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PMID: 22654675 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice.

PLoS genetics ·Vol. 8 ·No. 5 ·2012-00-00 ·Pages e1002723

Morel AP, Hinkal GW, Thomas C, Fauvet F, Courtois-Cox S, Wierinckx A, Devouassoux-Shisheboran M, Treilleux I, Tissier A, Gras B, Pourchet J, Puisieux I, Browne GJ, Spicer DB, Lachuer J, Ansieau S, Puisieux A

Abstract

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT-inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell-like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation.

MeSH Terms
Animals Breast Neoplasms/genetics,metabolism Cell Differentiation Cell Line Cell Transformation, Neoplastic/genetics,metabolism Claudins/genetics,metabolism Epithelial Cells/cytology,metabolism Epithelial-Mesenchymal Transition/genetics Female Gene Expression Regulation, Neoplastic Genes, ras Homeodomain Proteins/genetics,metabolism Humans Mammary Glands, Animal/cytology,metabolism Mammary Glands, Human/cytology,metabolism Mice Mice, Transgenic Protein Phosphatase 2/antagonists & inhibitors,metabolism Retinoblastoma Protein/metabolism Telomerase/metabolism Transcription Factors/genetics,metabolism Tumor Suppressor Protein p53/metabolism Twist-Related Protein 1/genetics,metabolism Zinc Finger E-box-Binding Homeobox 1
Chemicals
Claudins Homeodomain Proteins Retinoblastoma Protein Transcription Factors Tumor Suppressor Protein p53 Twist-Related Protein 1 ZEB1 protein, human Zinc Finger E-box-Binding Homeobox 1 TERT protein, human Telomerase Protein Phosphatase 2
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Morel Anne-Pierre
Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Hinkal George W
Thomas Clémence
Fauvet Frédérique
Courtois-Cox Stéphanie
Wierinckx Anne
Devouassoux-Shisheboran Mojgan
Treilleux Isabelle
Tissier Agnès
Gras Baptiste
Pourchet Julie
Puisieux Isabelle
Browne Gareth J
Spicer Douglas B
Lachuer Joël
Ansieau Stéphane
Puisieux Alain
Conflict of Interest

The authors have declared that no competing interests exist.

