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Epithelial Mesenchymal Transition Traits in Human Breast Cancer Cell Lines Parallel the CD44hi/CD24lo/- Stem Cell Phenotype in Human Breast Cancer

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Abstract

We review here the recently emerging relationship between epithelial-mesenchymal transition (EMT) and breast cancer stem cells (BCSC), and provide analyses of published data on human breast cancer cell lines, supporting their utility as a model for the EMT/BCSC state. Genome-wide transcriptional profiling of these cell lines has confirmed the existence of a subgroup with mesenchymal tendencies and enhanced invasive properties (‘Basal B’/Mesenchymal), distinct from subgroups with either predominantly luminal (‘Luminal’) or mixed basal/luminal (‘Basal A’) features (Neve et al. Cancer Cell, 2006). A literature-derived EMT gene signature has shown specific enrichment within the Basal B subgroup of cell lines, consistent with their over-expression of various EMT transcriptional drivers. Basal B cell lines are found to resemble BCSC, being CD44highCD24low. Moreover, gene products that distinguish Basal B from Basal A and Luminal cell lines (Basal B Discriminators) showed close concordance with those that define BCSC isolated from clinical material, as reported by Shipitsin et al. (Cancer Cell, 2007). CD24 mRNA levels varied across Basal B cell lines, correlating with other Basal B Discriminators. Many gene products correlating with CD24 status in Basal B cell lines were also differentially expressed in isolated BCSC. These findings confirm and extend the importance of the cellular product of the EMT with Basal B cell lines, and illustrate the value of analysing these cell lines for new leads that may improve breast cancer outcomes. Gene products specific to Basal B cell lines may serve as tools for the detection, quantification, and analysis of BCSC/EMT attributes.

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Abbreviations

ALDH1:

Aldehyde dehydrogenase 1 family, member A1

BCSC:

Breast cancer stem cells

BRCA1:

Breast cancer 1, early onset

C/EBP β-2:

CCAAT/enhancer binding protein (C/EBP), beta

CDH1:

E-cadherin

COX-2:

Cyclooxygenase-2

CTC:

Circulating tumor cells

DDR1:

Discoidin domain receptor tyrosine kinase 1

DTC:

Disseminated tumor cells

EGF:

Epidermal growth factor

EMT:

Epithelial-to-mesenchymal transition

EMT-SIG:

EMT-signature

EMP3:

Epithelial membrane protein 3

ER:

Estrogen receptor

EndMT:

Endothelial-to-mesenchymal transition

FAK:

Focal adhesion kinase

FOSL:

Fos-like antigen

GAS6:

Growth arrest-specific 6

HEEBO:

Human exonic evidence based oligonucleotide array

HOXB7:

Homeobox B7

HMLE:

Human mammary epithelial cells

HR:

Hazard recurrence

MaSC:

Mammary stem cells

MEC:

Mammary epithelial cells

MET:

Mesenchymal-to-epithelial transition

mRNA:

Messenger RNA

NFkB:

Nuclear factor kappa B

PGI/AMF:

Phosphoglucose isomerise/autocrine motility factor

PROCR:

Protein C receptor, endothelial (EPCR)

shRNA:

Short hairpin ribonucleic acid

Src:

Src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)

TGF-beta:

Transforming growth factor-beta

References

  1. Australian Institute of Health and Welfare. 2006.

  2. Australian Institute of Health and Welfare. 2008.

  3. American Cancer Society. 2004.

  4. Cristofanilli M. The biological information obtainable from circulating tumor cells. Breast. 2009;18 Suppl 3:S38–40.

    PubMed  Google Scholar 

  5. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–312.

    CAS  PubMed  Google Scholar 

  6. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.

    CAS  PubMed  Google Scholar 

  7. Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 1995;154(1):8–20.

    CAS  Google Scholar 

  8. Savagner P, Boyer B, Valles AM, Jouanneau J, Thiery JP. Modulations of the epithelial phenotype during embryogenesis and cancer progression. Cancer Treat Res. 1994;71:229–49.

