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Snail Family Regulation and Epithelial Mesenchymal Transitions in Breast Cancer Progression

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Since its initial description, the interconversion between epithelial and mesenchymal cells (designed as epithelial-mesenchymal or mesenchymal-epithelial transition, EMT or MET, respectively) has received special attention since it provides epithelial cells with migratory features. Different studies using cell lines have identified cytokines, intercellular signaling elements and transcriptional factors capable of regulating this process. Particularly, the identification of Snail family members as key effectors of EMT has opened new ways for the study of this cellular process. In this article we discuss the molecular pathways that control EMT, showing a very tight and interdependent regulation. We also analyze the contribution of EMT and Snail genes in the process of tumorigenesis using the mammary gland as cellular model.

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Abbreviations

EMT:

Epithelial-mesenchymal transition

MET:

Mesenchymal-epithelial transition

CDH1:

E-Cadherin gene

HDAC:

Histone deacetylases

PRC2:

Polycomb group of proteins

SBE:

Smad binding element

SCP:

C-terminal domain phosphatase

Ppa:

Partner of Paired

HGF:

Hepatocyte growth factor

Egr1:

Early growth response 1 gene

MAPK1:

Mitogen activated protein kinase 1

HMGA2:

High mobility group A2

ER-α:

Estrogen Receptor α

CSN2:

COP9 signalosome 2

TEB:

Terminal end buds

FSP:

Fibroblast specific protein

References

  1. Hay ED. Theory for epithelial-mesenchymal transformation based on the "fixed cortex" cell motility model. Cell Motil Cytoskeleton. 1989;14(4):455–7.

    CAS  PubMed  Google Scholar 

  2. Arnoux V, Come C, Kusewitt D, Savagner P. Cutaneous wound healing: a partial and reversible EMT. Rise and fall of epithelial phenotype: Concepts of epithelial-mesenchymal transition. In: Savagner P, editor.: Landes Biosciences; 2004

  3. 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 

  4. 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 

  5. 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 

  6. 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 

  7. Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature. 1998;392(6672):190–3.

    CAS  PubMed  Google Scholar 

  8. Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, et al. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol. 1991;113(1):173–85.

    CAS  PubMed  Google Scholar 

  9. Vleminckx K, Vakaet Jr L, Mareel M, Fiers W, van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991;66(1):107–19.

    CAS  PubMed  Google Scholar 

  10. Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta. 1994;1198(1):11–26.

    CAS  PubMed  Google Scholar 

  11. Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation. J Cell Sci. 2004;117(Pt 9):1675–85.

    CAS  PubMed  Google Scholar 

  12. Solanas G, Porta-de-la-Riva M, Agusti C, Casagolda D, Sanchez-Aguilera F, Larriba MJ, et al. E-cadherin controls beta-catenin and NF-kappaB transcriptional activity in mesenchymal gene expression. J Cell Sci. 2008;121(Pt 13):2224–34.

    CAS  PubMed  Google Scholar 

  13. Hennig G, Behrens J, Truss M, Frisch S, Reichmann E, Birchmeier W. Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo. Oncogene. 1995;11(3):475–84.

    CAS  PubMed  Google Scholar 

  14. Hennig G, Lowrick O, Birchmeier W, Behrens J. Mechanisms identified in the transcriptional control of epithelial gene expression. J Biol Chem. 1996;271(1):595–602.

    CAS  PubMed  Google Scholar 

  15. Kamei T, Matozaki T, Takai Y. Mechanisms of cell adhesion and migration. Gan To Kagaku Ryoho. 1999;26(9):1359–66.

    CAS  PubMed  Google Scholar 

  16. Le TL, Yap AS, Stow JL. Recycling of E-cadherin: a potential mechanism for regulating cadherin dynamics. J Cell Biol. 1999;146(1):219–32.

    CAS  PubMed  Google Scholar 

  17. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.

    CAS  PubMed  Google Scholar 

  18. Kinch MS, Clark GJ, Der CJ, Burridge K. Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia. J Cell Biol. 1995;130(2):461–71.

    CAS  PubMed  Google Scholar 

  19. 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 

  20. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2(2):84–9.

    CAS  PubMed  Google Scholar 

  21. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.

    CAS  PubMed  Google Scholar 

  22. Wang X, Zheng M, Liu G, Xia W, McKeown-Longo PJ, Hung MC, et al. Kruppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res. 2007;67(15):7184–93.

