Clinical and Translational Oncology

, Volume 14, Issue 4, pp 243–253 | Cite as

Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities

  • Ioannis A. VoutsadakisEmail author
Educational Series/Blue Series Advances in Translational Oncology


Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specific role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.


Malignant mixed Müllerian tumours Malignant mixed mesodermal tumours Endometrial carcinosarcoma Ubiquitin proteasome system Epithelial to mesenchymal transition 


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  1. 1.
    El-Nashar SA, Mariani A (2011) Uterine carcinosarcoma. Clin Obstet Gynecol 54:292–304PubMedCrossRefGoogle Scholar
  2. 2.
    Choijamts B, Jimi S, Kondo T et al (2011) CD133+ cancer stem cell-like cells derived from uterine carcinosarcoma (malignant mixed Müllerian tumor). Stem Cells 29:1485–1495PubMedCrossRefGoogle Scholar
  3. 3.
    Mani SA, Guo W, Liao M-J et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715PubMedCrossRefGoogle Scholar
  4. 4.
    D’Angelo E, Prat J (2011) Pathology of mixed Müllerian tumours. Best Practice Res Clin Obstet Gynaecol 25:705–718CrossRefGoogle Scholar
  5. 5.
    McCluggage WG (2002) Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas? J Clin Pathol 55:321–325PubMedCrossRefGoogle Scholar
  6. 6.
    Sreenan JJ, Hart WR (1995) Carcinosarcomas of the female genital tract. A pathologic study of 29 metastatic tumors: further evidence for the dominant role of the epithelial component and the conversion theory of histogenesis. Am J Surg Pathol 19:666–674PubMedCrossRefGoogle Scholar
  7. 7.
    Gorai I, Yanagibashi T, Taki A et al (1997) Uterine carcinosarcoma is derived from a single stem cell: an in vitro study. Int J Cancer 72:821–827PubMedCrossRefGoogle Scholar
  8. 8.
    Emoto M, Iwasaki H, Kikuchi M, Shirakawa K (1993) Characteristics of cloned cells of mixed Müllerian tumor of the human uterus. Cancer 71: 3065–3075PubMedCrossRefGoogle Scholar
  9. 9.
    Lien HC, Lin CW, Mao TL et al (2004) p53 overexpression and mutation in metaplastic carcinoma of the breast: genetic evidence for a monoclonal origin of both the carcinomatous and the heterogeneous sarcomatous components. J Pathol 204:131–139PubMedCrossRefGoogle Scholar
  10. 10.
    Van Deurzen CHM, Lee AHS, Gill MS et al (2011) Metaplastic breast carcinoma: tumour histogenesis or dedifferentiation? J Pathol 224:434–437PubMedCrossRefGoogle Scholar
  11. 11.
    Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428PubMedCrossRefGoogle Scholar
  12. 12.
    Stewart CJR, Little L (2009) Immunophenotypic features of MELF pattern invasion in endometrial adenocarcinoma: evidence for epithelial-mesenchymal transition. Histopathology 55:91–101PubMedCrossRefGoogle Scholar
  13. 13.
    Murray SK, Young RH, Scully RE (2003) Unusual epithelial and stromal changes in myoinvasive endometrioid adenocarcinomas: a study of their frequency, associated diagnostic problems, and prognostic significance. Int J Gynecol Pathol 22:324–333PubMedCrossRefGoogle Scholar
  14. 14.
    Stewart CJR, Crook ML, Little L, Louwen K (2011) Correlation between invasive pattern and immunophenotypic alterations in endocervical adenocarcinoma. Histopathology 58:720–728PubMedCrossRefGoogle Scholar
  15. 15.
    Götte M (2010) Endometrial cells get sidetracked. Side population cells promote epithelialmesenchymal transition in endometrial carcinoma. Am J Pathol 176:25–28PubMedCrossRefGoogle Scholar
  16. 16.
    Zhou S, Schuetz SD, Bunting KD et al (2001) The ABC transporter Brcp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7:1028–1034PubMedCrossRefGoogle Scholar
  17. 17.