    CAS  PubMed  Google Scholar 

  9. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17(5):548–58.

    CAS  PubMed  Google Scholar 

  10. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.

    CAS  PubMed  Google Scholar 

  11. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15(6):740–6.

    CAS  PubMed  Google Scholar 

  12. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.

    CAS  PubMed  Google Scholar 

  13. Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res. 2005;65(14):5991–5. discussion 5995.

    CAS  PubMed  Google Scholar 

  14. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83.

    CAS  PubMed  Google Scholar 

  15. Chaffer CL, Thompson EW, Williams ED. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs. 2007;185(1–3):7–19.

    PubMed  Google Scholar 

  16. Tsuji T, Ibaragi S, Hu GF. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res. 2009;69(18):7135–9.

    CAS  PubMed  Google Scholar 

  17. Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 2005;65(14):5996–6000. discussion 6000–1.

    CAS  PubMed  Google Scholar 

  18. Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006;66(17):8319–26.

    CAS  PubMed  Google Scholar 

  19. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172(7):973–81.

    CAS  PubMed  Google Scholar 

  20. Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13(5):555–62.

    CAS  PubMed  Google Scholar 

  21. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005;132(14):3151–61.

    CAS  PubMed  Google Scholar 

  22. Przybylo JA, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition: tumor progression at Snail’s pace. Int J Biochem Cell Biol. 2007;39(6):1082–8.

    CAS  PubMed  Google Scholar 

  23. Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 2005;65(20):9455–62.

    CAS  PubMed  Google Scholar 

  24. Hugo, Ackland ML, Lawrence MG, Clements JA, Williams ED, and Thompson EW. Epithelial - Mesenchymal and Mesenchymal - Epithelial Transitions in Carcinoma Progression. J Cell Physiol. 2007;213(2):374–83.

  25. Klymkowsky MW, Savagner P. Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol. 2009;174(5):1588–93.

    CAS  PubMed  Google Scholar 

  26. Tomaskovic-Crook E, Thompson EW, Thiery JP. Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res. 2009;11(6):213.

    PubMed  Google Scholar 

  27. Franci C, Takkunen M, Dave N, Alameda F, Gomez S, Rodriguez R, et al. Expression of Snail protein in tumor-stroma interface. Oncogene. 2006;25(37):5134–44.

    CAS  PubMed  Google Scholar 

  28. Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. 2002;21(20):3241–6.

    CAS  PubMed  Google Scholar 

  29. Come C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, et al. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res. 2006;12(18):5395–402.

    CAS  PubMed  Google Scholar 

  30. Elloul S, Elstrand MB, Nesland JM, Trope CG, Kvalheim G, Goldberg I, et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer. 2005;103(8):1631–43.

    CAS  PubMed  Google Scholar 

  31. Martin TA, Goyal A, Watkins G, Jiang WG. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol. 2005;12(6):488–96.

    PubMed  Google Scholar 

  32. Chen J, Imanaka N, Griffin JD. Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer. 2010;102(2):351–60.

    CAS  PubMed  Google Scholar 

  33. Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 2005;8(3):197–209.

    CAS  PubMed  Google Scholar 

  34. 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.

    CAS  PubMed  Google Scholar 

  35. Xue C, Plieth D, Venkov C, Xu C, Neilson EG. The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res. 2003;63(12):3386–94.

    CAS  PubMed  Google Scholar 

  36. Damonte P, Gregg JP, Borowsky AD, Keister BA, Cardiff RD. EMT tumorigenesis in the mouse mammary gland. Lab Invest. 2007;87(12):1218–26.

    CAS  PubMed  Google Scholar 

  37. Ross DT, Perou CM. A comparison of gene expression signatures from breast tumors and breast tissue derived cell lines. Dis Markers. 2001;17(2):99–109.

    CAS  PubMed  Google Scholar 

  38. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10(6):515–27.

    CAS  PubMed  Google Scholar 

  39. Charafe-Jauffret E, Ginestier C, Monville F, Finetti P, Adelaide J, Cervera N, et al. Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene. 2006;25(15):2273–84.