    CAS  PubMed  Google Scholar 

  23. Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;62(6):1613–8.

    CAS  PubMed  Google Scholar 

  24. Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 2001;7(6):1267–78.

    CAS  PubMed  Google Scholar 

  25. Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005;24(14):2375–85.

    CAS  PubMed  Google Scholar 

  26. Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA, et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem. 2001;276(29):27424–31.

    CAS  PubMed  Google Scholar 

  27. Ellenberger T, Fass D, Arnaud M, Harrison SC. Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer. Genes Dev. 1994;8(8):970–80.

    CAS  PubMed  Google Scholar 

  28. Vandewalle C, Van Roy F, Berx G. The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci. 2009;66(5):773–87.

    CAS  PubMed  Google Scholar 

  29. Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, Andersen H, et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res. 2005;33(20):6566–78.

    CAS  PubMed  Google Scholar 

  30. Grooteclaes ML, Frisch SM. Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene. 2000;19(33):3823–8.

    CAS  PubMed  Google Scholar 

  31. Grooteclaes M, Deveraux Q, Hildebrand J, Zhang Q, Goodman RH, Frisch SM. C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs. Proc Natl Acad Sci U S A. 2003;100(8):4568–73.

    CAS  PubMed  Google Scholar 

  32. Shi Y, Sawada J, Sui G, Affar el B, Whetstine JR, Lan F, et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003;422(6933):735–8.

    CAS  PubMed  Google Scholar 

  33. Alpatov R, Munguba GC, Caton P, Joo JH, Shi Y, Hunt ME, et al. Nuclear speckle-associated protein Pnn/DRS binds to the transcriptional corepressor CtBP and relieves CtBP-mediated repression of the E-cadherin gene. Mol Cell Biol. 2004;24(23):10223–35.

    CAS  PubMed  Google Scholar 

  34. Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3(3):155–66.

    CAS  PubMed  Google Scholar 

  35. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116(Pt 3):499–511.

    CAS  PubMed  Google Scholar 

  36. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28.

    CAS  PubMed  Google Scholar 

  37. Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004;18(10):1131–43.

    CAS  PubMed  Google Scholar 

  38. Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol. 2004;24(17):7559–66.

    CAS  PubMed  Google Scholar 

  39. Escriva M, Peiro S, Herranz N, Villagrasa P, Dave N, Montserrat-Sentis B, et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol Cell Biol. 2008;28(5):1528–40.

    CAS  PubMed  Google Scholar 

  40. Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell. 2009;15(3):195–206.

    CAS  PubMed  Google Scholar 

  41. Peinado H, Ballestar E, Esteller M, Cano A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 2004;24(1):306–19.

    CAS  PubMed  Google Scholar 

  42. Herranz N, Pasini D, Diaz VM, Franci C, Gutierrez A, Dave N, et al. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol. 2008;28(15):4772–81.

    CAS  PubMed  Google Scholar 

  43. Langer EM, Feng Y, Zhaoyuan H, Rauscher 3rd FJ, Kroll KL, Longmore GD. Ajuba LIM proteins are snail/slug corepressors required for neural crest development in Xenopus. Dev Cell. 2008;14(3):424–36.

    CAS  PubMed  Google Scholar 

  44. Nibu Y, Zhang H, Levine M. Interaction of short-range repressors with Drosophila CtBP in the embryo. Science. 1998;280(5360):101–4.

    CAS  PubMed  Google Scholar 

  45. Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, Albanell J, et al. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009;11(8):943–50.

    CAS  PubMed  Google Scholar 

  46. Stemmer V, de Craene B, Berx G, Behrens J. Snail promotes Wnt target gene expression and interacts with beta-catenin. Oncogene. 2008;27(37):5075–80.

    CAS  PubMed  Google Scholar 

  47. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004;6(10):931–40.

    CAS  PubMed  Google Scholar 

  48. Dominguez D, Montserrat-Sentis B, Virgos-Soler A, Guaita S, Grueso J, Porta M, et al. Phosphorylation regulates the subcellular location and activity of the snail transcriptional repressor. Mol Cell Biol. 2003;23(14):5078–89.

    CAS  PubMed  Google Scholar 

  49. Wu Y, Evers BM, Zhou BP. Small C-terminal domain phosphatase enhances snail activity through dephosphorylation. J Biol Chem. 2009;284(1):640–8.

