89. 89.
    Chaput N et al (2005) The potential of exosomes in immunotherapy. Expert Opin Biol Ther 5(6):737–747PubMedCrossRefGoogle Scholar
  90. 90.
    Liu C et al (2006) Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol 176(3):1375–1385PubMedGoogle Scholar
  91. 91.
    Ginestra A et al (1998) The amount and proteolytic content of vesicles shed by human cancer cell lines correlates with their in vitro invasiveness. Anticancer Res 18(5A):3433–3437PubMedGoogle Scholar
  92. 92.
    Clayton A et al (2007) Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 67(15):7458–7466PubMedCrossRefGoogle Scholar
  93. 93.
    Ng EK et al (2002) Presence of filterable and nonfilterable mRNA in the plasma of cancer patients and healthy individuals. Clin Chem 48(8):1212–1217PubMedGoogle Scholar
  94. 94.
    O’Driscoll L (2007) Extracellular nucleic acids and their potential as diagnostic, prognostic and predictive biomarkers. Anticancer Res 27(3):1257–1265PubMedGoogle Scholar
  95. 95.
    Rabinowits G et al (2009) Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 10(1):42–46PubMedCrossRefGoogle Scholar
  96. 96.
    Silva JM et al (2001) Detection of epithelial messenger RNA in the plasma of breast cancer patients is associated with poor prognosis tumor characteristics. Clin Cancer Res 7(9):2821–2825PubMedGoogle Scholar
  97. 97.
    Chen X et al (2000) Telomerase RNA as a detection marker in the serum of breast cancer patients. Clin Cancer Res 6(10):3823–3826PubMedGoogle Scholar
  98. 98.
    Silva J et al (2007) Circulating Bmi-1 mRNA as a possible prognostic factor for advanced breast cancer patients. Breast Cancer Res 9(4):R55PubMedCrossRefGoogle Scholar
  99. 99.
    Fuchs E, Weber K (1994) Intermediate filaments: structure, dynamics, function, and disease. Annu Rev Biochem 63:345–382PubMedGoogle Scholar
  100. 100.
    Dohmoto K et al (2001) The role of caspase 3 in producing cytokeratin 19 fragment (CYFRA21–1) in human lung cancer cell lines. Int J Cancer 91(4):468–473PubMedCrossRefGoogle Scholar
  101. 101.
    Pujol JL et al (1993) Serum fragment of cytokeratin subunit 19 measured by CYFRA 21–1 immunoradiometric assay as a marker of lung cancer. Cancer Res 53(1):61–66PubMedGoogle Scholar
  102. 102.
    Ravdin PM et al (2001) Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19(4):980–991PubMedGoogle Scholar
  103. 103.
    Stathopoulou A et al (2002) 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 20(16):3404–3412PubMedCrossRefGoogle Scholar
  104. 104.
    Xenidis N et al (2006) 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 24(23):3756–3762PubMedCrossRefGoogle Scholar
  105. 105.
    Daskalaki A et al (2009) Detection of cytokeratin-19 mRNA-positive cells in the peripheral blood and bone marrow of patients with operable breast cancer. Br J Cancer 101(4):589–597PubMedCrossRefGoogle Scholar
  106. 106.
    Xenidis N et al (2003) Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer. Ann Oncol 14(6):849–855PubMedCrossRefGoogle Scholar
  107. 107.
    Quintela-Fandino M et al (2006) Breast cancer-specific mRNA transcripts presence in peripheral blood after adjuvant chemotherapy predicts poor survival among high-risk breast cancer patients treated with high-dose chemotherapy with peripheral blood stem cell support. J Clin Oncol 24(22):3611–3618PubMedCrossRefGoogle Scholar
  108. 108.
    Wiedswang G et al (2004) Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res 10(16):5342–5348PubMedCrossRefGoogle Scholar
  109. 109.
    Ignatiadis M et al (2008) Circulating tumor cells in breast cancer. Curr Opin Obstet Gynecol 20(1):55–60PubMedCrossRefGoogle Scholar
  110. 110.
    Alix-Panabieres C et al (2009) Full-length cytokeratin-19 is released by human tumor cells: a potential role in metastatic progression of breast cancer. Breast Cancer Res 11(3):R39PubMedCrossRefGoogle Scholar
  111. 111.
    DePinho R (2000) The age of cancer. Nature 408(6809):248–254PubMedCrossRefGoogle Scholar
  112. 112.