    CAS  PubMed  Google Scholar 

  40. Thompson EW, Torri J, Sabol M, Sommers CL, Byers S, Valverius EM, et al. Oncogene-induced basement membrane invasiveness in human mammary epithelial cells. Clin Exp Metastasis. 1994;12(3):181–94.

    CAS  PubMed  Google Scholar 

  41. Thompson EW, Paik S, Brunner N, Sommers CL, Zugmaier G, Clarke R, et al. Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol. 1992;150(3):534–44.

    CAS  PubMed  Google Scholar 

  42. Sommers CL, Byers SW, Thompson EW, Torri JA, Gelmann EP. Differentiation state and invasiveness of human breast cancer cell lines. Breast Cancer Res Treat. 1994;31(2–3):325–35.

    CAS  PubMed  Google Scholar 

  43. Gilles C, Polette M, Piette J, Munaut C, Thompson EW, Birembaut P, et al. High level of MT-MMP expression is associated with invasiveness of cervical cancer cells. Int J Cancer. 1996;65(2):209–13.

    CAS  PubMed  Google Scholar 

  44. 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.

    CAS  PubMed  Google Scholar 

  45. 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.

    CAS  PubMed  Google Scholar 

  46. Dumont N, Wilson MB, Crawford YG, Reynolds PA, Sigaroudinia M, Tlsty TD. Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci U S A. 2008;105(39):14867–72.

    CAS  PubMed  Google Scholar 

  47. Whitehead RH, Bertoncello I, Webber LM, Pedersen JS. A new human breast carcinoma cell line (PMC42) with stem cell characteristics. I. Morphologic characterization. J Natl Cancer Inst. 1983;70(4):649–61.

    CAS  PubMed  Google Scholar 

  48. Ackland ML, Michalczyk A, Whitehead RH. PMC42, A novel model for the differentiated human breast. Exp Cell Res. 2001;263(1):14–22.

    CAS  PubMed  Google Scholar 

  49. Ackland ML, Newgreen D, Price JT, Fridman M, Waltham M, Arvanitis A, et al. Epidermal growth factor stimulates epithelio-mesenchymal transition in the stable human breast carcinoma cell line variant PMC42-LA. Lab Invest. 2003;83(3):435–48.

    CAS  PubMed  Google Scholar 

  50. Hugo HJ, Wafai R, Blick T, Thompson EW, Newgreen DF. Staurosporine augments EGF-mediated EMT in PMC42-LA cells through actin depolymerisation, focal contact size reduction and Snail1 induction - a model for cross-modulation. BMC Cancer. 2009;9:235–50.

    PubMed  Google Scholar 

  51. Newgreen DF, Minichiello J. Control of epitheliomesenchymal transformation. I. Events in the onset of neural crest cell migration are separable and inducible by protein kinase inhibitors. Dev Biol. 1995;170(1):91–101.

    CAS  PubMed  Google Scholar 

  52. Minichiello J, Ben-Ya’acov A, Hearn CJ, Needham B, Newgreen DF. Induction of epithelio-mesenchymal transformation of quail embryonic neural cells by inhibition of atypical protein kinase-C. Cell Tissue Res. 1999;295(2):195–206.

    CAS  PubMed  Google Scholar 

  53. Lebret SC, Newgreen DF, Thompson EW, Ackland ML. Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors. Breast Cancer Res. 2007;9(1):R19.

    PubMed  Google Scholar 

  54. Kao J, Salari K, Bocanegra M, Choi YL, Girard L, Gandhi J, et al. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One. 2009;4(7):e6146.

    PubMed  Google Scholar 

  55. Zajchowski DA, Bartholdi MF, Gong Y, Webster L, Liu HL, Munishkin A, et al. Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res. 2001;61(13):5168–78.

    CAS  PubMed  Google Scholar 

  56. Taylor V, Suter U. Epithelial membrane protein-2 and epithelial membrane protein-3: two novel members of the peripheral myelin protein 22 gene family. Gene. 1996;175(1–2):115–20.

