Breast Cancer Research and Treatment

, Volume 107, Issue 2, pp 195–210 | Cite as

SUMO and estrogen receptors in breast cancer

  • Michalis V. Karamouzis
  • Panagiotis A. Konstantinopoulos
  • Filitsa A. Badra
  • Athanasios G. Papavassiliou


Small ubiquitin-like modifier (SUMO) is a family of proteins structurally similar to ubiquitin that have been found to be covalently attached to certain lysine residues of specific target proteins. By contrast to ubiquitination, however, SUMO proteins do not promote protein degradation but, instead, modulate important functional properties, depending on the protein substrate. These properties include—albeit not limited to—subcellular localization, protein dimerization, DNA binding and/or transactivation of transcription factors, among them estrogen receptors. Moreover, it has been suggested that SUMO proteins might affect transcriptional co-factor complexes of the estrogen receptor signalling cascade. Tissue and/or state specificity seems to be one of their intriguing features. In this regard, elucidation of their contribution to estrogen receptor-mediated transcriptional activity during breast carcinogenesis will offer new insights into the molecular mechanisms governing sensitivity/resistance in currently applied endocrine treatment and/or chemoprevention, and provide novel routes to breast carcinoma therapeutics.


Breast cancer Estrogen receptor SUMO Sumoylation Post-translational modification 



Aromatase inhibitors


Activator protein-1


Androgen receptor


CAAT enhancer-binding protein


Epidermal growth factor receptor


Glucocorticoid receptor


Homologous to E6–AP C-terminus


Heat shock transcription factor


Heat shock protein


Insulin like growth factor-1 receptor


c-Jun N-terminal kinase


Mitogen-activated protein kinase


Proliferating cell nuclear antigen


Protein kinase A


Peroxisome proliferator-activated receptor γ


Progesterone receptor


Rexinoid receptor α


Sterol regulatory element-binding proteins


Transcription factor


Tyrosine kinase


  1. 1.
    Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282PubMedGoogle Scholar
  2. 2.
    Goldhirsch A, Glick JH, Gelber RD et al (2005) Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16:1569–1583PubMedGoogle Scholar
  3. 3.
    Dutertre M, Smith CL (2003) Ligand-independent interactions of p160/steroid receptor coactivators and CREB-binding protein (CBP) with estrogen receptor-alpha: regulation by phosphorylation sites in the A/B region depends on other receptor domains. Mol Endocrinol 17:1296–1314PubMedGoogle Scholar
  4. 4.
    Heldring N, Nilsson M, Buehrer B et al (2004) Identification of tamoxifen-induced coregulator interaction surfaces within the ligand-binding domain of estrogen receptors. Mol Cell Biol 24:3445–3459PubMedGoogle Scholar
  5. 5.
    Delaunay F, Pettersson K, Tujague M, Gustafsson JA (2000) Functional differences between the amino-terminal domains of estrogen receptors alpha and beta. Mol Pharmacol 58:584–590PubMedGoogle Scholar
  6. 6.
    Frasor J, Chang EC, Komm B et al (2006) Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res 66:7334–7340PubMedGoogle Scholar
  7. 7.
    Ruff M, Gangloff M, Wurtz JM, Moras D (2000) Estrogen receptor transcription and transactivation: structure-function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res 2:353–359PubMedGoogle Scholar
  8. 8.
    Wang Z, Zhang X, Shen P et al (2006) A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. Proc Natl Acad Sci USA 103:9063–9068PubMedGoogle Scholar
  9. 9.
    Leung YK, Mak P, Hassan S, Ho SM (2006) Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proc Natl Acad Sci USA 103:13162–13167PubMedGoogle Scholar
