Advertisement

High-Throughput Screening of Protein Interaction Networks in the TGFβ Interactome: Understanding the Signaling Mechanisms Driving Tumor Progression

  • Miriam Barrios-Rodiles
  • Alicia Viloria-Petit
  • Kevin R. Brown
  • Igor Jurisica
  • Jeffrey L. Wrana
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

High-throughput (HT) proteomic techniques allow the study of hundreds to thousands of proteins simultaneously. Several HT methodologies have been developed to determine protein-protein interactions (PPIs) and therefore protein function in mammalian cells. A few of these, including protein complementation assays, mass spectrometry, yeast two-hybrid and luminescence-based mammalian interactome (LUMIER) mapping, have been applied to the study of TGFβ signaling. PPIs revealed with these techniques have been crucial in elucidating novel components of the TGFβ signaling network involved in tissue homeostasis and cancer. A good example of this is the recently described TGFβ/Par6 polarity pathway, which was initially discovered in a LUMIER screen for PPIs. A role of this pathway in the process of epithelial-mesenchymal transition has been demonstrated, suggesting its potential involvement in cancer metastasis. Thus, proteomic data are becoming an essential tool for unraveling the dynamic networks that drive cancer onset and tumor progression.

Key Words

High throughput protein-protein interactions networks EMT metastasis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Barrios-Rodiles M, Brown KR, Ozdamar B, et al. High-throughput mapping of a dynamic signaling network in mammalian cells. Science 2005;307:1621–1625.PubMedCrossRefGoogle Scholar
  2. 2.
    Eyckerman S, Verhee A, der Heyden JV, et al. Design and application of a cytokine-receptor-based interaction trap. Nat Cell Biol 2001;3:1114–1119.PubMedCrossRefGoogle Scholar
  3. 3.
    Boute N, Jockers R, Issad T. The use of resonance energy transfer in high-throughput screening: BRET versus PRET. Trends Pharmacol Sci 2002;23:351–354.PubMedCrossRefGoogle Scholar
  4. 4.
    Michnick SW. Protein fragment complementation strategies for biochemical network mapping. Curr Opin Biotechnol 2003;14:610–617.PubMedCrossRefGoogle Scholar
  5. 5.
    Schweitzer B, Predki P, Snyder M. Microarrays to characterize protein interactions on a whole-proteome scale. Proteomics 2003;3:2190–2199.PubMedCrossRefGoogle Scholar
  6. 6.
    Uetz P, Hughes RE. Systematic and large-scale two-hybrid screens. Curr Opin Microbiol 2000;3: 303–308.PubMedCrossRefGoogle Scholar
  7. 7.
    Gavin AC, Superti-Furga G. Protein complexes and proteome organization from yeast to man. Curr Opin Chem Biol 2003;7:21–27.PubMedCrossRefGoogle Scholar
  8. 8.
    Rossi F, Charlton CA, Blau HM. Monitoring protein-protein interactions in intact eukaryotic cells by beta-galactosidase complementation. Proc Natl Acad Sci USA 1997;94:8405–8410.PubMedCrossRefGoogle Scholar
  9. 9.
    Hu CD, Chinenov Y, Kerppola TK. Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol Cell 2002;9:789–798.PubMedCrossRefGoogle Scholar
  10. 10.
    Remy I, Michnick SW. Visualization of biochemical networks in living cells. Proc Natl Acad Sci USA 2001;98:7678–7683.PubMedCrossRefGoogle Scholar
  11. 11.
    Hu CD, Kerppola TK. Simultaneous visualization of multiple protein interactions in living cells using multicolor fluorescence complementation analysis. Nat Biotechnol 2003;21:539–545.PubMedCrossRefGoogle Scholar
  12. 12.
    Remy I, Michnick SW. Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt. Mol Cell Biol 2004;24:1493–1504.PubMedCrossRefGoogle Scholar
  13. 13.
    Remy I, Montmarquette A, Michnick SW. PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol 2004;6:358–365.PubMedCrossRefGoogle Scholar
  14. 14.
    Conery AR, Cao Y, Thompson EA, Townsend CM, Jr, Ko TC, Luo K. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 2004;6:366–372.PubMedCrossRefGoogle Scholar
  15. 15.
    Song K, Wang H, Krebs TL, Danielpour D. Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. EMBO J 2006;25:58–69.PubMedCrossRefGoogle Scholar
  16. 16.
    Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci USA 2003;100:8621–8623.PubMedCrossRefGoogle Scholar
  17. 17.