    CAS  PubMed  Google Scholar 

  57. Zhou W, Jiang Z, Li X, Xu F, Liu Y, Wen P, et al. EMP3 overexpression in primary breast carcinomas is not associated with epigenetic aberrations. J Korean Med Sci. 2009;24(1):97–103.

    PubMed  Google Scholar 

  58. Evtimova V, Zeillinger R, Weidle UH. Identification of genes associated with the invasive status of human mammary carcinoma cell lines by transcriptional profiling. Tumour Biol. 2003;24(4):189–98.

    PubMed  Google Scholar 

  59. Fumoto S, Tanimoto K, Hiyama E, Noguchi T, Nishiyama M, Hiyama K. EMP3 as a candidate tumor suppressor gene for solid tumors. Expert Opin Ther Targets. 2009;13(7):811–22.

    CAS  PubMed  Google Scholar 

  60. Varnum BC, Young C, Elliott G, Garcia A, Bartley TD, Fridell YW, et al. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature. 1995;373(6515):623–6.

    CAS  PubMed  Google Scholar 

  61. Sharif MN, Sosic D, Rothlin CV, Kelly E, Lemke G, Olson EN, et al. Twist mediates suppression of inflammation by type I IFNs and Axl. J Exp Med. 2006;203(8):1891–901.

    CAS  PubMed  Google Scholar 

  62. Hafizi S, Dahlback B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev. 2006;17(4):295–304.

    CAS  PubMed  Google Scholar 

  63. Zhang YX, Knyazev PG, Cheburkin YV, Sharma K, Knyazev YP, Orfi L, et al. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res. 2008;68(6):1905–15.

    CAS  PubMed  Google Scholar 

  64. Gjerdrum C, Tiron C, Hoiby T, Stefansson I, Haugen H, Sandal T, et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010;107(3):1124–9.

    CAS  PubMed  Google Scholar 

  65. McCormack O, Chung WY, Fitzpatrick P, Cooke F, Flynn B, Harrison M, et al. Growth arrest-specific gene 6 expression in human breast cancer. Br J Cancer. 2008;98(6):1141–6.

    CAS  Google Scholar 

  66. Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009;69(17):6871–8.

    CAS  PubMed  Google Scholar 

  67. Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, et al. R428, a selective small molecule inhibitor of axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010;70(4):1544–54.

    CAS  PubMed  Google Scholar 

  68. Li Y, Ye X, Tan C, Hongo JA, Zha J, Liu J, et al. Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene. 2009;28(39):3442–55.

    CAS  PubMed  Google Scholar 

  69. Chiappetta G, Ferraro A, Botti G, Monaco M, Pasquinelli R, Vuttariello E, et al. FRA-1 protein overexpression is a feature of hyperplastic and neoplastic breast disorders. BMC Cancer. 2007;7:17–27.

    PubMed  Google Scholar 

  70. Song Y, Song S, Zhang D, Zhang Y, Chen L, Qian L, et al. An association of a simultaneous nuclear and cytoplasmic localization of Fra-1 with breast malignancy. BMC Cancer. 2006;6:298–304.

    PubMed  Google Scholar 

  71. Luo YP, Zhou H, Krueger J, Kaplan C, Liao D, Markowitz D, et al. The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression. Oncogene. 2010;29(5):662–73.

    CAS  PubMed  Google Scholar 

  72. Chen H, Zhu G, Li Y, Padia RN, Dong Z, Pan ZK, et al. Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res. 2009;69(24):9228–35.

    CAS  PubMed  Google Scholar 

  73. 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.

    CAS  PubMed  Google Scholar 

  74. Toole BP. Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities. Clin Cancer Res. 2009;15(24):7462–8.

    CAS  PubMed  Google Scholar 

  75. 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.

    CAS  PubMed  Google Scholar 

  76. Lynch MD, Cariati M, Purushotham AD. Breast cancer, stem cells and prospects for therapy. Breast Cancer Res. 2006;8(3):211–21.

    PubMed  Google Scholar 

  77. Lim SC, Oh SH. The role of CD24 in various human epithelial neoplasias. Pathol Res Pract. 2005;201(7):479–86.

    CAS  PubMed  Google Scholar 

  78. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8(10):755–68.