  10. 10.
    Karamouzis MV, Papavassiliou AG (2006) The IGF-1 network in lung carcinoma therapeutics. Trends Mol Med 12:595–602PubMedGoogle Scholar
  11. 11.
    Levin ER (2005) Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol 19:1951–1959PubMedGoogle Scholar
  12. 12.
    Wang RA, Mazumdar A, Vadlamudi RK, Kumar R (2002) P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary epithelium. EMBO J 21:5437–5447PubMedGoogle Scholar
  13. 13.
    Song RX, Santen RJ (2006) Membrane initiated estrogen signaling in breast cancer. Biol Reprod 75:9–16PubMedGoogle Scholar
  14. 14.
    Gururaj AE, Rayala SK, Vadlamudi RK, Kumar R (2006) Novel mechanisms of resistance to endocrine therapy: genomic and nongenomic considerations. Clin Cancer Res 12:1001s–1007sPubMedGoogle Scholar
  15. 15.
    Carroll JS, Brown M (2006) Estrogen receptor target gene: an evolving concept. Mol Endocrinol 20:1707–1714PubMedGoogle Scholar
  16. 16.
    Deroo BJ, Korach KS (2006) Estrogen receptors and human disease. J Clin Invest 116:561–570PubMedGoogle Scholar
  17. 17.
    Labhart P, Karmakar S, Salicru EM et al (2005) Identification of target genes in breast cancer cells directly regulated by the SRC-3/AIB1 coactivator. Proc Natl Acad Sci USA 102:1339–1344PubMedGoogle Scholar
  18. 18.
    Rosenfeld MG, Lunyak VV, Glass CK (2006) Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20:1405–1428PubMedGoogle Scholar
  19. 19.
    den Hollander P, Rayala SK, Coverley D, Kumar R (2006) Ciz1, a novel DNA-binding coactivator of the estrogen receptor {alpha}, confers hypersensitivity to estrogen action. Cancer Res 66:11021–11029Google Scholar
  20. 20.
    Belandia B, Orford RL, Hurst HC, Parker MG (2002) Targeting of SWI/SNF chromatin remodelling complexes to estrogen-responsive genes. EMBO J 21:4094–4103PubMedGoogle Scholar
  21. 21.
    Mo R, Rao SM, Zhu YJ (2006) Identification of the MLL2 complex as a coactivator for estrogen receptor alpha. J Biol Chem 281:15714–15720PubMedGoogle Scholar
  22. 22.
    Kim JH, Li H, Stallcup MR (2003) CoCoA, a nuclear receptor coactivator which acts through an N-terminal activation domain of p160 coactivators. Mol Cell 12:1537–1549PubMedGoogle Scholar
  23. 23.
    Zhou D, Ye JJ, Li Y et al (2006) The molecular basis of the interaction between the proline-rich SH3-binding motif of PNRC and estrogen receptor alpha. Nucleic Acids Res 34:5974–5986PubMedGoogle Scholar
  24. 24.
    Lee YH, Coonrod SA, Kraus WL et al (2005) Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. Proc Natl Acad Sci USA 102:3611–3616PubMedGoogle Scholar
  25. 25.
    Kobayashi Y, Kitamoto T, Masuhiro Y et al (2000) p300 mediates functional synergism between AF-1 and AF-2 of estrogen receptor alpha and beta by interacting directly with the N-terminal A/B domains. J Biol Chem 275:15645–15651PubMedGoogle Scholar
  26. 26.
    Webb P, Nguyen P, Shinsako J et al (1998) Estrogen receptor activation function 1 works by binding p160 coactivator proteins. Mol Endocrinol 12:1605–1618PubMedGoogle Scholar
  27. 27.
    Ding L, Yan J, Zhu J et al (2003) Ligand-independent activation of estrogen receptor alpha by XBP-1. Nucleic Acids Res 31:5266–5274PubMedGoogle Scholar
  28. 28.
    Faulds MH, Pettersson K, Gustafsson JA, Haldosen LA (2001) Cross-talk between ERs and signal transducer and activator of transcription 5 is E2 dependent and involves two functionally separate mechanisms. Mol Endocrinol 15:1929–1940PubMedGoogle Scholar
  29. 29.
    Klinge CM, Jernigan SC, Mattingly KA et al (2004) Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors. J Mol Endocrinol 33:387–410PubMedGoogle Scholar
  30. 30.