    Dasí F et al (2006) Real-time quantification of human telomerase reverse transcriptase mRNA in the plasma of patients with prostate cancer. Ann NY Acad Sci 1075:204–210PubMedCrossRefGoogle Scholar
  113. 113.
    Li H et al (2009) Relationship between the expression of hTERT and EYA4 mRNA in peripheral blood mononuclear cells with the progressive stages of carcinogenesis of the esophagus. J Exp Clin Cancer Res 28:145PubMedCrossRefGoogle Scholar
  114. 114.
    Elder E et al (2003) KI-67 and hTERT expression can aid in the distinction between malignant and benign pheochromocytoma and paraganglioma. Mod Pathol 16(3):246–255PubMedCrossRefGoogle Scholar
  115. 115.
    Shen C et al (2009) The detection of circulating tumor cells of breast cancer patients by using multimarker (Survivin, hTERT and hMAM) quantitative real-time PCR. Clin Biochem 42(3):194–200PubMedCrossRefGoogle Scholar
  116. 116.
    Jacobs JJ, van Lohuizen M (2002) Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta 1602(2):151–161PubMedGoogle Scholar
  117. 117.
    Raaphorst FM (2005) Deregulated expression of Polycomb-group oncogenes in human malignant lymphomas and epithelial tumors. Hum Mol Genet 14 Spec No 1, R93–R100Google Scholar
  118. 118.
    Song LB et al (2009) The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial–mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest 119(12):3626–3636PubMedCrossRefGoogle Scholar
  119. 119.
    Bachmann IM et al (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24(2):268–273PubMedCrossRefGoogle Scholar
  120. 120.
    Kleer CG et al (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 100(20):11606–11611PubMedCrossRefGoogle Scholar
  121. 121.
    van Lohuizen M et al (1991) Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 65(5):737–752PubMedCrossRefGoogle Scholar
  122. 122.
    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):6063–6071PubMedCrossRefGoogle Scholar
  123. 123.
    Kim JH et al (2004) Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. Breast 13(5):383–388PubMedCrossRefGoogle Scholar
  124. 124.
    Vonlanthen S et al (2001) The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 84(10):1372–1376PubMedCrossRefGoogle Scholar
  125. 125.
    Kim JH et al (2004) The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett 203(2):217–224PubMedCrossRefGoogle Scholar
  126. 126.
    Klug J et al (2000) Uteroglobin/Clara cell 10-kDa family of proteins: nomenclature committee report. Ann NY Acad Sci 923:348–354PubMedCrossRefGoogle Scholar
  127. 127.
    Ni J et al (2000) All human genes of the uteroglobin family are localized on chromosome 11q12.2 and form a dense cluster. Ann NY Acad Sci 923:25–42PubMedCrossRefGoogle Scholar
  128. 128.
    Watson MA, Fleming TP (1994) Isolation of differentially expressed sequence tags from human breast cancer. Cancer Res 54(17):4598–4602PubMedGoogle Scholar
  129. 129.
    Watson MA et al (1998) Structure and transcriptional regulation of the human mammaglobin gene, a breast cancer associated member of the uteroglobin gene family localized to chromosome 11q13. Oncogene 16(6):817–824PubMedCrossRefGoogle Scholar
  130. 130.
    Tassi RA et al (2008) Mammaglobin B expression in human endometrial cancer. Int J Gynecol Cancer 18(5):1090–1096PubMedCrossRefGoogle Scholar
  131. 131.
    Watson MA, Fleming TP (1996) Mammaglobin, a mammary-specific member of the uteroglobin gene family, is overexpressed in human breast cancer. Cancer Res 56(4):860–865PubMedGoogle Scholar
  132. 132.
    Zafrakas M et al (2006) Expression analysis of mammaglobin A (SCGB2A2) and lipophilin B (SCGB1D2) in more than 300 human tumors and matching normal tissues reveals their co-expression in gynecologic malignancies. BMC Cancer 6:88PubMedCrossRefGoogle Scholar
  133. 133.
    Nunez-Villar MJ et al (2003) Elevated mammaglobin (h-MAM) expression in breast cancer is associated with clinical and biological features defining a less aggressive tumour phenotype. Breast Cancer Res 5(3):R65–R70PubMedCrossRefGoogle Scholar
  134. 134.
    Fleming TP, Watson MA (2000) Mammaglobin, a breast-specific gene, and its utility as a marker for breast cancer. Ann NY Acad Sci 923:78–89PubMedCrossRefGoogle Scholar
  135. 135.