    Shaner NC, Steinbach PA, Tsien RY. A guide to choosing fluorescent proteins. Nat Methods 2005;2: 905–909.PubMedCrossRefGoogle Scholar
  18. 18.
    Gingras AC, Aebersold R, Raught B. Advances in protein complex analysis using mass spectrometry. J Physiol 2005;563:11–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Ho Y, Gruhler A, Heilbut A, et al. Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 2002;415:180–183.PubMedCrossRefGoogle Scholar
  20. 20.
    Rigaut G, Shevchenko A, Rutz B, Wilm M, Mann M, Seraphin B. A generic protein purification method for protein complex characterization and proteome exploration. Nat Biotechnol 1999;17: 1030–1032.PubMedCrossRefGoogle Scholar
  21. 21.
    Gavin AC, Bosche M, Krause R, et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 2002;415:141–147.PubMedCrossRefGoogle Scholar
  22. 22.
    Gavin AC, Aloy P, Grandi P, et al. Proteome survey reveals modularity of the yeast cell machinery. Nature 2006;400:631–636.CrossRefGoogle Scholar
  23. 23.
    Bouwmeester T, Bauch A, Ruffner H, et al. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 2004;6:97–105.PubMedCrossRefGoogle Scholar
  24. 24.
    Brajenovic M, Joberty G, Kuster B, Bouwmeester T, Drewes G. Comprehensive proteomic analysis of human Par protein complexes reveals an interconnected protein network. J Biol Chem 2004;279: 12,804–12,811.PubMedCrossRefGoogle Scholar
  25. 25.
    Knuesel M, Wan Y, Xiao Z, et al. Identification of novel protein-protein interactions using a versatile mammalian tandem affinity purification expression system. Mol Cell Proteomics 2003;2:1225–1233.PubMedCrossRefGoogle Scholar
  26. 26.
    Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 1999;286:771–774.PubMedCrossRefGoogle Scholar
  27. 27.
    Grimsby S, Jaensson H, Dubrovska A, Lomnytska M, Hellman U, Souchelnytskyi S. Proteomics-based identification of proteins interacting with Smad3: SREBP-2 forms a complex with Smad3 and inhibits its transcriptional activity. FEBS Lett 2004;577:93–100.PubMedCrossRefGoogle Scholar
  28. 28.
    Mann M, Jensen ON. Proteomic analysis of post-translational modifications. Nat Biotechnol 2003; 21:255–261.PubMedCrossRefGoogle Scholar
  29. 29.
    Stasyk T, Dubrovska A, Lomnytska M, et al. Phosphoproteome profiling of transforming growth factor (TGF)-beta signaling: abrogation of TGFbeta1-dependent phosphorylation of transcription factor-II-I (TFII-I) enhances cooperation of TFII-I and Smad3 in transcription. Mol Biol Cell 2005; 16:4765–4780.PubMedCrossRefGoogle Scholar
  30. 30.
    Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 2005;23:9408–9421.PubMedCrossRefGoogle Scholar
  31. 31.
    DeGregori J. The genetics of the E2F family of transcription factors: shared functions and unique roles. Biochim Biophys Acta 2002;1602:131–150.PubMedGoogle Scholar
  32. 32.
    Ong SE, Blagoev B, Kratchmarova I, et al. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics 2002;1: 376–386.PubMedCrossRefGoogle Scholar
  33. 33.
    Blagoev B, Ong SE, Kratchmarova I, Mann M. Temporal analysis of phosphotyrosine-dependent signaling networks by quantitative proteomics. Nat Biotechnol 2004;22:1139–1145.PubMedCrossRefGoogle Scholar
  34. 34.
    Attisano L, Wrana JL. Signal transduction by the TGF-beta superfamily. Science 2002;296:1646–1647.PubMedCrossRefGoogle Scholar
  35. 35.
    Uetz P, Finley RL, Jr. From protein networks to biological systems. FEBS Lett 2005;579:1821–1827.PubMedCrossRefGoogle Scholar
  36. 36.
    McCraith S, Holtzman T, Moss B, Fields S. Genome-wide analysis of vaccinia virus protein-protein interactions. Proc Natl Acad Sci USA 2000;97:4879–4884.PubMedCrossRefGoogle Scholar
  37. 37.
    Schwikowski B, Uetz P, Fields S. A network of protein-protein interactions in yeast. Nat Biotechnol 2000;18:1257–1261.PubMedCrossRefGoogle Scholar
  38. 38.