    Dobrzycka KM, Townson SM, Jiang S, Oesterreich S (2003) Estrogen receptor corepressors – a role in human breast cancer? Endocr Relat Cancer 10:517–536PubMedGoogle Scholar
  31. 31.
    Shang Y, Brown M (2002) Molecular determinants for the tissue specificity of SERMs. Science 295:2465–2468PubMedGoogle Scholar
  32. 32.
    Norris JD, Fan D, Sherk A, McDonnell DP (2002) A negative coregulator for the human ER. Mol Endocrinol 16:459–468PubMedGoogle Scholar
  33. 33.
    Frasor J, Danes JM, Komm B et al (2003) Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144:4562–4574PubMedGoogle Scholar
  34. 34.
    Augereau P, Badia E, Balaguer P et al (2006) Negative regulation of hormone signaling by RIP140. J Steroid Biochem Mol Biol 102:51–59PubMedGoogle Scholar
  35. 35.
    Fernandes I, Bastien Y, Wai T et al (2003) Ligand-dependent nuclear receptor corepressor LCoR functions by histone deacetylase-dependent and -independent mechanisms. Mol Cell 11:139–150PubMedGoogle Scholar
  36. 36.
    Shi Y, Sawada J, Sui G et al (2003) Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422:735–738PubMedGoogle Scholar
  37. 37.
    Leader JE, Wang C, Fu M, Pestell RG (2006): Epigenetic regulation of nuclear steroid receptors. Biochem Pharmacol 72:1589–1596PubMedGoogle Scholar
  38. 38.
    Loven MA, Muster N, Yates JR, Nardulli AM (2003) A novel estrogen receptor alpha-associated protein, template-activating factor Ibeta, inhibits acetylation and transactivation. Mol Endocrinol 17:67–78PubMedGoogle Scholar
  39. 39.
    Lopez-Garcia J, Periyasamy M, Thomas RS et al (2006) ZNF366 is an estrogen receptor corepressor that acts through CtBP and histone deacetylases. Nucleic Acids Res 34:6126–6136PubMedGoogle Scholar
  40. 40.
    Lannigan DA (2003) Estrogen receptor phosphorylation. Steroids 68:1–9PubMedGoogle Scholar
  41. 41.
    Gburcik V, Bot N, Maggiolini M, Picard D (2005) SPBP is a phosphoserine-specific repressor of estrogen receptor alpha. Mol Cell Biol 25:3421–3430PubMedGoogle Scholar
  42. 42.
    Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182PubMedGoogle Scholar
  43. 43.
    Cui Y, Niu A, Pestell R (2006) Metastasis-associated protein 2 is a repressor of estrogen receptor alpha whose overexpression leads to estrogen-independent growth of human breast cancer cells. Mol Endocrinol 20:2020–2035PubMedGoogle Scholar
  44. 44.
    Jiang S, Meyer R, Kang K et al (2006) Scaffold attachment factor SAFB1 suppresses estrogen receptor alpha-mediated transcription in part via interaction with nuclear receptor corepressor. Mol Endocrinol 20:311–320PubMedGoogle Scholar
  45. 45.
    Townson SM, Dobrzycka KM, Lee AV et al (2003) SAFB2, a new scaffold attachment factor homolog and estrogen receptor corepressor. J Biol Chem 278:20059–20068PubMedGoogle Scholar
  46. 46.
    Wong CW, McNally C, Nickbarg E et al (2002) Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade. Proc Natl Acad Sci USA 99:14783–14788PubMedGoogle Scholar
  47. 47.
    Karamouzis MV, Gorgoulis VG, Papavassiliou AG (2002) Transcription factors and neoplasia: vistas in novel drug design. Clin Cancer Res 8:949–961PubMedGoogle Scholar
  48. 48.
    Kinyamu HK, Chen J, Archer TK (2005) Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors. J Mol Endocrinol 34:281–297PubMedGoogle Scholar
  49. 49.
    Welchman RL, Gordon C, Mayer RJ (2005) Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nat Rev Mol Cell Biol 6:599–609PubMedGoogle Scholar
  50. 50.
    Tanaka K, Nishide J, Okazaki K et al (1999) Characterization of a fission yeast SUMO-1 homologue, pmt3p, required for multiple nuclear events, including the control of telomere length and chromosome segregation. Mol Cell Biol 19:8660–8672PubMedGoogle Scholar