    CAS  PubMed  Google Scholar 

  79. Kristiansen G, Sammar M, Altevogt P. Tumour biological aspects of CD24, a mucin-like adhesion molecule. J Mol Histol. 2004;35(3):255–62.

    CAS  PubMed  Google Scholar 

  80. 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.

    CAS  PubMed  Google Scholar 

  81. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene. 2004;23(43):7274–82.

    CAS  PubMed  Google Scholar 

  82. Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med. 2007;58:267–84.

    CAS  PubMed  Google Scholar 

  83. 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.

    CAS  PubMed  Google Scholar 

  84. Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106(33):13820–5.

    CAS  PubMed  Google Scholar 

  85. Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, et al. Purification and unique properties of mammary epithelial stem cells. Nature. 2006;439(7079):993–7.

    CAS  PubMed  Google Scholar 

  86. Trzpis M, McLaughlin PM, de Leij LM, Harmsen MC. Epithelial cell adhesion molecule: more than a carcinoma marker and adhesion molecule. Am J Pathol. 2007;171(2):386–95.

    CAS  PubMed  Google Scholar 

  87. Wright MH, Robles AI, Herschkowitz JI, Hollingshead MG, Anver MR, Perou CM, et al. Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1. Mol Cancer. 2008;7:29–40.

    PubMed  Google Scholar 

  88. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439(7072):84–8.

    CAS  PubMed  Google Scholar 

  89. Radisky DC, LaBarge MA. Epithelial-mesenchymal transition and the stem cell phenotype. Cell Stem Cell. 2008;2(6):511–2.

    CAS  PubMed  Google Scholar 

  90. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 2008;3(8):e2888.

    PubMed  Google Scholar 

  91. 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.

    CAS  PubMed  Google Scholar 

  92. Santisteban M, Reiman JM, Asiedu MK, Behrens MD, Nassar A, Kalli KR, et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 2009;69(7):2887–95.

    CAS  PubMed  Google Scholar 

  93. DiMeo TA, Anderson K, Phadke P, Fan C, Perou CM, Naber S, et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res. 2009;69(13):5364–73.

    CAS  PubMed  Google Scholar 

  94. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15(8):907–13.

    CAS  PubMed  Google Scholar 

  95. Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68(4):989–97.

    CAS  PubMed  Google Scholar 

  96. Logullo AF, Nonogaki S, Pasini FS, Osorio CA, Soares FA, Brentani MM. Concomitant expression of epithelial-mesenchymal transition biomarkers in breast ductal carcinoma: association with progression. Oncol Rep. 2010;23(2):313–20.

    PubMed  Google Scholar 

  97. Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007;8(5):R76.

    PubMed  Google Scholar 

  98. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 2009;69(10):4116–24.

    CAS  PubMed  Google Scholar 

  99. Lien HC, Hsiao YH, Lin YS, Yao YT, Juan HF, Kuo WH, et al. Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial-mesenchymal transition. Oncogene. 2007;26(57):7859–71.

    CAS  PubMed  Google Scholar 

  100. Mimeault M, Batra SK. Functions of tumorigenic and migrating cancer progenitor cells in cancer progression and metastasis and their therapeutic implications. Cancer Metastasis Rev. 2007;26(1):203–14.

    CAS  PubMed  Google Scholar 

  101. Mimeault M, Batra SK. Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann Oncol. 2007;18(10):1605–19.

    CAS  PubMed  Google Scholar 

  102. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5(9):744–9.

    CAS  PubMed  Google Scholar 

  103. Brabletz T, Jung A, Hermann K, Gunther K, Hohenberger W, Kirchner T. Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract. 1998;194(10):701–4.

    CAS  PubMed  Google Scholar 

  104. Kokkinos MI, Wafai R, Wong MK, Newgreen DF, Thompson EW, Waltham M. Vimentin and epithelial-mesenchymal transition in human breast cancer-observations in vitro and in vivo. Cells Tissues Organs. 2007;185:191–203.