    CAS  PubMed  Google Scholar 

  50. MacPherson MR, Molina P, Souchelnytskyi S, Wernstedt C, Martin-Perez J, Portillo F, et al. Phosphorylation of serine 11 and serine 92 as new positive regulators of human Snail1 function: potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A. Mol Biol Cell. 2009;21(2):244–53.

    PubMed  Google Scholar 

  51. Yang Z, Rayala S, Nguyen D, Vadlamudi RK, Chen S, Kumar R. Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail’s subcellular localization and functions. Cancer Res. 2005;65(8):3179–84.

    CAS  PubMed  Google Scholar 

  52. Peinado H, Iglesias de la Cruz MC, Olmeda D, Csiszar K, Fong KS, Vega S, et al. A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 2005;24(19):3446–58.

    CAS  PubMed  Google Scholar 

  53. Vinas-Castells R, Beltran M, Valls G, Gomez I, Garcia JM, Montserrat-Sentis B, et al. The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. J Biol Chem. 2010;285(6):3794–805.

    CAS  PubMed  Google Scholar 

  54. Hemavathy K, Guru SC, Harris J, Chen JD, Ip YT. Human Slug is a repressor that localizes to sites of active transcription. Mol Cell Biol. 2000;20(14):5087–95.

    CAS  PubMed  Google Scholar 

  55. Vernon AE, LaBonne C. Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa. Development. 2006;133(17):3359–70.

    CAS  PubMed  Google Scholar 

  56. Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH, et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol. 2009;11(6):694–704.

    CAS  PubMed  Google Scholar 

  57. Kataoka H, Murayama T, Yokode M, Mori S, Sano H, Ozaki H, et al. A novel snail-related transcription factor Smuc regulates basic helix-loop-helix transcription factor activities via specific E-box motifs. Nucleic Acids Res. 2000;28(2):626–33.

    CAS  PubMed  Google Scholar 

  58. Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM, et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell. 2005;123(4):641–53.

    CAS  PubMed  Google Scholar 

  59. Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P, Ben-Ze’ev A. Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol. 2003;163(4):847–57.

    CAS  PubMed  Google Scholar 

  60. Arnoux V, Nassour M, L’Helgoualc’h A, Hipskind RA, Savagner P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol Biol Cell. 2008;19(11):4738–49.

    CAS  PubMed  Google Scholar 

  61. Grotegut S, von Schweinitz D, Christofori G, Lehembre F. Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J. 2006;25(15):3534–45.

    CAS  PubMed  Google Scholar 

  62. Thuault S, Tan EJ, Peinado H, Cano A, Heldin CH, Moustakas A. HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem. 2008;283(48):33437–46.

    CAS  PubMed  Google Scholar 

  63. Palmer MB, Majumder P, Green MR, Wade PA, Boss JM. A 3′ enhancer controls snail expression in melanoma cells. Cancer Res. 2007;67(13):6113–20.

    CAS  PubMed  Google Scholar 

  64. Peiro S, Escriva M, Puig I, Barbera MJ, Dave N, Herranz N, et al. Snail1 transcriptional repressor binds to its own promoter and controls its expression. Nucleic Acids Res. 2006;34(7):2077–84.

    CAS  PubMed  Google Scholar 

  65. Freeman M. Feedback control of intercellular signalling in development. Nature. 2000;408(6810):313–9.

    CAS  PubMed  Google Scholar 

  66. Sakai D, Suzuki T, Osumi N, Wakamatsu Y. Cooperative action of Sox9, Snail2 and PKA signaling in early neural crest development. Development. 2006;133(7):1323–33.

    CAS  PubMed  Google Scholar 

  67. Moreno-Bueno G, Cubillo E, Sarrio D, Peinado H, Rodriguez-Pinilla SM, Villa S, et al. Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition. Cancer Res. 2006;66(19):9543–56.

    CAS  PubMed  Google Scholar 

  68. Robert G, Gaggioli C, Bailet O, Chavey C, Abbe P, Aberdam E, et al. SPARC represses E-cadherin and induces mesenchymal transition during melanoma development. Cancer Res. 2006;66(15):7516–23.

    CAS  PubMed  Google Scholar 

  69. Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114(4):569–81.

    CAS  PubMed  Google Scholar 

  70. Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, et al. Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene. 2007;26(53):7445–56.