  51. 51.
    Boddy MN, Howe K, Etkin LD et al (1996) PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene 13:971–982PubMedGoogle Scholar
  52. 52.
    Okura T, Gong L, Kamitani T et al (1996) Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin. J Immunol 157:4277–4281PubMedGoogle Scholar
  53. 53.
    Ulrich HD (2005) Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest. Trends Cell Biol 15:525–532PubMedGoogle Scholar
  54. 54.
    Konstantinopoulos PA, Papavassiliou AG (2006) The potential of proteasome inhibition in the treatment of colon cancer. Expert Opin Investig Drugs 15:1067–1075PubMedGoogle Scholar
  55. 55.
    Hay RT (2005) SUMO: a history of modification. Mol Cell 18:1–12PubMedGoogle Scholar
  56. 56.
    Seeler JS, Dejean A (2003) Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol 4:690–699PubMedGoogle Scholar
  57. 57.
    Gocke CB, Yu H, Kang J (2005) Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates. J Biol Chem 280:5004–5012PubMedGoogle Scholar
  58. 58.
    Kamitani T, Nguyen HP, Yeh ET (1997) Preferential modification of nuclear proteins by a novel ubiquitin-like molecule. J Biol Chem 272:14001–14004PubMedGoogle Scholar
  59. 59.
    Johnson ES, Schwienhorst I, Dohmen RJ, Blobel G (1997) The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. EMBO J 16:5509–5519PubMedGoogle Scholar
  60. 60.
    Gong L, Kamitani T, Fujise K et al (1997) Preferential interaction of sentrin with a ubiquitin-conjugating enzyme, Ubc9. J Biol Chem 272:28198–28201PubMedGoogle Scholar
  61. 61.
    Johnson ES, Blobel G (1997) Ubc9p is the conjugating enzyme for the ubiquitin-like protein Smt3p. J Biol Chem 272:26799–26802PubMedGoogle Scholar
  62. 62.
    Kamitani T, Nguyen HP, Kito K et al (1998) Covalent modification of PML by the sentrin family of ubiquitin-like proteins. J Biol Chem 273:3117–3120PubMedGoogle Scholar
  63. 63.
    Tatham MH, Chen Y, Hay RT (2003) Role of two residues proximal to the active site of Ubc9 in substrate recognition by the Ubc9 SUMO-1 thiolester complex. Biochemistry 42:3168–3179PubMedGoogle Scholar
  64. 64.
    Liu B, Mink S, Wong KA et al (2004) PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nat Immunol 5:891–898PubMedGoogle Scholar
  65. 65.
    Pichler A, Gast A, Seeler JS et al (2002) The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108:109–120PubMedGoogle Scholar
  66. 66.
    Kagey MH, Melhuish TA, Wotton D (2003) The polycomb protein Pc2 is a SUMO E3. Cell 113:127–137PubMedGoogle Scholar
  67. 67.
    Schwartz DC, Hochstrasser M (2003) A superfamily of protein tags: ubiquitin, SUMO and related modifiers. Trends Biochem Sci 28:321–328PubMedGoogle Scholar
  68. 68.
    Hochstrasser M (2001) SP-RING for SUMO: new functions bloom for a ubiquitin-like protein. Cell 107:5–8PubMedGoogle Scholar
  69. 69.
    Schmidt D, Muller S (2003) PIAS/SUMO: new partners in transcriptional regulation. Cell Mol Life Sci 60:2561–2574PubMedGoogle Scholar
  70. 70.
    Sharrocks AD (2006) PIAS proteins and transcriptional regulation–more than just SUMO E3 ligases? Genes Dev 20:754–758PubMedGoogle Scholar
  71. 71.
    Reverter D, Lima CD (2005) Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature 435:687–692PubMedGoogle Scholar
  72. 72.
    Alarcon-Vargas D, Ronai Z (2002) SUMO in cancer–wrestlers wanted. Cancer Biol Ther 1:237–242PubMedGoogle Scholar
  73. 73.
    Kamitani T, Kito K, Nguyen HP et al (1998) Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem 273:11349–11359PubMedGoogle Scholar
  74. 74.
    Saitoh H, Hinchey J (2000) Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 275:6252–6258PubMedGoogle Scholar
  75. 75.