References (61)
61 references, click to expand
  1. The epithelial-mesenchymal transition generates cells with properties of stem cells.
    Cell. 2008 May 16;133(4):704-15 PMID: 18485877
  2. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease.
    J Clin Invest. 2009 Jun;119(6):1438-49 PMID: 19487820
  3. Systemic spread is an early step in breast cancer.
    Cancer Cell. 2008 Jan;13(1):58-68 PMID: 18167340
  4. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A.
    Cell. 1990 Jan 12;60(1):167-76 PMID: 2153055
  5. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models.
    Clin Cancer Res. 2009 Jul 15;15(14):4649-64 PMID: 19567590
  6. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics.
    Cancer Res. 2009 May 15;69(10):4116-24 PMID: 19435916
  7. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence.
    Cancer Cell. 2008 Jul 8;14(1):79-89 PMID: 18598946
  8. Twist1 homodimers enhance FGF responsiveness of the cranial sutures and promote suture closure.
    Dev Biol. 2008 Jun 15;318(2):323-34 PMID: 18471809
  9. Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells.
    Genes Dev. 2001 Jan 1;15(1):50-65 PMID: 11156605
  10. Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A.
    Science. 1999 Mar 26;283(5410):2089-91 PMID: 10092233
  11. Enumeration of the simian virus 40 early region elements necessary for human cell transformation.
    Mol Cell Biol. 2002 Apr;22(7):2111-23 PMID: 11884599
  12. EMT tumorigenesis in the mouse mammary gland.
    Lab Invest. 2007 Dec;87(12):1218-26 PMID: 17922020
  13. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?
    Nat Rev Cancer. 2007 Jun;7(6):415-28 PMID: 17508028
  14. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  15. Introduction of SV40ER and hTERT into mammospheres generates breast cancer cells with stem cell properties.
    Oncogene. 2012 Apr 12;31(15):1896-909 PMID: 21874052
  16. p53, Stem Cells, and Reprogramming: Tumor Suppression beyond Guarding the Genome.
    Genes Cancer. 2011 Apr;2(4):404-19 PMID: 21779509
  17. Tissue deformation modulates twist expression to determine anterior midgut differentiation in Drosophila embryos.
    Dev Cell. 2008 Sep;15(3):470-477 PMID: 18804441
  18. ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events.
    Mol Cell. 2010 Apr 9;38(1):114-27 PMID: 20385094
  19. TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype.
    Cancer Res. 2011 Jul 1;71(13):4707-19 PMID: 21555371
  20. Role of Ras signaling in the induction of snail by transforming growth factor-beta.
    J Biol Chem. 2009 Jan 2;284(1):245-253 PMID: 19010789
  21. Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors.
    Cancer Res. 2010 May 15;70(10):4174-84 PMID: 20424117
  22. Creation of human tumour cells with defined genetic elements.
    Nature. 1999 Jul 29;400(6743):464-8 PMID: 10440377
  23. Aberrant function of the Ras signal transduction pathway in human breast cancer.
    Breast Cancer Res Treat. 1995 Jul;35(1):133-44 PMID: 7612899
  24. Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice.
    Transgenic Res. 2001 Dec;10(6):545-53 PMID: 11817542
  25. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer.
    Breast Cancer Res. 2010;12(5):R68 PMID: 20813035
  26. Protein phosphatase 2A regulatory subunits and cancer.
    Biochim Biophys Acta. 2009 Jan;1795(1):1-15 PMID: 18588945
  27. Twist1 dimer selection regulates cranial suture patterning and fusion.
    Dev Dyn. 2006 May;235(5):1345-57 PMID: 16502419
  28. TWISTing an embryonic transcription factor into an oncoprotein.
    Oncogene. 2010 Jun 3;29(22):3173-84 PMID: 20383196
  29. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2.
    J Exp Med. 2011 May 9;208(5):875-83 PMID: 21518799
  30. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers.
    Nat Med. 2009 Aug;15(8):907-13 PMID: 19648928
  31. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs.
    Nat Cell Biol. 2011 Mar;13(3):317-23 PMID: 21336307
  32. Metaplastic breast carcinoma: tumour histogenesis or dedifferentiation?
    J Pathol. 2011 Aug;224(4):434-7 PMID: 21462188
  33. Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression.
    Neoplasia. 2009 Dec;11(12):1318-28 PMID: 20019840
  34. Mouse model for probing tumor suppressor activity of protein phosphatase 2A in diverse signaling pathways.
    Cell Cycle. 2012 Feb 1;11(3):451-9 PMID: 22262169
  35. Cre-mediated gene deletion in the mammary gland.
    Nucleic Acids Res. 1997 Nov 1;25(21):4323-30 PMID: 9336464
  36. Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe.
    Am J Pathol. 2009 May;174(5):1588-93 PMID: 19342369
  37. Identification of regions in polyomavirus middle T and small t antigens important for association with protein phosphatase 2A.
    J Virol. 1995 Jun;69(6):3721-8 PMID: 7538174
  38. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis.
    Dev Cell. 2008 Jun;14(6):818-29 PMID: 18539112
  39. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling.
    Biochem J. 2001 Feb 1;353(Pt 3):417-39 PMID: 11171037
  40. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.
    Proc Natl Acad Sci U S A. 2011 May 10;108(19):7950-5 PMID: 21498687
  41. Generation of breast cancer stem cells through epithelial-mesenchymal transition.
    PLoS One. 2008 Aug 06;3(8):e2888 PMID: 18682804
  42. Activation of beta -catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias.
    Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):219-24 PMID: 11773619
  43. Epithelial-mesenchymal transitions in development and disease.
    Cell. 2009 Nov 25;139(5):871-90 PMID: 19945376
  44. Defining the cellular precursors to human breast cancer.
    Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2772-7 PMID: 21940501
  45. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells.
    Cancer Cell. 2004 Dec;6(6):625-30 PMID: 15607966
  46. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis.
    PLoS Genet. 2012;8(5):e1002650 PMID: 22654667
  47. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.
    Cancer Cell. 2006 Dec;10(6):515-27 PMID: 17157791
  48. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis.
    Cell. 2004 Jun 25;117(7):927-39 PMID: 15210113
  49. Identification of specific PP2A complexes involved in human cell transformation.
    Cancer Cell. 2004 Feb;5(2):127-36 PMID: 14998489
  50. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions.
    Cell Cycle. 2011 Dec 15;10(24):4256-71 PMID: 22134354
  51. Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells.
    Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2778-83 PMID: 21633010
  52. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes.
    Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54 PMID: 20713713
  53. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.
    Genes Dev. 2001 Dec 15;15(24):3243-8 PMID: 11751630
  54. A system for stable expression of short interfering RNAs in mammalian cells.
    Science. 2002 Apr 19;296(5567):550-3 PMID: 11910072
  55. Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties.
    Stem Cells. 2012 Feb;30(2):292-303 PMID: 22102611
  56. Mammary epithelial cells undergo secretory differentiation in cycling virgins but require pregnancy for the establishment of terminal differentiation.
    Development. 1995 Jul;121(7):2079-90 PMID: 7635053
  57. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells.
    Cancer Res. 2009 Apr 1;69(7):2887-95 PMID: 19276366
  58. Deconstructing the molecular portraits of breast cancer.
    Mol Oncol. 2011 Feb;5(1):5-23 PMID: 21147047
  59. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression.
    EMBO Mol Med. 2009 Sep;1(6-7):303-14 PMID: 20049734
  60. Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest.
    Mol Cell Biol. 1999 Aug;19(8):5642-51 PMID: 10409753
  61. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors.
    Genome Biol. 2007;8(5):R76 PMID: 17493263
Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002723
Published
2012-00-00
Epub
2012-00-24
Pages
e1002723
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3359981
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pgen.1002723 PMC Full Text View journal details
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