    Uetz P, Giot L, Cagney G, et al. A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 2000;403:623–627.PubMedCrossRefGoogle Scholar
  39. 39.
    Li S, Armstrong CM, Bertin N, et al. A map of the interactome network of the metazoan C. elegans. Science 2004;303:540–543.PubMedCrossRefGoogle Scholar
  40. 40.
    Giot L, Bader JS, Brouwer C, et al. A protein interaction map of Drosophila melanogaster. Science 2003;302:1727–1736.PubMedCrossRefGoogle Scholar
  41. 41.
    Stelzl U, Worm U, Lalowski M, et al. A human protein-protein interaction network: a resource for annotating the proteome. Cell 2005;122:957–968.PubMedCrossRefGoogle Scholar
  42. 42.
    Rual JF, Venkatesan K, Hao T, et al. Towards a proteome-scale map of the human protein-protein interaction network. Nature 2005;437:1173–1178.PubMedCrossRefGoogle Scholar
  43. 43.
    Vidal M, Legrain P. Yeast forward and reverse ‘n’-hybrid systems. Nucleic Acids Res 1999;27:919–929.PubMedCrossRefGoogle Scholar
  44. 44.
    Legrain P, Wojcik J, Gauthier JM. Protein-protein interaction maps: a lead towards cellular functions. Trends Genet 2001;17:346–352.PubMedCrossRefGoogle Scholar
  45. 45.
    Uetz P. Two-hybrid arrays. Curr Opin Chem Biol 2002;6:57–62.PubMedCrossRefGoogle Scholar
  46. 46.
    Drewes G, Bouwmeester T. Global approaches to protein-protein interactions. Curr Opin Cell Biol 2003;15:199–205.PubMedCrossRefGoogle Scholar
  47. 47.
    Aronheim A, Zandi E, Hennemann H, Elledge SJ, Karin M. Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions. Mol Cell Biol 1997;17:3094–3102.PubMedGoogle Scholar
  48. 48.
    Vidalain PO, Boxem M, Ge H, Li S, Vidal M. Increasing specificity in high-throughput yeast twohybrid experiments. Methods 2004;32:363–370.PubMedCrossRefGoogle Scholar
  49. 49.
    Stagljar I, Korostensky C, Johnsson N, te Heesen S. A genetic system based on split-ubiquitin for the analysis of interactions between membrane proteins in vivo. Proc Natl Acad Sci USA 1998;95: 5187–5192.PubMedCrossRefGoogle Scholar
  50. 50.
    Fearon ER, Finkel T, Gillison ML, et al. Karyoplasmic interaction selection strategy: a general strategy to detect protein-protein interactions in mammalian cells. Proc Natl Acad Sci USA 1992;89:7958–7962.PubMedCrossRefGoogle Scholar
  51. 51.
    Tewari M, Hu PJ, Ahn JS, et al. Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-beta signaling network. Mol Cell 2004;13:469–482.PubMedCrossRefGoogle Scholar
  52. 52.
    Macias-Silva M, Li W, Leu JI, Crissey MA, Taub R. Up-regulated transcriptional repressors SnoN and Ski bind Smad proteins to antagonize transforming growth factor-beta signals during liver regeneration. J Biol Chem 2002;277:28,483–28,490.PubMedCrossRefGoogle Scholar
  53. 53.
    Chen YG, Shields D. ADP-ribosylation factor-1 stimulates formation of nascent secretory vesicles from the trans-Golgi network of endocrine cells. J Biol Chem 1996:271:5297–5300.PubMedCrossRefGoogle Scholar
  54. 54.
    Colland F, Jacq X, Trouplin V, et al. Functional proteomics mapping of a human signaling pathway. Genome Res 2004;14:1324–1332.PubMedCrossRefGoogle Scholar
  55. 55.
    Shi W, Sun C, He B, et al. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol 2004;164:291–300.PubMedCrossRefGoogle Scholar
  56. 56.
    Jiao K, Zhou Y, Hogan BL. Identification of mZnf8, a mouse Kruppel-like transcriptional repressor, as a novel nuclear interaction partner of Smad1. Mol Cell Biol 2002;22:7633–7644.PubMedCrossRefGoogle Scholar
  57. 57.
    Lin F, Morrison JM, Wu W, Worman HJ. MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Hum Mol Genet 2005;14:437–445.PubMedCrossRefGoogle Scholar
  58. 58.
    Subramaniam V, Li H, Wong M, et al. The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase. Br J Cancer 2003;89:1538–1544.PubMedCrossRefGoogle Scholar
  59. 59.