    Tatham MH, Jaffray E, Vaughan OA et al (2001) Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem 276:35368–35374PubMedGoogle Scholar
  76. 76.
    Owerbach D, McKay EM, Yeh ET et al (2005) A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. Biochem Biophys Res Commun 337:517–520PubMedGoogle Scholar
  77. 77.
    Cheng J, Bawa T, Lee P et al. (2006) Role of desumoylation in the development of prostate cancer. Neoplasia 8:667–676PubMedGoogle Scholar
  78. 78.
    Gong L, Millas S, Maul GG, Yeh ET (2000) Differential regulation of sentrinized proteins by a novel sentrin-specific protease. J Biol Chem 275:3355–3359PubMedGoogle Scholar
  79. 79.
    Bailey D, O’Hare P (2004) Characterization of the localization and proteolytic activity of the SUMO-specific protease, SENP1. J Biol Chem 279:692–703PubMedGoogle Scholar
  80. 80.
    Hang J, Dasso M (2002) Association of the human SUMO-1 protease SENP2 with the nuclear pore. J Biol Chem 277:19961–19966PubMedGoogle Scholar
  81. 81.
    Zhang H, Saitoh H, Matunis MJ (2002) Enzymes of the SUMO modification pathway localize to filaments of the nuclear pore complex. Mol Cell Biol 22:6498–6508PubMedGoogle Scholar
  82. 82.
    Best JL, Ganiatsas S, Agarwal S et al (2001) SUMO-1 protease-1 regulates gene transcription through PML. Mol Cell 10:843–855Google Scholar
  83. 83.
    Nishida T, Kaneko F, Kitagawa M, Yasuda H (2001) Characterization of a novel mammalian SUMO-1/Smt3-specific isopeptidase, a homologue of rat axam, which is an axin-binding protein promoting beta-catenin degradation. J Biol Chem 276:39060–39066PubMedGoogle Scholar
  84. 84.
    Nishida T, Tanaka H, Yasuda H (2000) A novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase. Eur J Biochem 267:6423–6427PubMedGoogle Scholar
  85. 85.
    Faus H, Haendler B (2006) Post-translational modifications of steroid receptors. Biomed Pharmacother 60:520–528PubMedGoogle Scholar
  86. 86.
    Gong L, Yeh ET (2006) Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J Biol Chem 281:15869–15877PubMedGoogle Scholar
  87. 87.
    Johnson ES (2004) Protein modification by SUMO. Annu Rev Biochem 73:355–382PubMedGoogle Scholar
  88. 88.
    Muller S, Ledl A, Schmidt D (2004) SUMO: a regulator of gene expression and genome integrity. Oncogene 23:1998–2008PubMedGoogle Scholar
  89. 89.
    Christians ES, Zhou Q, Renard J, Benjamin IJ (2003) Heat shock proteins in mammalian development. Semin Cell Dev Biol 14:283–290PubMedGoogle Scholar
  90. 90.
    Shuai K, Liu B (2005) Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5:593–605PubMedGoogle Scholar
  91. 91.
    Chauchereau A, Amazit L, Quesne M et al (2003) Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1. J Biol Chem 278:12335–12343PubMedGoogle Scholar
  92. 92.
    Gill G (2004) SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev 18:2046–2059PubMedGoogle Scholar
  93. 93.
    Poukka H, Karvonen U, Janne OA, Palvimo JJ (2000) Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Proc Natl Acad Sci USA 97:14145–14150PubMedGoogle Scholar
  94. 94.
    Abdel-Hafiz H, Takimoto GS, Tung L, Horwitz KB (2002) The inhibitory function in human progesterone receptor N termini binds SUMO-1 protein to regulate autoinhibition and transrepression. J Biol Chem 277:33950–33956PubMedGoogle Scholar
  95. 95.
    Le Drean Y, Mincheneau N, Le Goff P, Michel D (2002) Potentiation of glucocorticoid receptor transcriptional activity by sumoylation. Endocrinology 143:3482–3489PubMedGoogle Scholar
  96. 96.
    Ohshima T, Koga H, Shimotohno K (2004) Transcriptional activity of peroxisome proliferator-activated receptor gamma is modulated by SUMO-1 modification. J Biol Chem 279:29551–29557PubMedGoogle Scholar