    CAS  PubMed  Google Scholar 

  71. Barbera MJ, Puig I, Dominguez D, Julien-Grille S, Guaita-Esteruelas S, Peiro S, et al. Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene. 2004;23(44):7345–54.

    CAS  PubMed  Google Scholar 

  72. Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM. Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol. 2005;168(1):29–33.

    CAS  PubMed  Google Scholar 

  73. Kuphal S, Poser I, Jobin C, Hellerbrand C, Bosserhoff AK. Loss of E-cadherin leads to upregulation of NFkappaB activity in malignant melanoma. Oncogene. 2004;23(52):8509–19.

    CAS  PubMed  Google Scholar 

  74. Jamora C, Lee P, Kocieniewski P, Azhar M, Hosokawa R, Chai Y, et al. A signaling pathway involving TGF-beta2 and snail in hair follicle morphogenesis. PLoS Biol. 2005;3(1):e11.

    PubMed  Google Scholar 

  75. Dhasarathy A, Kajita M, Wade PA. The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha. Mol Endocrinol. 2007;21(12):2907–18.

    CAS  PubMed  Google Scholar 

  76. Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell. 2003;113(2):207–19.

    CAS  PubMed  Google Scholar 

  77. De Craene B, van Roy F, Berx G. Unraveling signalling cascades for the Snail family of transcription factors. Cell Signal. 2005;17(5):535–47.

    PubMed  Google Scholar 

  78. Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E, et al. Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem. 2002;277(42):39209–16.

    CAS  PubMed  Google Scholar 

  79. Beltran M, Puig I, Pena C, Garcia JM, Alvarez AB, Pena R, et al. A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev. 2008;22(6):756–69.

    CAS  PubMed  Google Scholar 

  80. Palmer HG, Gonzalez-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, et al. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 2001;154(2):369–87.

    CAS  PubMed  Google Scholar 

  81. Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, et al. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8(12):1398–406.

    CAS  PubMed  Google Scholar 

  82. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7):927–39.

    CAS  PubMed  Google Scholar 

  83. Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP. Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell. 2009;15(5):416–28.

    CAS  PubMed  Google Scholar 

  84. Hinck L, Silberstein GB. Key stages in mammary gland development: the mammary end bud as a motile organ. Breast Cancer Res. 2005;7(6):245–51.

    CAS  PubMed  Google Scholar 

  85. Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn. 2006;235(12):3404–12.

    CAS  PubMed  Google Scholar 

  86. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403–10.

    CAS  PubMed  Google Scholar 

  87. Halachmi S, DeMarzo AM, Chow NH, Halachmi N, Smith AE, Linn JF, et al. Genetic alterations in urinary bladder carcinosarcoma: evidence of a common clonal origin. Eur Urol. 2000;37(3):350–7.

    CAS  PubMed  Google Scholar 

  88. Saegusa M, Hashimura M, Kuwata T, Okayasu I. Requirement of the Akt/beta-catenin pathway for uterine carcinosarcoma genesis, modulating E-cadherin expression through the transactivation of slug. Am J Pathol. 2009;174(6):2107–15.

    CAS  PubMed  Google Scholar 

  89. Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006;10(5):437–49.

    CAS  PubMed  Google Scholar 

  90. Moll R, Mitze M, Frixen UH, Birchmeier W. Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas. Am J Pathol. 1993;143(6):1731–42.

    CAS  PubMed  Google Scholar 

  91. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    CAS  PubMed  Google Scholar 

  92. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869–74.

    CAS  PubMed  Google Scholar 

  93. Dontu G, El-Ashry D, Wicha MS. Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab. 2004;15(5):193–7.

    CAS  PubMed  Google Scholar 

  94. Cho KB, Cho MK, Lee WY, Kang KW. Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. Cancer Lett. 2010 Feb 7, [Epub ahead of print] doi:10.1016/j.canlet.2010.01.013

  95. Smith AP, Verrecchia A, Faga G, Doni M, Perna D, Martinato F, et al. A positive role for Myc in TGFbeta-induced Snail transcription and epithelial-to-mesenchymal transition. Oncogene. 2009;28(3):422–30.

    CAS  PubMed  Google Scholar 

  96. Storci G, Sansone P, Trere D, Tavolari S, Taffurelli M, Ceccarelli C, et al. The basal-like breast carcinoma phenotype is regulated by SLUG gene expression. J Pathol. 2008;214(1):25–37.