    Kato K, Takao T, Kuboyama A et al (2010) Endometrial cancer side-population cells show prominent migration and have a potential to differentiate into the mesenchymal cell lineage. Am J Pathol 176:381–392PubMedCrossRefGoogle Scholar
  18. 18.
    Leblanc M, Poncelet C, Soriano D et al (2001) Alteration of CD44 and cadherins expression: possible association with augmented aggressiveness and invasiveness of endometrial carcinoma. Virchows Arch 438:78–85PubMedCrossRefGoogle Scholar
  19. 19.
    Montserrat N, Mozos A, Llobet D et al (2011) Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma. Hum Pathol doi: 10.1016/j.humpath.2011.06.021Google Scholar
  20. 20.
    Voutsadakis IA (2010) Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer. Atlas Genet Cytogen Oncol Haematol. January. html
  21. 21.
    Kirkin V, Dikic I (2011) Ubiquitin networks in cancer. Curr Opin Genet Dev 21:21–28PubMedCrossRefGoogle Scholar
  22. 22.
    Behrends C, Harper JW (2011) Constructing and decoding unconventional ubiquitin chains. Nat Struct Mol Biol 18:520–528PubMedCrossRefGoogle Scholar
  23. 23.
    van Wijk SJL, Timmers HTM (2010) The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins. FASEB J 24:981–993PubMedCrossRefGoogle Scholar
  24. 24.
    Amerik AY, Hochstrasser M (2004) Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 1695:189–207PubMedCrossRefGoogle Scholar
  25. 25.
    Voutsadakis IA (2007) Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. J Cell Mol Med 11:252–285PubMedCrossRefGoogle Scholar
  26. 26.
    Soond SM, Chantry A (2011) How ubiquitination regulates the TGF-β signaling pathway: new insights and new players. Bioessays 33:749–758PubMedCrossRefGoogle Scholar
  27. 27.
    Okuda T, Sekizawa A, Purwosunu Y et al (2010) Genetics of endometrial cancers. Obstet Gynecol Int, article id 984013Google Scholar
  28. 28.
    Voss MA, Ganesan R, Ludeman L et al (2012) Should grade 3 endometrioid endometrial carcinoma be considered a type 2 cancer: a clinical and pathological evaluation. Gynecol Oncol 124:15–20PubMedCrossRefGoogle Scholar
  29. 29.
    Lax SF (2007) Molecular genetic changes in epithelial, stromal and mixed neoplasms of the endometrium. Pathology 39:46–54PubMedCrossRefGoogle Scholar
  30. 30.
    Saegusa M, Hashimura M, Kuwata T, Okayasu I (2009) Requirement of the akt/β-catenin pathway for uterine carcinosarcoma genesis, modulating E-cadherin expression through the transactivation of Slug. Am J Pathol 174:2107–2115PubMedCrossRefGoogle Scholar
  31. 31.
    Schipf A, Mayr D, Kirchner T, Diebold J (2008) Molecular genetic aberrations of ovarian and uterine carcinosarcomas: a CGH and FISH study. Virchows Arch 452:259–268PubMedCrossRefGoogle Scholar
  32. 32.
    Chiyoda T, Tsuda H, Tanaka H et al (2012) Expression profiles of carcinosarcoma of the uterine corpus: are these similar to carcinoma or sarcoma? Genes Chrom Cancer 51:229–239PubMedCrossRefGoogle Scholar
  33. 33.
    Ng SS, Mahmoudi T, Danenberg E et al (2009) Phosphatidylinositol 3-kinase signaling does not activate the Wnt cascade. J Biol Chem 284:35308–35313PubMedCrossRefGoogle Scholar
  34. 34.
    Saegusa M, Hashimura M, Kuwata T et al (2007) Crosstalk between NF-κB/p65 and β-catenin/ TCF4/p300 signalling pathways through alterations in GSK-3β expression during trans-differentiation of endometrial carcinoma cells. J Pathol 213:35–45PubMedCrossRefGoogle Scholar
  35. 35.
    Dai C, Gu W (2010) p53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med 16:528–536PubMedCrossRefGoogle Scholar
  36. 36.