    Azmi P, Seth A. RNF11 is a multifunctional modulator of growth factor receptor signalling and transcriptional regulation. Eur J Cancer 2005;41:2549–2560.PubMedCrossRefGoogle Scholar
  60. 60.
    Visvader JE, Venter D, Hahm K, et al. The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer. Proc Natl Acad Sci USA 2001;98: 14,452–14,457.PubMedCrossRefGoogle Scholar
  61. 61.
    Lu Z, Lam KS, Wang N, Xu X, Cortes M, Andersen B. LMO4 can interact with Smad proteins and modulate transforming growth factor-beta signaling in epithelial cells. Oncogene 2006;25:2920–2930.PubMedCrossRefGoogle Scholar
  62. 62.
    Ito T, Chiba T, Ozawa R, Yoshida M, Hattori M, Sakaki Y. A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci USA 2001;98:4569–4574.PubMedCrossRefGoogle Scholar
  63. 63.
    Russ AP, Lampel S. The druggable genome: an update. Drug Discov Today 2005;10:1607–1610.PubMedCrossRefGoogle Scholar
  64. 64.
    Stagljar I, Fields S. Analysis of membrane protein interactions using yeast-based technologies. Trends Biochem Sci 2002;27:559–563.PubMedCrossRefGoogle Scholar
  65. 65.
    Siegel PM, Massagué J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 2003;3:807–821.PubMedCrossRefGoogle Scholar
  66. 66.
    Pawson T. Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell 2004;116:191–203.PubMedCrossRefGoogle Scholar
  67. 67.
    Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol 2005;21:659–693.PubMedCrossRefGoogle Scholar
  68. 68.
    Abdollah S, Macias-Silva M, Tsukazaki T, Hayashi H, Attisano L, Wrana JL. TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J Biol Chem 1997;272:27,678–27,685.PubMedCrossRefGoogle Scholar
  69. 69.
    Aderem A. Systems biology: its practice and challenges. Cell 2005;121:511–513.PubMedCrossRefGoogle Scholar
  70. 70.
    Sultan M, Wigle DA, Cumbaa CA, et al. Binary tree-structured vector quantization approach to clustering and visualizing microarray data. Bioinformatics 2002;18 Suppl 1:S111–S119.PubMedGoogle Scholar
  71. 71.
    Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem 2003;72:743–781.PubMedCrossRefGoogle Scholar
  72. 72.
    Wilkes MC, Murphy SJ, Garamszegi N, Leof EB. Cell-type-specific activation of PAK2 by transforming growth factor beta independent of Smad2 and Smad3. Mol Cell Biol 2003;23:8878–8889.PubMedCrossRefGoogle Scholar
  73. 73.
    Chen W, Yazicioglu M, Cobb MH. Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily. J Biol Chem 2004;279:11,129–11,136.PubMedCrossRefGoogle Scholar
  74. 74.
    Feldman GJ, Mullin JM, Ryan MP. Occludin: structure, function and regulation. Adv Drug Deliv Rev 2005;57:883–917.PubMedCrossRefGoogle Scholar
  75. 75.
    Rhodes DR, Chinnaiyan AM. Integrative analysis of the cancer transcriptome. Nat Genet 2005;37: Suppl:S31–S37.PubMedCrossRefGoogle Scholar
  76. 76.
    Brown KR, Jurisica I. Online predicted human interaction database. Bioinformatics 2005;21:2076–2082.PubMedCrossRefGoogle Scholar
  77. 77.
    Bader GD, Donaldson I, Wolting C, Ouellette BF, Pawson T, Hogue CW. BIND — The Biomolecular Interaction Network Database. Nucleic Acids Res 2001;29:242–245.PubMedCrossRefGoogle Scholar
  78. 78.
    Peri S, Navarro JD, Amanchy R, et al. Development of human protein reference database as an initial platform for approaching systems biology in humans. Genome Res 2003;13:2363–2371.PubMedCrossRefGoogle Scholar
  79. 79.
    Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature 1980;283:139–146.PubMedCrossRefGoogle Scholar
  80. 80.
    Liotta LA, Kohn EC. Cancer’s deadly signature. Nat Genet 2003;33:10–11.PubMedCrossRefGoogle Scholar
  81. 81.
    Bissell MJ, Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell 2005;7:17–23.PubMedGoogle Scholar
  82. 82.
    Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet 2003;33:49–54.PubMedCrossRefGoogle Scholar
  83. 83.
    Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005;24: 5764–5774.PubMedCrossRefGoogle Scholar
  84. 84.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.PubMedCrossRefGoogle Scholar
  85. 85.
    Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996;10:2462–2477.PubMedCrossRefGoogle Scholar
  86. 86.
    Putz E, Witter K, Offner S, et al. Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res 1999;59:241–248.PubMedGoogle Scholar
  87. 87.
    Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740–746.PubMedCrossRefGoogle Scholar
  88. 88.
    Huber MA, Azoitei N, Baumann B, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004;114:569–581.PubMedGoogle Scholar
  89. 89.
    Willipinski-Stapelfeldt B, Riethdorf S, Assmann V, et al. Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 2005;11:8006–8014.PubMedCrossRefGoogle Scholar
  90. 90.
    Welch DR, Fabra A, Nakajima M. Transforming growth factor beta stimulates mammary adenocarcinoma cell invasion and metastatic potential. Proc Natl Acad Sci USA 1990;87:7678–7682.PubMedCrossRefGoogle Scholar
  91. 91.
    Bandyopadhyay A, Zhu Y, Cibull ML, Bao L, Chen C, Sun L. A soluble transforming growth factor beta type III receptor suppresses tumorigenicity and metastasis of human breast cancer MDA-MB-231 cells. Cancer Res 1999;59:5041–5046.PubMedGoogle Scholar
  92. 92.
    Bandyopadhyay A. Lopez-Casillas F, Malik SN, et al. Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 2002;62:4690–4695.PubMedGoogle Scholar
  93. 93.
    Yang YA, Dukhanina O, Tang B, et al. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 2002;109:1607–1615.PubMedGoogle Scholar
  94. 94.
    Muraoka RS, Dumont N, Ritter CA, et al. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 2002;109:1607–1615.Google Scholar
  95. 95.
    Muraoka RS, Koh Y, Roebuck LR, et al. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol 2003;23:8691–8703.PubMedCrossRefGoogle Scholar
  96. 96.
    Siegel PM, Shu W, Cardiff RD, Muller WJ, Massagué J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA 2003;100:8430–8435.PubMedCrossRefGoogle Scholar
  97. 97.
    Tang B, Vu M, Booker T, et al. TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest 2003;112:1116–1124.PubMedGoogle Scholar
  98. 98.
    Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005;17:548–558.PubMedCrossRefGoogle Scholar
  99. 99.
    Dandachi N, Hauser-Kronberger C, More E, et al. Co-expression of tenascin-C and vimentin in human breast cancer cells indicates phenotypic transdifferentiation during tumour progression: correlation with histopathological parameters, hormone receptors, and oncoproteins. J Pathol 2001;193: 181–189.PubMedCrossRefGoogle Scholar
  100. 100.
    Muraoka-Cook RS, Dumont N, Arteaga CL. Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin Cancer Res 2005;11:937s–943s.PubMedGoogle Scholar
  101. 101.
    Dalal BI, Keown PA, Greenberg AH. Immunocytochemical localization of secreted transforming growth factor-beta 1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am J Pathol 1993;143:381–389.PubMedGoogle Scholar
  102. 102.
    Chakravarthy D, Green AR, Green VL, Kerin MJ, Speirs V. Expression and secretion of TGF-beta isoforms and expression of TGF-beta-receptors I, II and III in normal and neoplastic human breast. Int J Oncol 1999;15:187–194.PubMedGoogle Scholar
  103. 103.
    Desruisseau S, Palmari J, Giusti C, Romain S, Martin PM, Berthois Y. Determination of TGFbeta1 protein level in human primary breast cancers and its relationship with survival. Br J Cancer 2006; 94:239–246.PubMedCrossRefGoogle Scholar
  104. 104.
    van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530–536.CrossRefGoogle Scholar
  105. 105.
    van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999–2009.PubMedCrossRefGoogle Scholar
  106. 106.
    Zavadil J, Bitzer M, Liang D, et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci USA 2001;98:6686–6691.PubMedCrossRefGoogle Scholar
  107. 107.
    Jechlinger M, Grunert S, Tamir IH, et al. Expression profiling of epithelial plasticity in tumor progression. Oncogene 2003;22:7155–7169.PubMedCrossRefGoogle Scholar
  108. 108.
    Valcourt U, Kowanetz M, Niimi H, Heldin C-H, Moustakas A. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 2005;16:1987–2002.PubMedCrossRefGoogle Scholar
  109. 109.