    CAS  PubMed  Google Scholar 

  97. 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 

  98. Williams DJ, Cohen C, To TV, Page AJ, Lawson D, Sussman ZM, et al. Triple-negative breast carcinoma in women from Vietnam and the United States: characterization of differential marker expression by tissue microarray. Hum Pathol. 2009;40(8):1176–81.

    CAS  PubMed  Google Scholar 

  99. Nakshatri H, Srour EF, Badve S. Breast cancer stem cells and intrinsic subtypes: controversies rage on. Curr Stem Cell Res Ther. 2009;4(1):50–60.

    CAS  PubMed  Google Scholar 

  100. 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 

  101. Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell. 2008;14(1):79–89.

    CAS  PubMed  Google Scholar 

  102. Come SE, Buzdar AU, Arteaga CL, Bissell MJ, Brown MA, Ellis MJ, et al. Proceedings of the third international conference on recent advances and future directions in endocrine manipulation of breast cancer: conference summary statement. Clin Cancer Res. 2004;10(1 Pt 2):327S–30S.

    PubMed  Google Scholar 

  103. 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 

  104. Franci C, Gallen M, Alameda F, Baro T, Iglesias M, Virtanen I, et al. Snail1 protein in the stroma as a new putative prognosis marker for colon tumours. PLoS One. 2009;4(5):e5595.

    PubMed  Google Scholar 

  105. 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 

  106. 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 

  107. Jechlinger M, Grunert S, Tamir IH, Janda E, Ludemann S, Waerner T, et al. Expression profiling of epithelial plasticity in tumor progression. Oncogene. 2003;22(46):7155–69.

    CAS  PubMed  Google Scholar 

  108. Liu M, Casimiro MC, Wang C, Shirley LA, Jiao X, Katiyar S, et al. p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proc Natl Acad Sci U S A. 2009;106(45):19035–9.

    CAS  PubMed  Google Scholar 

  109. Chen YC, Chen YW, Hsu HS, Tseng LM, Huang PI, Lu KH, et al. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun. 2009;385(3):307–13.

    CAS  PubMed  Google Scholar 

  110. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 2009;27(9):2059–68.

    CAS  PubMed  Google Scholar 

  111. 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 

  112. 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 

  113. Rowe RG, Li XY, Hu Y, Saunders TL, Virtanen I, Garcia de Herreros A, et al. Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs. J Cell Biol. 2009;184(3):399–408.

    CAS  PubMed  Google Scholar 

  114. Ota I, Li XY, Hu Y, Weiss SJ. Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci U S A. 2009;106(48):20318–23.

    CAS  PubMed  Google Scholar 

  115. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449(7162):557–63.

    CAS  PubMed  Google Scholar 

  116. Chua KN, Ma J, Thiery JP. Targeted therapies in control of EMT in carcinoma and fibrosis. Drug Discov Today. 2008;4:261–7.

    Google Scholar 

  117. 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 

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Acknowledgements

We thank Rosa Viñas for her help in the correction of this manuscript. Research in AGH laboratory is funded by the Spanish Ministry of Science (SAF2006-00339), Fundació La Marató, Instituto Carlos III (RD06/0020/0040) and Generalitat de Catalunya (2009SGR121). Research in PS laboratory is supported by institutional funds (INSERM U896), by Foundation de France (2009 006685) and Ligue Nationale contra le Cancer.

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Authors and Affiliations

  1. IMIM-Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, C/Doctor Aiguader, 88, 08003, Barcelona, Spain

    Antonio Garcia de Herreros & Sandra Peiró

  2. IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U896, Montpellier, 34298, France

    Mayssaa Nassour & Pierre Savagner

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  1. Antonio Garcia de Herreros
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  2. Sandra Peiró
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  3. Mayssaa Nassour
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  4. Pierre Savagner
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Correspondence to Antonio Garcia de Herreros or Pierre Savagner.

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de Herreros, A.G., Peiró, S., Nassour, M. et al. Snail Family Regulation and Epithelial Mesenchymal Transitions in Breast Cancer Progression. J Mammary Gland Biol Neoplasia 15, 135–147 (2010). https://doi.org/10.1007/s10911-010-9179-8

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  • DOI: https://doi.org/10.1007/s10911-010-9179-8

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