    Solomon H, Madar S, Rotter V (2011) Mutant p53 gain of function is interwoven into the hallmarks of cancer. J Pathol 225:475–478PubMedCrossRefGoogle Scholar
  37. 37.
    Chang CJ, Chao CH, Xia W et al (2011) p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 13:317–323PubMedCrossRefGoogle Scholar
  38. 38.
    Wang S-P, Wang W-L, Chang Y-L et al (2009) p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nature Cell Biol 11:694–704PubMedCrossRefGoogle Scholar
  39. 39.
    Liu M, Casimiro MC, Wang C et al (2009) p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proc Natl Acad Sci U S A 106:19035–19039PubMedCrossRefGoogle Scholar
  40. 40.
    Zhang Y, Yan W, Chen X (2011) Mutant p53 disrupts MCF-10A cell polarity in three-dimensional culture via epithelial-to-mesenchymal transitions. J Biol Chem 286:16218–16228PubMedCrossRefGoogle Scholar
  41. 41.
    Kogan-Sakin I, Tabach Y, Buganim Y et al (2011) Mutant p53R175H upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells. Cell Death Diff 18:271–281CrossRefGoogle Scholar
  42. 42.
    Ohashi S, Natsuizaka M, Wong GS et al (2010) Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors. Cancer Res 70: 4174–4184PubMedCrossRefGoogle Scholar
  43. 43.
    Leng RP, Lin Y, Ma W et al (2003) Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112:779–791PubMedCrossRefGoogle Scholar
  44. 44.
    Dornan D, Wertz I, Shimizu H et al (2004) The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429:86–92PubMedCrossRefGoogle Scholar
  45. 45.
    Chen D, Kon N, Li M et al (2005) ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 121:1071–1083PubMedCrossRefGoogle Scholar
  46. 46.
    Esser C, Scheffner M, Hohfeld J (2005) The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol Chem 280:27443–27448PubMedCrossRefGoogle Scholar
  47. 47.
    Buza N, Tavassoli FA (2009) Comparative analysis of p16 and p53 expression in uterine malignant mixed Mullerian tumors. Int J Gynecol Pathol 28:514–521PubMedCrossRefGoogle Scholar
  48. 48.
    Taylor NP, Zighelboim I, Huettner PC et al (2006) DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis. Mod Pathol 19:1333–1338PubMedCrossRefGoogle Scholar
  49. 49.
    Lee S-J, Kim HS, Kim HS et al (2007) Immunohistochemical study of DNA topoisomerase I, p53, and Ki-67 in uterine carcinosarcomas. Hum Pathol 38:1226–1231PubMedCrossRefGoogle Scholar
  50. 50.
    Kanthan R, Senger J-LB, Diudea D (2010) Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins. World J Surg Oncol 8:60PubMedCrossRefGoogle Scholar
  51. 51.
    Keeling L, Taraporewalla D, Perunovic B, Smith JHF (2011) Uterine carcinosarcoma with p53-positive intraepithelial component. Histopathology 59:1277–1278PubMedCrossRefGoogle Scholar
  52. 52.
    Cowling VH, Cole MD (2006) Mechanism of transcriptional activation by the Myc oncoproteins. Semin Cancer Biol 16:242–252PubMedCrossRefGoogle Scholar
  53. 53.
    Saegusa M, Hashimura M, Kuwata T et al (2004) ß-catenin simultaneously induces activation of the p53-p21WAF1 pathway and overexpression of cyclin D1 during squamous differentiation of endometrial carcinoma cells. Am J Pathol 164: 1739–1749PubMedCrossRefGoogle Scholar
  54. 54.
    Yada M, Hatakeyama S, Kamura T et al (2004) Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J 23:2116–2125PubMedCrossRefGoogle Scholar
  55. 55.
    Amati B (2004) Myc degradation: dancing with ubiquitin ligases. Proc Natl Acad Sci U S A 101: 8843–8844PubMedCrossRefGoogle Scholar
  56. 56.
    Yeh P-Y, Lu Y-S, Ou D-L, Cheng A-L (2011) IκB kinases increase Myc protein stability and enhance progression of breast cancer cells. Mol Cancer 10:53PubMedCrossRefGoogle Scholar
  57. 57.
