Snail Family Regulation and Epithelial Mesenchymal Transitions in Breast Cancer Progression

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.

[1]  Y. Shi,et al.  Nuclear Speckle-Associated Protein Pnn/DRS Binds to the Transcriptional Corepressor CtBP and Relieves CtBP- Mediated Repression of the E-Cadherin Gene , 2004, Molecular and Cellular Biology.

[2]  Zhiyuan Hu,et al.  Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors , 2007, Genome Biology.

[3]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  A. G. de Herreros,et al.  Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling , 2001, The Journal of cell biology.

[5]  Héctor Peinado,et al.  Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? , 2007, Nature Reviews Cancer.

[6]  A. Ghanate,et al.  Snail and Slug Mediate Radioresistance and Chemoresistance by Antagonizing p53‐Mediated Apoptosis and Acquiring a Stem‐Like Phenotype in Ovarian Cancer Cells , 2009, Stem cells.

[7]  Robert A. Weinberg,et al.  Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. , 2008, Developmental cell.

[8]  K. Helin,et al.  Polycomb Complex 2 Is Required for E-cadherin Repression by the Snail1 Transcription Factor , 2008, Molecular and Cellular Biology.

[9]  W. Birchmeier,et al.  Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas. , 1993, The American journal of pathology.

[10]  E. Fearon,et al.  The SLUG zinc-finger protein represses E-cadherin in breast cancer. , 2002, Cancer research.

[11]  Charis Eng,et al.  Direct evidence for epithelial-mesenchymal transitions in breast cancer. , 2008, Cancer research.

[12]  S. Weiss,et al.  Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs , 2009, The Journal of cell biology.

[13]  B. Zhou,et al.  Small C-terminal Domain Phosphatase Enhances Snail Activity through Dephosphorylation* , 2009, Journal of Biological Chemistry.

[14]  Andreas Sommer,et al.  NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression , 2004 .

[15]  Archana Dhasarathy,et al.  The Transcription Factor Snail Mediates Epithelial to Mesenchymal Transitions by Repression of Estrogen Receptor - , 2007 .

[16]  E. Guccione,et al.  A positive role for Myc in TGFβ-induced Snail transcription and epithelial-to-mesenchymal transition , 2009, Oncogene.

[17]  G. Berx,et al.  DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells , 2005, Oncogene.

[18]  A. G. de Herreros,et al.  A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. , 2008, Genes & development.

[19]  Gema Moreno-Bueno,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. , 2006, Cancer research.

[20]  S. Frisch,et al.  Evidence for a function of CtBP in epithelial gene regulation and anoikis , 2000, Oncogene.

[21]  I. Roninson,et al.  Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast carcinoma cells. , 2006, Cancer research.

[22]  M. Fraga,et al.  The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors , 2003, Journal of Cell Science.

[23]  L. Nelles,et al.  Activation of NF-κB by Akt upregulates Snail expression and induces epithelium mesenchyme transition , 2007, Oncogene.

[24]  C. Wernstedt,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 , 2010, Molecular biology of the cell.

[25]  A. G. de Herreros,et al.  The Hypoxia-controlled FBXL14 Ubiquitin Ligase Targets SNAIL1 for Proteasome Degradation* , 2009, The Journal of Biological Chemistry.

[26]  Yi-Wei Chen,et al.  Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. , 2009, Biochemical and biophysical research communications.

[27]  G. Colditz,et al.  Proceedings of the Fourth International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer: conference summary statement. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[28]  D. Nguyen,et al.  Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. , 2005, Cancer research.

[29]  Z. Werb,et al.  Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[30]  Carlos S. Moreno,et al.  MTA3, a Mi-2/NuRD Complex Subunit, Regulates an Invasive Growth Pathway in Breast Cancer , 2003, Cell.

[31]  G. Berx,et al.  The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. , 2001, Molecular cell.

[32]  Y. Ip,et al.  Human Slug Is a Repressor That Localizes to Sites of Active Transcription , 2000, Molecular and Cellular Biology.

[33]  Eduard Batlle,et al.  Snail Induction of Epithelial to Mesenchymal Transition in Tumor Cells Is Accompanied by MUC1 Repression andZEB1 Expression* , 2002, The Journal of Biological Chemistry.

[34]  Thomas Kirchner,et al.  Migrating cancer stem cells — an integrated concept of malignant tumour progression , 2005, Nature Reviews Cancer.

[35]  A. Look,et al.  Slug Antagonizes p53-Mediated Apoptosis of Hematopoietic Progenitors by Repressing puma , 2005, Cell.

[36]  Francisco Portillo,et al.  The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression , 2000, Nature Cell Biology.

[37]  N. Dave,et al.  Expression of Snail protein in tumor–stroma interface , 2006, Oncogene.

[38]  G. Berx,et al.  SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell–cell junctions , 2005, Nucleic acids research.

[39]  Ker-Chau Li,et al.  p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug , 2009, Nature Cell Biology.

[40]  Gema Moreno-Bueno,et al.  Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. , 2008, Cancer research.