    Fanger GR et al (2002) Detection of mammaglobin in the sera of patients with breast cancer. Tumour Biol 23(4):212–221PubMedCrossRefGoogle Scholar
  136. 136.
    Zach O et al (1999) Detection of circulating mammary carcinoma cells in the peripheral blood of breast cancer patients via a nested reverse transcriptase polymerase chain reaction assay for mammaglobin mRNA. J Clin Oncol 17(7):2015–2019PubMedGoogle Scholar
  137. 137.
    Cerveira N et al (2004) Highly sensitive detection of the MGB1 transcript (mammaglobin) in the peripheral blood of breast cancer patients. Int J Cancer 108(4):592–595PubMedCrossRefGoogle Scholar
  138. 138.
    Marques AR et al (2009) Detection of human mammaglobin mRNA in serial peripheral blood samples from patients with non-metastatic breast cancer is not predictive of disease recurrence. Breast Cancer Res Treat 114(2):223–232PubMedCrossRefGoogle Scholar
  139. 139.
    Mikhitarian K et al (2008) Detection of mammaglobin mRNA in peripheral blood is associated with high grade breast cancer: interim results of a prospective cohort study. BMC Cancer 8:55PubMedCrossRefGoogle Scholar
  140. 140.
    Fu M et al (2004) Minireview: Cyclin D1: normal and abnormal functions. Endocrinology 145(12):5439–5447PubMedCrossRefGoogle Scholar
  141. 141.
    Butt AJ et al (2005) Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr Relat Cancer 12(Suppl 1):S47–S59PubMedCrossRefGoogle Scholar
  142. 142.
    Carney WP et al (2004) Monitoring the circulating levels of the HER2/neu oncoprotein in breast cancer. Clin Breast Cancer 5(2):105–116PubMedCrossRefGoogle Scholar
  143. 143.
    Apostolaki S et al (2009) Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance. Breast Cancer Res Treat 117(3):525–534PubMedCrossRefGoogle Scholar
  144. 144.
    Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355PubMedCrossRefGoogle Scholar
  145. 145.
    Hennessy E, O’Driscoll L (2008) Molecular medicine of microRNAs: structure, function and implications for diabetes. Expert Rev Mol Med 10:e24PubMedCrossRefGoogle Scholar
  146. 146.
    Gartel A, Kandel E (2008) miRNAs: Little known mediators of oncogenesis. Semin Cancer Biol 18(2):103–110PubMedCrossRefGoogle Scholar
  147. 147.
    Lawrie C et al (2008) Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol 141(5):672–675PubMedCrossRefGoogle Scholar
  148. 148.
    Mitchell P et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105(30):10513–10518PubMedCrossRefGoogle Scholar
  149. 149.
    Chen X et al (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006PubMedCrossRefGoogle Scholar
  150. 150.
    Taylor D, Gercel-Taylor C (2008) MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110(1):13–21PubMedCrossRefGoogle Scholar
  151. 151.
    Heneghan H et al (2010) Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg 251(3):499–505PubMedCrossRefGoogle Scholar
  152. 152.
    Duffy M (2005) Predictive markers in breast and other cancers: a review. Clin Chem 51(3):494–503PubMedCrossRefGoogle Scholar
  153. 153.
    Gasparini G et al (2006) Is tailored therapy feasible in oncology? Crit Rev Oncol Hematol 57(1):79–101PubMedCrossRefGoogle Scholar
  154. 154.
    Hayes D (2005) Prognostic and predictive factors for breast cancer: translating technology to oncology. J Clin Oncol 23(8):1596–1597PubMedCrossRefGoogle Scholar
  155. 155.
    McShane L et al (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23(36):9067–9072PubMedCrossRefGoogle Scholar
  156. 156.
    Barker AD et al (2009) I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 86(1):97–100PubMedCrossRefGoogle Scholar
  157. 157.
    Pepe MS et al (2001) Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 93(14):1054–1061PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Anne M. Friel
    • 1
  • Claire Corcoran
    • 1
  • John Crown
    • 2
  • Lorraine O’Driscoll
    • 1
  1. 1.School of Pharmacy and Pharmaceutical Sciences & Molecular Therapeutics for Cancer IrelandTrinity College DublinDublin 2Ireland
  2. 2.Molecular Therapeutics for Cancer IrelandDublin City UniversityDublin 9Ireland

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