  97. 97.
    Choi SJ, Chung SS, Rho EJ et al (2006) Negative modulation of RXRalpha transcriptional activity by small ubiquitin-related modifier (SUMO) modification and its reversal by SUMO-specific protease SUSP1. J Biol Chem 281:30669–30677PubMedGoogle Scholar
  98. 98.
    Desterro JM, Rodriguez MS, Hay RT (1998) SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell 2:233–239PubMedGoogle Scholar
  99. 99.
    Ji Z, Degerny C, Vintonenko N et al (2007) Regulation of the Ets-1 transcription factor by sumoylation and ubiquitinylation. Oncogene 26:395–406PubMedGoogle Scholar
  100. 100.
    Iniguez-Lluhi JA, Pearce D (2000) A common motif within the negative regulatory regions of multiple factors inhibits their transcriptional synergy. Mol Cell Biol 20:6040–6050PubMedGoogle Scholar
  101. 101.
    Kagey MH, Melhuish TA, Powers SE, Wotton D (2005) Multiple activities contribute to Pc2 E3 function. EMBO J 24:108–119PubMedGoogle Scholar
  102. 102.
    David G, Neptune MA, DePinho RA (2002) SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J Biol Chem 277:23658–23663PubMedGoogle Scholar
  103. 103.
    Girdwood D, Bumpass D, Vaughan OA et al (2003) P300 transcriptional repression is mediated by SUMO modification. Mol Cell 11:1043–1054PubMedGoogle Scholar
  104. 104.
    Kirsh O, Seeler JS, Pichler A et al (2002) The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J 21:2682–2691PubMedGoogle Scholar
  105. 105.
    Yang SH, Sharrocks AD (2004) SUMO promotes HDAC-mediated transcriptional repression. Mol Cell 13:611–617PubMedGoogle Scholar
  106. 106.
    Konstantinopoulos PA, Papavassiliou AG (2006) Chromatin-modulating agents as epigenetic anticancer drugs–‘the die is cast’. Drug Discov Today 11:91–93PubMedGoogle Scholar
  107. 107.
    Shiio Y, Eisenman RN (2003) Histone sumoylation is associated with transcriptional repression. Proc Natl Acad Sci USA 100:13225–13230PubMedGoogle Scholar
  108. 108.
    Ling Y, Sankpal UT, Robertson AK et al (2004) Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription. Nucleic Acids Res 32:598–610PubMedGoogle Scholar
  109. 109.
    Bossis G, Melchior F (2006) SUMO: regulating the regulator. Cell Div 1:13PubMedGoogle Scholar
  110. 110.
    Galy A, Neron B, Planque N et al (2002) Activated MAPK/ERK kinase (MEK-1) induces transdifferentiation of pigmented epithelium into neural retina. Dev Biol 248:251–264PubMedGoogle Scholar
  111. 111.
    Wood LD, Irvin BJ, Nucifora G et al (2003) Small ubiquitin-like modifier conjugation regulates nuclear export of TEL, a putative tumor suppressor. Proc Natl Acad Sci USA 100:3257–3262PubMedGoogle Scholar
  112. 112.
    Kwek SS, Derry J, Tyner AL et al (2001) Functional analysis and intracellular localization of p53 modified by SUMO-1. Oncogene 20:2587–2599PubMedGoogle Scholar
  113. 113.
    Schmidt D, Muller S (2002) Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA 99:2872–2877PubMedGoogle Scholar
  114. 114.
    Cheng J, Perkins ND, Yeh ET (2005) Differential regulation of c-Jun-dependent transcription by SUMO-specific proteases. J Biol Chem 280:14492–14498PubMedGoogle Scholar
  115. 115.
    Hoeller D, Hecker CM, Dikic I (2006) Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 6:776–788PubMedGoogle Scholar
  116. 116.
    Baek SH (2006) A novel link between SUMO modification and cancer metastasis. Cell Cycle 5:1492–1495PubMedGoogle Scholar
  117. 117.
    Kim JH, Choi HJ, Kim B et al (2006) Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis. Nat Cell Biol 8:631–639PubMedGoogle Scholar
  118. 118.
    Singh RR, Kumar R (2005) Steroid hormone receptor signaling in tumorigenesis. J Cell Biochem 96:490–505PubMedGoogle Scholar