[41]  H. Pehamberger,et al.  NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. , 2004, The Journal of clinical investigation.

[42]  Yutaka Kawakami,et al.  Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. , 2009, Cancer cell.

[43]  W. Birchmeier,et al.  E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells , 1991, The Journal of cell biology.

[44]  C. Der,et al.  Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia , 1995, The Journal of cell biology.

[45]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[46]  Ross Tubo,et al.  Mesenchymal stem cells within tumour stroma promote breast cancer metastasis , 2007, Nature.

[47]  W. Birchmeier,et al.  Progression of carcinoma cells is associated with alterations in chromatin structure and factor binding at the E-cadherin promoter in vivo. , 1995, Oncogene.

[48]  Ellen M. Langer,et al.  Ajuba LIM proteins are snail/slug corepressors required for neural crest development in Xenopus. , 2008, Developmental cell.

[49]  P. Wade,et al.  A 3' enhancer controls snail expression in melanoma cells. , 2007, Cancer research.

[50]  S. Weiss,et al.  A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. , 2006, Nature cell biology.

[51]  I. Puig,et al.  Phosphorylation Regulates the Subcellular Location and Activity of the Snail Transcriptional Repressor , 2003, Molecular and Cellular Biology.

[52]  J. Thiery,et al.  Targeted therapies in control of EMT in carcinoma and fibrosis , 2007 .

[53]  M. Freeman.  Feedback control of intercellular signalling in development , 2000, Nature.

[54]  C. Heldin,et al.  HMGA2 and Smads Co-regulate SNAIL1 Expression during Induction of Epithelial-to-Mesenchymal Transition* , 2008, Journal of Biological Chemistry.

[55]  E. Ballestar,et al.  Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex , 2004, Molecular and Cellular Biology.

[56]  I. Roninson,et al.  Cell Adhesion Molecule L 1 Disrupts E-Cadherin-Containing Adherens Junctions and Increases Scattering and Motility of MCF 7 Breast Carcinoma Cells , 2006 .

[57]  R. Maestro,et al.  Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. , 2008, Cancer cell.

[58]  Gerhard Christofori,et al.  A causal role for E-cadherin in the transition from adenoma to carcinoma , 1998, Nature.

[59]  M. Nieto,et al.  A New Role for E12/E47 in the Repression ofE-cadherin Expression and Epithelial-Mesenchymal Transitions* , 2001, The Journal of Biological Chemistry.

[60]  I. Ellis,et al.  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. , 2002, Histopathology.

[61]  Yang Shi,et al.  Coordinated histone modifications mediated by a CtBP co-repressor complex , 2003, Nature.

[62]  A. G. de Herreros,et al.  Snail1 transcriptional repressor binds to its own promoter and controls its expression , 2006, Nucleic acids research.

[63]  G. Dontu,et al.  Breast cancer, stem/progenitor cells and the estrogen receptor , 2004, Trends in Endocrinology & Metabolism.

[64]  Robert D Cardiff,et al.  The transcriptional repressor Snail promotes mammary tumor recurrence. , 2005, Cancer cell.

[65]  P. Savagner.  Rise and Fall of Epithelial Phenotype: Concepts of Epithelial-Mesenchymal Transition , 2005 .

[66]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. , 1999, Critical reviews in oncology/hematology.

[67]  S. Weiss,et al.  Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1 , 2009, Proceedings of the National Academy of Sciences.

[68]  G. Berx,et al.  Snail promotes Wnt target gene expression and interacts with β-catenin , 2008, Oncogene.

[69]  S. Murray,et al.  Repression of PTEN Phosphatase by Snail1 Transcriptional Factor during Gamma Radiation-Induced Apoptosis , 2008, Molecular and Cellular Biology.

[70]  M. Hung,et al.  Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition , 2004, Nature Cell Biology.

[71]  R. Hipskind,et al.  Erk5 controls Slug expression and keratinocyte activation during wound healing. , 2008, Molecular biology of the cell.

[72]  W. Birchmeier,et al.  Mechanisms Identified in the Transcriptional Control of Epithelial Gene Expression (*) , 1996, The Journal of Biological Chemistry.

[73]  Lindsay Hinck,et al.  Key stages in mammary gland development: The mammary end bud as a motile organ , 2005, Breast Cancer Research.

[74]  W. Birchmeier,et al.  Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. , 1994, Biochimica et biophysica acta.

[75]  P. Abbe,et al.  SPARC represses E-cadherin and induces mesenchymal transition during melanoma development. , 2006, Cancer research.

[76]  D. Sakai,et al.  Cooperative action of Sox9, Snail2 and PKA signaling in early neural crest development , 2006, Development.

[77]  Harikrishna Nakshatri,et al.  Breast cancer stem cells and intrinsic subtypes: controversies rage on. , 2009, Current stem cell research & therapy.

[78]  K. Green.  Faculty Opinions recommendation of Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. , 2004 .

[79]  M. Saegusa,et al.  Requirement of the Akt/beta-catenin pathway for uterine carcinosarcoma genesis, modulating E-cadherin expression through the transactivation of slug. , 2009, The American journal of pathology.