    Trimboli AJ, Fukino K, de Bruin A et al (2008) Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 68:937–945PubMedCrossRefGoogle Scholar
  58. 58.
    Cho KB, Cho MK, Lee WY, Kang KW (2010) Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. Cancer Lett 293:230–239PubMedCrossRefGoogle Scholar
  59. 59.
    Ma L, Young J, Prabhala H et al (2010) miR-9, a MYC/MYCN-activated microRNA, regulates Ecadherin and cancer metastasis. Nature Cell Biol 12:247–256PubMedGoogle Scholar
  60. 60.
    Myatt SS, Wang J, Monteiro LJ et al (2010) Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res 70:367–377PubMedCrossRefGoogle Scholar
  61. 61.
    Khew-Goodall Y, Goodall GJ (2010) Myc-modulated miR-9 makes more metastases. Nature Cell Biol 12:209–211PubMedGoogle Scholar
  62. 62.
    Weihua Z, Saji S, Mäkinen S et al (2000) Estrogen receptor (ER) β, a modulator of ERα in the uterus. Proc Natl Acad Sci U S A 97:5936–5941PubMedCrossRefGoogle Scholar
  63. 63.
    Harris HA (2007) Estrogen receptor-β: recent lessons from in vivo studies. Mol Endocrinol 21:1–13PubMedCrossRefGoogle Scholar
  64. 64.
    Huang GS, Arend RC, Li M et al (2009) Tissue microarray analysis of hormonal signalling pathways in uterine carcinosarcoma. Am J Obstet Gynecol 200:457.e1–457.e5CrossRefGoogle Scholar
  65. 65.
    Shabani N, Mylonas I, Jeschke U et al (2007) Expression of estrogen receptors α and β, and progesterone receptors A and B in human mucinous carcinoma of the endometrium. Anticancer Res 27:2027–2034PubMedGoogle Scholar
  66. 66.
    Wu W, Slomovitz BM, Celestino J et al (2003) Coordinate expression of cdc25B and ER-α is frequent in low-grade endometrioid endometrial carcinoma but uncommon in high-grade endometrioid and nonendometrioid carcinomas. Cancer Res 63:6195–6199PubMedGoogle Scholar
  67. 67.
    Nilsson S, Koehler KF, Gustafsson J-Å (2011) Development of subtype-elective oestrogen receptor-based therapeutics. Nat Rev Drug Discov 10: 778–792PubMedCrossRefGoogle Scholar
  68. 68.
    Collins F, MacPherson S, Brown P et al (2009) Expression of oestrogen receptors, ERalpha, ERbeta, and ERbeta variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERalpha. BMC Cancer 16:330CrossRefGoogle Scholar
  69. 69.
    Chen Y-J, Li H-Y, Huang C-H et al (2010) Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. J Pathol 222:261–270PubMedCrossRefGoogle Scholar
  70. 70.
    Ito I, Hanyu A, Wayama M et al (2010) Estrogen inhibits transforming growth factor β signalling by promoting Smad2/3 degradation. J Biol Chem 285:14747–14755PubMedCrossRefGoogle Scholar
  71. 71.
    Ren Y, Wu L, Frost AR et al (2009) Dual effects of TGF-β on ERα-mediated estrogenic transcriptional activity in breast cancer. Mol Cancer 8:111PubMedCrossRefGoogle Scholar
  72. 72.
    Lei XF, Wang L, Yang J, Sun L-Z (2009) TGFß signaling supports survival and metastasis of endometrial cancer cells. Cancer Manag Res 1:15–24Google Scholar
  73. 73.
    Massagué J (2008) TGFß in cancer. Cell 134:215–230PubMedCrossRefGoogle Scholar
  74. 74.
    Vincent T, Neve EPA, Johnson JR et al (2009) A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. Nat Cell Biol 11:943–950PubMedCrossRefGoogle Scholar
  75. 75.
    Huang GS, Gunter MJ, Arend RC et al (2010) Co-expression of GPR30 and ERß and their association with disease progression in uterine carcinosarcoma. Am J Obstet Gynecol 203:242.e1–5CrossRefGoogle Scholar
  76. 76.