  119. 119.
    Chen D, Pace PE, Coombes RC, Ali S (1999) Phosphorylation of human estrogen receptor alpha by protein kinase A regulates dimerization. Mol Cell Biol 19:1002–1015PubMedGoogle Scholar
  120. 120.
    Sentis S, Le Romancer M, Bianchin C et al (2005) Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity. Mol Endocrinol 19:2671–2684PubMedGoogle Scholar
  121. 121.
    Wang L, Banerjee S (2004) Differential PIAS3 expression in human malignancy. Oncol Rep 11:1319–1324PubMedGoogle Scholar
  122. 122.
    Fuqua SA, Wiltschke C, Zhang QX et al (2000) A hypersensitive estrogen receptor-alpha mutation in premalignant breast lesions. Cancer Res 60:4026–4029PubMedGoogle Scholar
  123. 123.
    Zhang H, Yi X, Sun X et al (2004) Differential gene regulation by the SRC family of coactivators. Genes Dev 18:1753–1765PubMedGoogle Scholar
  124. 124.
    Wu RC, Qin J, Yi P et al (2004) Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic reponses to multiple cellular signaling pathways. Mol Cell 15:937–949PubMedGoogle Scholar
  125. 125.
    Torres-Arzayus MI, Font de Mora J, Yuan J et al (2004) High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell 6:263–274PubMedGoogle Scholar
  126. 126.
    Rowan BG, Weigel NL, O’Malley BW (2000) Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. J Biol Chem 275:4475–4483PubMedGoogle Scholar
  127. 127.
    Lopez GN, Turck CW, Schaufele F et al (2001) Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity. J Biol Chem 276:22177–22182PubMedGoogle Scholar
  128. 128.
    Font de Mora J, Brown M (2000) AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol 20:5041–5047Google Scholar
  129. 129.
    Kotaja N, Karvonen U, Janne OA, Palvimo JJ (2002) The nuclear receptor interaction domain of GRIP1 is modulated by covalent attachment of SUMO-1. J Biol Chem 277:30283–30288PubMedGoogle Scholar
  130. 130.
    Wu H, Sun L, Zhang Y et al (2006) Coordinated regulation of AIB1 transcriptional activity by sumoylation and phosphorylation. J Biol Chem 281:21848–21856PubMedGoogle Scholar
  131. 131.
    Karamouzis MV, Papadas T, Varakis I et al (2002) Induction of the CBP transcriptional co-activator early during laryngeal carcinogenesis. J Cancer Res Clin Oncol 128:135–140PubMedGoogle Scholar
  132. 132.
    Kuo HY, Chang CC, Jeng JC et al (2005) SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx. Proc Natl Acad Sci USA 102:16973–16978PubMedGoogle Scholar
  133. 133.
    Tiefenbach J, Novac N, Ducasse M et al (2006) SUMOylation of the corepressor N-CoR modulates its capacity to repress transcription. Mol Biol Cell 17:1643–1651PubMedGoogle Scholar
  134. 134.
    Lu Z, Wu H, Mo YY (2006) Regulation of bcl-2 expression by Ubc9. Exp Cell Res 312:1865–1875PubMedGoogle Scholar
  135. 135.
    Tremblay A, Tremblay GB, Labrie F, Giguere V (1999) Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1. Mol Cell 3:513–519PubMedGoogle Scholar
  136. 136.
    Bjornstrom L, Sjoberg M (2004) Estrogen receptor-dependent activation of AP-1 via non-genomic signalling. Nucl Recept 2:3PubMedGoogle Scholar
  137. 137.
    Cheung E, Acevedo ML, Cole PA, Kraus WL (2005) Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1. Proc Natl Acad Sci USA 102:559–564PubMedGoogle Scholar
  138. 138.
    Lin X, Sun B, Liang M et al (2003) Opposed regulation of corepressor CtBP by SUMOylation and PDZ binding. Mol Cell 11:1389–1396PubMedGoogle Scholar
  139. 139.
    Sobko A, Ma H, Firtel RA (2002) Regulated SUMOylation and ubiquitination of DdMEK1 is required for proper chemotaxis. Dev Cell 2:745–756PubMedGoogle Scholar
  140. 140.
    Normanno N, Di Maio M, De Maio E et al (2005) Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocr Relat Cancer 12:721–747PubMedGoogle Scholar