[80]  Charles M Perou,et al.  A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. , 2009, Cancer research.

[81]  A. G. Herreros,et al.  The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells , 2000, Nature Cell Biology.

[82]  M. Levine,et al.  Interaction of short-range repressors with Drosophila CtBP in the embryo. , 1998, Science.

[83]  W. Fiers,et al.  Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role , 1991, Cell.

[84]  Elaine Fuchs,et al.  A Signaling Pathway Involving TGF-β2 and Snail in Hair Follicle Morphogenesis , 2004, PLoS biology.

[85]  Ann E. Vernon,et al.  Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa , 2006, Development.

[86]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[87]  Thomas Waerner,et al.  Expression profiling of epithelial plasticity in tumor progression , 2003, Oncogene.

[88]  M. Nieto,et al.  The snail superfamily of zinc-finger transcription factors , 2002, Nature Reviews Molecular Cell Biology.

[89]  Suimin Qiu,et al.  Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. , 2009, Cancer cell.

[90]  Raghu Kalluri,et al.  The epithelial–mesenchymal transition: new insights in signaling, development, and disease , 2006, The Journal of cell biology.

[91]  P. Wade,et al.  Aberrant Expression of the Transcription Factors Snail and Slug Alters the Response to Genotoxic Stress , 2004, Molecular and Cellular Biology.

[92]  L. Montanaro,et al.  The basal‐like breast carcinoma phenotype is regulated by SLUG gene expression , 2008, The Journal of pathology.

[93]  R. Crystal,et al.  A SNAIL1–SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial–mesenchymal transition , 2009, Nature Cell Biology.

[94]  G. Berx,et al.  The role of the ZEB family of transcription factors in development and disease , 2009, Cellular and Molecular Life Sciences.

[95]  Jos Jonkers,et al.  Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. , 2006, Cancer cell.

[96]  A. Bosserhoff,et al.  Loss of E-cadherin leads to upregulation of NFkappaB activity in malignant melanoma. , 2004, Oncogene.

[97]  I. Fabregat,et al.  Snail blocks the cell cycle and confers resistance to cell death. , 2004, Genes & development.

[98]  A. Puisieux,et al.  Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition , 2008, PloS one.

[99]  K. Csiszȧr,et al.  A molecular role for lysyl oxidase‐like 2 enzyme in Snail regulation and tumor progression , 2005, The EMBO journal.

[100]  S. Ramaswamy,et al.  Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis , 2004, Cell.

[101]  M. Klymkowsky,et al.  Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. , 2009, The American journal of pathology.

[102]  K. Kang,et al.  Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. , 2010, Cancer letters.

[103]  A. G. de Herreros,et al.  E-cadherin controls β-catenin and NF-κB transcriptional activity in mesenchymal gene expression , 2008, Journal of Cell Science.

[104]  Avri Ben-Ze'ev,et al.  Autoregulation of E-cadherin expression by cadherin–cadherin interactions , 2003, The Journal of cell biology.

[105]  E. Hay.  Theory for epithelial-mesenchymal transformation based on the "fixed cortex" cell motility model. , 1989, Cell motility and the cytoskeleton.

[106]  F. Alameda,et al.  Snail1 Protein in the Stroma as a New Putative Prognosis Marker for Colon Tumours , 2009, PloS one.

[107]  Cynthia Cohen,et al.  Triple-negative breast carcinoma in women from Vietnam and the United States: characterization of differential marker expression by tissue microarray. , 2009, Human pathology.

[108]  O. Nativ,et al.  Genetic Alterations in Urinary Bladder Carcinosarcoma: Evidence of a Common Clonal Origin , 2000, European Urology.

[109]  S. Harrison,et al.  Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer. , 1994, Genes & development.

[110]  G. Berx,et al.  Unraveling signalling cascades for the Snail family of transcription factors. , 2005, Cellular signalling.

[111]  Ker-Chau Li,et al.  p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug , 2009, Nature Cell Biology.

[112]  S. Dedhar,et al.  Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells , 2004, Oncogene.

[113]  P. McKeown-Longo,et al.  Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. , 2007, Cancer research.

[114]  P. Fortina,et al.  p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo , 2009, Proceedings of the National Academy of Sciences.

[115]  M. Ozawa,et al.  The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation , 2004, Journal of Cell Science.

[116]  S. Nishikawa,et al.  A novel snail-related transcription factor Smuc regulates basic helix-loop-helix transcription factor activities via specific E-box motifs. , 2000, Nucleic acids research.

[117]  Eric S. Lander,et al.  Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening , 2009, Cell.

[118]  Q. Deveraux,et al.  C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[119]  J. Stow,et al.  Recycling of E-cadherin: a potential mechanism for regulating cadherin dynamics. , 1999 .

[120]  G. Christofori,et al.  Hepatocyte growth factor induces cell scattering through MAPK/Egr‐1‐mediated upregulation of Snail , 2006, The EMBO journal.