    Google Scholar 

  105. Korsching E, Packeisen J, Liedtke C, Hungermann D, Wulfing P, van Diest PJ, et al. The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol. 2005;206(4):451–7.

    CAS  PubMed  Google Scholar 

  106. 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.

    CAS  PubMed  Google Scholar 

  107. Becker S, Becker-Pergola G, Wallwiener D, Solomayer EF, Fehm T. Detection of cytokeratin-positive cells in the bone marrow of breast cancer patients undergoing adjuvant therapy. Breast Cancer Res Treat. 2006;97(1):91–6.

    CAS  PubMed  Google Scholar 

  108. Becker S, Solomayer E, Becker-Pergola G, Wallwiener D, Fehm T. Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients. Breast Cancer Res Treat. 2007;106(2):239–43.

    PubMed  Google Scholar 

  109. Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000;342(8):525–33.

    CAS  PubMed  Google Scholar 

  110. 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(8):781–91.

    CAS  PubMed  Google Scholar 

  111. Braun S, Pantel K. Diagnosis and clinical significance of disseminated tumor cells in bone marrow. Dtsch Med Wochenschr. 2000;125(41):1237–9.

    CAS  PubMed  Google Scholar 

  112. Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, et al. 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. 2006;12(14 Pt 1):4218–24.

    CAS  PubMed  Google Scholar 

  113. Wimberger P, Heubner M, Otterbach F, Fehm T, Kimmig R, Kasimir-Bauer S. Influence of platinum-based chemotherapy on disseminated tumor cells in blood and bone marrow of patients with ovarian cancer. Gynecol Oncol. 2007;107(2):331–8.

    CAS  PubMed  Google Scholar 

  114. 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.

    CAS  PubMed  Google Scholar 

  115. Watson MA, Ylagan LR, Trinkaus KM, Gillanders WE, Naughton MJ, Weilbaecher KN, Fleming TP, Aft RL. Isolation and molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients. Clin Cancer Res. 2007;13:5001–9.

    Google Scholar 

  116. Pantel K, Schlimok G, Angstwurm M, Weckermann D, Schmaus W, Gath H, et al. Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother. 1994;3(3):165–73.

    CAS  PubMed  Google Scholar 

  117. 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.

    PubMed  Google Scholar 

  118. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–59.

    CAS  PubMed  Google Scholar 

  119. Hoeflich KP, O’Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 2009;15(14):4649–64.

    CAS  PubMed  Google Scholar 

  120. Cho KB, Cho MK, Lee WY, and Kang KW. Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. Cancer Lett. 2010;293(2):230–9.

    Google Scholar 

  121. Wendt MK, Schiemann WP. Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-beta signaling and metastasis. Breast Cancer Res. 2009;11(5):R68.

    PubMed  Google Scholar 

  122. Funasaka T, Hogan V, Raz A. Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. Cancer Res. 2009;69(13):5349–56.

    CAS  PubMed  Google Scholar 

  123. Arima Y, Inoue Y, Shibata T, Hayashi H, Nagano O, Saya H, et al. Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition. Cancer Res. 2008;68(13):5104–12.

    CAS  PubMed  Google Scholar 

  124. Tumbarello DA, Turner CE. Hic-5 contributes to epithelial-mesenchymal transformation through a RhoA/ROCK-dependent pathway. J Cell Physiol. 2007;211(3):736–47.

    CAS  PubMed  Google Scholar 

  125. Wu X, Chen H, Parker B, Rubin E, Zhu T, Lee JS, et al. HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition. Cancer Res. 2006;66(19):9527–34.

    CAS  PubMed  Google Scholar 

  126. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene. 2007;26(5):711–24.

    CAS  PubMed  Google Scholar 

  127. Bundy L, Wells S, Sealy L. C/EBPbeta-2 confers EGF-independent growth and disrupts the normal acinar architecture of human mammary epithelial cells. Mol Cancer. 2005;4:43.