    Smith HO, Leslie KK, Singh M et al (2007) GPR30: a novel indicator of poor survival for endometrial carcinoma. Am J Obstet Gynecol 196:386.e1–386.e11CrossRefGoogle Scholar
  77. 77.
    Wang D, Hu L, Zhang G et al (2010) G proteincoupled receptor 30 in tumor development. Endocrine 38:29–37PubMedCrossRefGoogle Scholar
  78. 78.
    Vivacqua A, Romeo E, De Marco P et al (2011) GPER mediates the Egr-1 expression induced by 17ß-estradiol and 4-hydroxitamoxifen in breast and endometrial cancer cells. Breast Cancer Res Treat DOI 10.1007/s10549-011-1901-8Google Scholar
  79. 79.
    Kleuser B, Malek D, Gust R et al (2008) 17-β-Estradiol inhibits transforming growth factor-β signaling and function in breast cancer cells via activation of extracellular signal-regulated kinase through the G protein-coupled receptor 30. Mol Pharmacol 74:1533–1543PubMedCrossRefGoogle Scholar
  80. 80.
    Pandey DP, Lappano R, Albanito L et al (2009) Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J 28:523–532PubMedCrossRefGoogle Scholar
  81. 81.
    Ignatov A, Ignatov T, Weißenborn C et al (2011) G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer. Breast Cancer Res Treat 128:457–466PubMedCrossRefGoogle Scholar
  82. 82.
    He Y-Y, Cai B, Yang Y-X et al (2009) Estrogenic G protein-coupled receptor 30 signaling is involved in regulation of endometrial carcinoma by promoting proliferation, invasion potential, and interleukin-6 secretion via the MEK/ERK mitogen-activated protein kinase pathway. Cancer Sci 100:1051–1061PubMedCrossRefGoogle Scholar
  83. 83.
    Leung F, Terzibachian J-J, Govyadovskiy A et al (2009) Tamoxifen in the adjuvant setting for breast cancer: reflections about the risk of uterine carcinosarcoma. Gyn Obstet Fertil 37:447–451CrossRefGoogle Scholar
  84. 84.
    Fan M, Nakshatri H, Nephew KP (2004) Inhibiting proteasomal proteolysis sustains estrogen receptor-α activation. Mol Endocrinol 18:2603–2615PubMedCrossRefGoogle Scholar
  85. 85.
    Prenzel T, Begus-Nahrmann Y, Kramer F et al (2011) Estrogen-dependent gene transcription in human breast cancer cells relies upon proteasomedependent monoubiquitination of histone H2B. Cancer Res 71:5739–5753PubMedCrossRefGoogle Scholar
  86. 86.
    Stanišić V, Malovannaya A, Qin J et al (2009) OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER)α and affects ERα transcriptional activity. J Biol Chem 284:16135–16145PubMedCrossRefGoogle Scholar
  87. 87.
    Hislop JN, von Zastrow M (2011) Role of ubiquitination in endocytic trafficking of G-proteincoupled receptors. Traffic 12:137–148PubMedCrossRefGoogle Scholar
  88. 88.
    Cheng S-B, Quinn JA, Graeber CT, Filardo EJ (2011) Down-modulation of the G-protein-coupled Estrogen Receptor, GPER, from the cell surface occurs via a trans-Golgi-proteasome pathway. J Biol Chem 286:22441–22455PubMedCrossRefGoogle Scholar
  89. 89.
    Inoue Y, Imamura T (2008) Regulation of TGF-β family signaling by E3 ubiquitin ligases. Cancer Sci 99:2107–2112PubMedCrossRefGoogle Scholar
  90. 90.
    Lin X, Liang M, Feng XH (2000) Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 275: 36818–36822PubMedCrossRefGoogle Scholar
  91. 91.
    Bengoechea-Alonso MT, Ericsson J (2010) Tumor suppressor Fbw7 regulates TGFß signaling by targeting TGIF1 for degradation. Oncogene 29: 5322–5328PubMedCrossRefGoogle Scholar
  92. 92.
    Wan M, Tang Y, Tytler EM et al (2004) Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1. J Biol Chem 279:14484–14487PubMedCrossRefGoogle Scholar
  93. 93.