    Michiels S, Koscielny S, Hill C. Prediction of cancer outcome with microarrays: a multiple random validation strategy. Lancet 2005;365:488–492.PubMedCrossRefGoogle Scholar
  110. 110.
    Segal E, Wang H, Koller D. Discovering molecular pathways from protein interaction and gene expression data. Bioinformatics 2003;19 Suppl 1:i264–i271.PubMedCrossRefGoogle Scholar
  111. 111.
    Segal E, Shapira M, Regev A, et al. Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat Genet 2003;34:166–176.PubMedCrossRefGoogle Scholar
  112. 112.
    Segal E, Friedman N, Kaminski N, Regev A, Koller D. From signatures to models: understanding cancer using microarrays. Nat Genet 2005;37 Suppl:S38–S45.PubMedCrossRefGoogle Scholar
  113. 113.
    Ohno S. Intercellular junctions and cellular polarity: the PAR-aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. Curr Opin Cell Biol 2001;13:641–648.PubMedCrossRefGoogle Scholar
  114. 114.
    Bissell MJ, Bilder D. Polarity determination in breast tissue: desmosomal adhesion, myoepithelial cells, and laminin 1. Breast Cancer Res 2003;5:117–119.PubMedCrossRefGoogle Scholar
  115. 115.
    Watts JL, Etemad-Moghadam B, Guo S, et al. par-6, a gene involved in the establishment of asymmetry in early C. elegans embryos, mediates the asymmetric localization of PAR-3. Development 1996; 122:3133–3140.PubMedGoogle Scholar
  116. 116.
    Etienne-Manneville S, Hall A. Cell polarity: Par6, aPKC and cytoskeletal crosstalk. Curr Opin Cell Biol 2003;15:67–72.PubMedCrossRefGoogle Scholar
  117. 117.
    Bose R, Wrana JL. Regulation of Par6 by extracellular signals. Curr Opin Cell Biol 2006;18: 206–212.PubMedCrossRefGoogle Scholar
  118. 118.
    Roh MH, Margolis B. Composition and function of PDZ protein complexes during cell polarization. Am J Physiol Renal Physiol 2003;285:F377–F387.PubMedGoogle Scholar
  119. 119.
    Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 2005;307:1603–1609.PubMedCrossRefGoogle Scholar
  120. 120.
    Seton-Rogers SE, Lu Y, Hines LM, et al. Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 2004;101:1257–1262.PubMedCrossRefGoogle Scholar
  121. 121.
    Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL. Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. J Biol Chem 2004;279:24,505–24,513.PubMedCrossRefGoogle Scholar
  122. 122.
    Zhou BP, Deng J, Xia W, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004;6:931–940.PubMedCrossRefGoogle Scholar
  123. 123.
    Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation. J Cell Sci 2004;117:1675–1685.PubMedCrossRefGoogle Scholar
  124. 124.
    Blanco MJ, Moreno-Bueno G, Sarrio D, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 2002;21:3241–3246.PubMedCrossRefGoogle Scholar
  125. 125.
    Moody SE, Perez D, Pan TC, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 2005;8:197–209.PubMedCrossRefGoogle Scholar
  126. 126.
    Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 2000;275:36,803–36,810.PubMedCrossRefGoogle Scholar
  127. 127.
    von Stein W, Ramrath A, Grimm A, Muller-Borg M, Wodarz A. Direct association of Bazooka/PAR-3 with the lipid phosphatase PTEN reveals a link between the PAR/aPKC complex and phosphoinositide signaling. Development 2005;132:1675–1686.CrossRefGoogle Scholar
  128. 128.
    Kanzaki M, Mora S, Hwang JB, Saltiel, AR, Pessin JE. Atypical protein kinase C (PKCzeta/lambda) is a convergent downstream target of the insulin-stimulated phosphatidylinositol, 3-kinase and TC10 signaling pathways. J Cell Biol 2004;164:279–290.PubMedCrossRefGoogle Scholar
  129. 129.
    Aranda V, Haire T, Nolan ME, et al. Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol 2006;8:1235–1245.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2008

Authors and Affiliations

  • Miriam Barrios-Rodiles
    • 1
  • Alicia Viloria-Petit
    • 1
  • Kevin R. Brown
    • 2
  • Igor Jurisica
    • 2
  • Jeffrey L. Wrana
    • 2
  1. 1.Program in Molecular Biology and Cancer, Centre for Systems Biology, Samuel Lumenfeld Research InstituteMount Sinai HospitalTorontoCanada
  2. 2.Division of Signaling BiologyOntario Cancer InstituteTorontoCanada

Personalised recommendations