    PubMed  Google Scholar 

  128. Tanaka H, Shirkoohi R, Nakagawa K, Qiao H, Fujita H, Okada F, et al. siRNA gelsolin knockdown induces epithelial-mesenchymal transition with a cadherin switch in human mammary epithelial cells. Int J Cancer. 2006;118(7):1680–91.

    CAS  PubMed  Google Scholar 

  129. Guan F, Handa K, Hakomori SI. Specific glycosphingolipids mediate epithelial-to-mesenchymal transition of human and mouse epithelial cell lines. Proc Natl Acad Sci U S A. 2009;106(18):7461–6.

    CAS  PubMed  Google Scholar 

  130. 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.

    CAS  PubMed  Google Scholar 

  131. Hiscox S, Jiang WG, Obermeier K, Taylor K, Morgan L, Burmi R, et al. Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. Int J Cancer. 2006;118(2):290–301.

    CAS  PubMed  Google Scholar 

  132. Planas-Silva MD, Waltz PK. Estrogen promotes reversible epithelial-to-mesenchymal-like transition and collective motility in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2007;104(1–2):11–21.

    CAS  PubMed  Google Scholar 

  133. Shtutman M, Levina E, Ohouo P, Baig M, Roninson IB. Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast carcinoma cells. Cancer Res. 2006;66(23):11370–80.

    CAS  PubMed  Google Scholar 

  134. Micalizzi DS, Christensen KL, Jedlicka P, Coletta RD, Baron AE, Harrell JC, et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Invest. 2009;119(9):2678–90.

    CAS  PubMed  Google Scholar 

  135. Allington TM, Galliher-Beckley AJ, Schiemann WP. Activated Abl kinase inhibits oncogenic transforming growth factor-beta signaling and tumorigenesis in mammary tumors. FASEB J. 2009;23(12):4231–43.

    CAS  PubMed  Google Scholar 

  136. Neil JR, Johnson KM, Nemenoff RA, Schiemann WP. Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms. Carcinogenesis. 2008;29(11):2227–35.

    CAS  PubMed  Google Scholar 

  137. Lee YH, Albig AR, Regner M, Schiemann BJ, Schiemann WP. Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis. 2008;29(12):2243–51.

    CAS  PubMed  Google Scholar 

  138. Galliher AJ, Schiemann WP. Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res. 2006;8(4):R42.

    PubMed  Google Scholar 

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Acknowledgements

The research effort associated with this article was funded in part by the U.S. Army Medical Research and Materiel Command (BC0213201 and BC084667), the Victorian Breast Cancer Research Consortium, The Cancer Council Victoria (#509295) and the National Breast Cancer Foundation (Australia). TB and EWT were supported in part by the Victorian Breast Cancer Research Consortium. HH is supported by a fellowship from the National Breast Cancer Foundation, Australia. EW is the recipient of an AUS Aid Scholarship. Parts of this work were also supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research (Contract DE-AC03-76SF00098) and the California Breast Cancer Research Program (CBCRP) grant # 7FB-0027. SAM lab is supported by V foundations V Scholar award and M. D. Anderson Research Trust Fellow award. RAW is supported in part by the Breast Cancer Research Foundation. The authors are grateful to Dr. Kornelia Polyak for providing prepublication data from the Shipitsin et al. study (2007) for comparative analysis.

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Correspondence to Erik W. Thompson.

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Supplementary Table 1

The literature pertaining to EMT in breast cancer was searched and molecules shown empirically to cause EMT or change during EMT were assembled. In some cases, additional family members were included. Gene products known to be differentially expressed across different breast cancer cell lines were not included on the basis of that alone. Although not comprehensive, EMT-SIG is an ad hoc, literature-derived gene list from the breast cancer literature. (XLS 20 kb)

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Blick, T., Hugo, H., Widodo, E. et al. Epithelial Mesenchymal Transition Traits in Human Breast Cancer Cell Lines Parallel the CD44hi/CD24lo/- Stem Cell Phenotype in Human Breast Cancer. J Mammary Gland Biol Neoplasia 15, 235–252 (2010). https://doi.org/10.1007/s10911-010-9175-z

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