    Hurt EM, Saykally JN, Anose BM et al (2008) Expression of the ZEB1 (δEF1) transcription factor in human: additional insights. Mol Cell Biochem 318:89–99PubMedCrossRefGoogle Scholar
  94. 94.
    Spoelstra NS, Manning NG, Higashi Y et al (2006) The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers. Cancer Res 66:3893–3902PubMedCrossRefGoogle Scholar
  95. 95.
    Singh M, Spoelstra NS, Jean A et al (2008) ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol 21:912–923PubMedCrossRefGoogle Scholar
  96. 96.
    Kyo S, Sakaguchi J, Ohno S et al (2006) High Twist expression is involved in infiltrative endometrial cancer and affects patient survival. Hum Pathol 37:431–438PubMedCrossRefGoogle Scholar
  97. 97.
    Tsukamoto H, Shibata K, Kajiyama H et al (2007) Irradiation-induced epithelial-mesenchymal transition (EMT) related to invasive potential in endometrial carcinoma cells. Gynecol Oncol 107:500–504PubMedCrossRefGoogle Scholar
  98. 98.
    Yoshida H, Broaddus R, Cheng W et al (2006) Deregulation of the HOXA10 homeobox gene in endometrial carcinoma: role in epithelial-mesenchymal transition. Cancer Res 66:889–897PubMedCrossRefGoogle Scholar
  99. 99.
    Blechschmidt K, Kremmer E, Hollweck R et al (2007) The E-cadherin repressor Snail plays a role in tumor progression of endometrioid adenocarcinomas. Diagn Mol Pathol 16:222–228PubMedCrossRefGoogle Scholar
  100. 100.
    Castilla MÁ, Moreno-Bueno G, Romero-Pérez L et al (2010) Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma. J Pathol 223:72–80PubMedCrossRefGoogle Scholar
  101. 101.
    Huszar M, Pfeifer M, Schirmer U et al (2010) Upregulation of L1CAM is linked to loss of hormone receptors and E-cadherin in aggressive subtypes of endometrial carcinomas. J Pathol 220:551–561PubMedCrossRefGoogle Scholar
  102. 102.
    Howe EN, Cochrane DR, Richer JK (2011) Targets of miR-200c mediate suppression of cell motility and anoikis resistance. Breast Cancer Res 13:R45PubMedCrossRefGoogle Scholar
  103. 103.
    Dong P, Kaneuchi M, Watari H et al (2011) MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer 10:99PubMedCrossRefGoogle Scholar
  104. 104.
    Lander R, Nordin K, LaBonne C (2011) The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1. J Cell Biol 194:17–25PubMedCrossRefGoogle Scholar
  105. 105.
    Vernon AE, LaBonne C (2006) Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa. Development 133:3359–3370PubMedCrossRefGoogle Scholar
  106. 106.
    Viñas-Castells R, Beltran M, Valls G et al (2010) The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. J Biol Chem 285:3794–3805PubMedCrossRefGoogle Scholar
  107. 107.
    Harris TJC, Tepass U (2010) Adherens junctions: from molecules to morphogenesis. Nat Rev Mol Cell Biol 11:502–514PubMedCrossRefGoogle Scholar
  108. 108.
    Meng W, Takeichi M (2009) Adherens junction: molecular architecture and regulation. Cold Spring Harb Perspect Biol 1:a002899PubMedCrossRefGoogle Scholar
  109. 109.
    Fujita Y, Krause G, Scheffner M et al (2002) Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol 4:222–231PubMedCrossRefGoogle Scholar
  110. 110.
    Rodríguez-Rigueiro T, Valladares-Ayerbes M, Haz-Conde M et al (2011) Hakai reduces cellsubstratum adhesion and increases epithelial cell invasion. BMC Cancer 11:474PubMedCrossRefGoogle Scholar
  111. 111.
    Shih H-C, Shiozawa T, Miyamoto T et al (2004) Immunohistochemical expression of E-cadherin and β-catenin in the normal and malignant human endometrium: an inverse correlation between Ecadherin and nuclear β-catenin expression. Anticancer Res 24:3843–3850PubMedGoogle Scholar
  112. 112.