  141. 141.
    Lewis JS, Jordan VC (2005) Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat Res 591:247–263PubMedGoogle Scholar
  142. 142.
    Ring A, Dowsett M (2004) Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11:643–658PubMedGoogle Scholar
  143. 143.
    Osborne CK, Bardou V, Hopp TA et al (2003) Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 95:353–361PubMedCrossRefGoogle Scholar
  144. 144.
    Anzick SL, Kononen J, Walker RL et al (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277:965–968PubMedGoogle Scholar
  145. 145.
    Yang SH, Jaffray E, Hay RT, Sharrocks AD (2003) Dynamic interplay of the SUMO and ERK pathways in regulating Elk-1 transcriptional activity. Mol Cell 12:63–74PubMedGoogle Scholar
  146. 146.
    Jepsen K, Hermanson O, Onami TM et al (2000) Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102:753–763PubMedGoogle Scholar
  147. 147.
    Nicholson RI, Hutcheson IR, Knowlden JM et al (2004) Non endocrine pathways and endocrine resistance: observations with antiestrogens and signal transduction inhibitors in combination. Clin Cancer Res 10:346S–354SPubMedGoogle Scholar
  148. 148.
    Bruggemeier RW (2006) Update on the use of aromatase inhibitors in breast cancer. Expert Opin Pharmacother 7:1919–1930Google Scholar
  149. 149.
    Dowsett M, Martin LA, Smith I, Johnston S (2005) Mechanisms of resistance to aromatase inhibitors. J Steroid Biochem Mol Biol 95:167–172PubMedGoogle Scholar
  150. 150.
    Choi JY, Nowell SA, Blanco JG, Ambrosone CB (2006) The role of genetic variability in drug metabolism pathways in breast cancer prognosis. Pharmacogenomics 7:613–624PubMedGoogle Scholar
  151. 151.
    Martin LA, Farmer I, Johnston SR et al (2003) Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 278:30458–30468PubMedGoogle Scholar
  152. 152.
    Brodie A, Jelovac D, Macedo L et al (2005) Therapeutic observations in MCF-7 aromatase xenografts. Clin Cancer Res 11:884s–888sPubMedGoogle Scholar
  153. 153.
    Teyssier C, Belguise K, Galtier F, Chalbos D (2001) Characterization of the physical interaction between estrogen receptor alpha and JUN proteins. J Biol Chem 276:36361–36369PubMedGoogle Scholar
  154. 154.
    Bossis G, Malnou CE, Farras R et al (2005) Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol 25:6964–6979PubMedGoogle Scholar
  155. 155.
    Mo YY, Moschos SJ (2005) Targeting Ubc9 for cancer therapy. Expert Opin Ther Targets 9:1203–1216PubMedGoogle Scholar
  156. 156.
    Jacquiau HR, van Waardenburg RC et al (2005) Defects in SUMO (small ubiquitin-related modifier) conjugation and deconjugation alter cell sensitivity to DNA topoisomerase I-induced DNA damage. J Biol Chem 280:23566–23575PubMedGoogle Scholar
  157. 157.
    Johnston SR (2005) Combinations of endocrine and biological agents: present status of therapeutic and presurgical investigations. Clin Cancer Res 11:889s–899sPubMedGoogle Scholar
  158. 158.
    Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5:417–421PubMedGoogle Scholar
  159. 159.
    Boggio R, Colombo R, Hay RT et al (2004) A mechanism for inhibiting the SUMO pathway. Mol Cell 16:549–561PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Michalis V. Karamouzis
    • 1
  • Panagiotis A. Konstantinopoulos
    • 1
    • 2
  • Filitsa A. Badra
    • 3
  • Athanasios G. Papavassiliou
    • 1
  1. 1.Department of Biological Chemistry, Medical SchoolUniversity of AthensAthensGreece
  2. 2.Division of Hematology – Oncology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  3. 3.Radiology Department‘Thriassion’ General HospitalAthensGreece

Personalised recommendations