    Nishimura I, Ohishi Y, Oda Y et al (2011) Expression and localization of E-cadherin and βcatenin in uterine carcinosarcoma. Virchows Arch 458:85–94PubMedCrossRefGoogle Scholar
  113. 113.
    Stefansson IM, Salvesen HB, Akslen LA (2004) Prognostic impact of alterations in P-cadherin expression and related cell adhesion markers in endometrial cancer. J Clin Oncol 22:1242–1252PubMedCrossRefGoogle Scholar
  114. 114.
    Mannelqvist M, Stefansson IM, Bredholt G et al (2011) Gene expression patterns related to vascular invasion and aggressive features in endometrial cancer. Am J Pathol 178:861–871PubMedCrossRefGoogle Scholar
  115. 115.
    Tanimoto H, Shigemasa K, Sasaki M et al (2000) Differential expression of matrix metalloprotease-7 in each component of uterine carcinosarcoma. Oncol Rep 7:1209–1212PubMedGoogle Scholar
  116. 116.
    Haga A, Funasaka T, Deyashiki Y, Raz A (2008) Autocrine motility factor stimulates the invasiveness of malignant cells as well as up-regulation of matrix metalloproteinase-3 expression via a MAPK pathway. FEBS Lett 582:1877–1882PubMedCrossRefGoogle Scholar
  117. 117.
    Hirota Y, Osuga Y, Hirata T et al (2005) Evidence for the presence of protease-activated receptor 2 and its possible implication in remodeling of human endometrium. J Clin Endocrinol Metab 90:1662–1669PubMedCrossRefGoogle Scholar
  118. 118.
    Tobinai K (2007) Proteasome inhibitor, bortezomib, for myeloma and lymphoma. Int J Clin Oncol 12:318–326PubMedCrossRefGoogle Scholar
  119. 119.
    Jain S, Diefenbach C, Zain J, O’Connor OA (2011) Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evidence 6:43–57PubMedCrossRefGoogle Scholar
  120. 120.
    Driscoll JJ, DeChowdhury R (2010) Therapeutically targeting the SUMOylation, ubiquitination and proteasome pathways as a novel anticancer strategy. Targ Oncol 5:281–289CrossRefGoogle Scholar
  121. 121.
    D’Arcy P, Brnjic S, Hägg Olofsson M et al (2011) Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med 17:1636–1640PubMedCrossRefGoogle Scholar
  122. 122.
    Zhao M, Vuori K (2011) The docking protein p130Cas regulates cell sensitivity to proteasome inhibition. BMC Biol 9:73PubMedCrossRefGoogle Scholar
  123. 123.
    Voutsadakis IA (2011) Molecular predictors of gemcitabine response in pancreatic cancer. World J Gastrointest Oncol 3:153–164PubMedCrossRefGoogle Scholar
  124. 124.
    Wang M, Medeiros BC, Erba HP et al (2011) Targeting protein neddylation: a novel therapeutic strategy for the treatment of cancer. Expert Opin Ther Targets 15:253–264PubMedCrossRefGoogle Scholar
  125. 125.
    Liu G, Xirodimas DP (2010) NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways. Oncogene 29:2252–2261PubMedCrossRefGoogle Scholar
  126. 126.
    Broemer M, Tenev T, Rigbolt KTG et al (2010) Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases. Mol Cell 40:810–822PubMedCrossRefGoogle Scholar
  127. 127.
    Dickens MP, Fitzgerald R, Fischer PM (2010) Small-molecule inhibitors of MDM2 as a new anticancer therapeutics. Semin Cancer Biol 20:10–18PubMedCrossRefGoogle Scholar
  128. 128.
    Zhuang C, Miao Z, Zhu L et al (2011) Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53-MDM2 protein-protein interaction. Eur J Med Chem 46:5654–5661PubMedCrossRefGoogle Scholar

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© Feseo 2012

Authors and Affiliations

  1. 1.Centre Pluridisciplinaire d’OncologieCentre Hospitalier Universitaire VaudoisLausanneSwitzerland

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