Abstract
The activation of the APC/β-catenin signalling pathway due to β-catenin mutations has been implicated in the development of a subset of endometrial carcinomas (ECs). However, up to 25% of ECs have β-catenin nuclear accumulation without evidence of β-catenin mutations, suggesting alterations of other molecules that can modulate the Wnt pathway, such as APC, γ-catenin, AXIN1 and AXIN2. We investigated the expression pattern of β- and γ-catenin in a group of 128 endometrial carcinomas, including 95 endometrioid endometrial carcinomas (EECs) and 33 non-endometrioid endometrial carcinomas (NEECs). In addition, we evaluated the presence of loss of heterozygosity and promoter hypermethylation of the APC gene and mutations in the APC, β- and γ-catenin, AXIN1, AXIN2, and RAS genes, and phospho-Akt expression. No APC mutations were detected but LOH at the APC locus was found in 24.3% of informative cases. APC promoter 1A hypermethylation was observed in 46.6% of ECs, and was associated with the endometrioid phenotype (P=0.034) and microsatellite instability (P=0.008). Neither LOH nor promoter hypermethylation of APC was associated with nuclear catenin expression. Nuclear β-catenin expression was found in 31.2% of EECs and 3% of NEECs (P=0.002), and was significantly associated with β-catenin gene exon 3 mutations (P<0.0001). β-catenin gene exon 3 mutations were associated with the endometrioid phenotype, and were detected in 14 (14.9%) EECs, but in none of the NEECs (P=0.02). γ-catenin nuclear expression was found in 10 ECs; it was not associated with the histological type but was associated with more advanced stages (P=0.042). No mutations in γ-catenin, AXIN1 and 2 genes were detected in this series. Neither RAS mutations nor phospho-Akt expression, which were found in 16 and 27.6% of the cases, respectively, were associated with β-catenin nuclear expression. Our results demonstrated a high prevalence of alterations in molecules of the APC/β-catenin pathway, but only mutations in β-catenin gene are associated with aberrant nuclear localization of β-catenin.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aberle H, Bauer A, Stappert J, Kispert A, Kemler R . 1997 EMBO J. 16: 3797–3804
Bailey T, Biddlestone L, Shepherd N, Barr H, Warner PH, Jankowski J . 1998 Am. J. Pathol. 152: 135–144
Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W . 1998 Science 280: 596–599
Boland CR, Thibodeau SN, Hamilton SR, Sidransky DA, Eshalman JR, Burt RW, Meltzer SJ, Rodríguez-Bigas MA, Fodde R, Ranzani GN, Srivastava SA . 1998 Cancer Res. 58: 5248–5257
Caca K, Kolling FT, Ji X, Hayes M, Qian J, Yahanda A, Rimm DL, Costa J, Fearon E . 1999 Cell Growth Diff. 10: 369–376
Chesire DR, Ewing CM, Gage WR, Isaacs WB . 2002 Oncogene 21: 2679–2694
Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sörensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsh T . 2001 Cancer Res. 61: 7039–7043
Desbois-Mouthon C, Cadoret A, Blivet-Van Eggelpoël MJ, Bertrand F, Cherqui G, Perret C, Capeau J . 2001 Oncogene 20: 252–259
Ding VW, Rui-Hong C, McCormick F . 2000 J. Biol. Chem. 275: 32475–32481
Dong SM, Kim H-S, Rha S-H, Sidransky D . 2001 Clin. Cancer Res. 7: 1982–1986
Duval A, Iacopetta B, Ranzani GN, Lothe RA, Thomas G, Hamelin R . 1999 Oncogene 18: 6806–6809
Espada J, Pérez-Moreno M, Braga VMM, Rodríguez-Viciana P, Cano A . 1999 J. Cell Biol. 146: 967–980
Esteller M, Levine R, Baylin SB, Hedrick Elleson L, Herman JG . 1998 Oncogene 17: 2413–2417
Esteller M, Spark A, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Gonzalez S, Tarafa G, Sidransky D, Meltzer J, Baylin SB, Herman JG . 2000 Cancer Res. 60: 4366–4371
Fearnhead NS, Britton MP, Bodmer WF . 2001 Hum. Mol. Genet. 10: 721–733
Fujino T, Risinger JI, Collins NK, Liu F, Nishii H, Takahasi H, Westphal E-M, Barrett JC, Sasaki H, Kohler F, Berchuck A, Boyd J . 1994 Cancer Res. 54: 4294–4298
Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hiroashi S . 1998 Cancer Res. 58: 3526–3528
Gamallo C, Palacios J, Moreno-Bueno G, Calvo de Mora J, Suárez A, Armas A . 1999 Am. J. Pathol. 155: 527–536
García-Rostán G, Camp RL, Herrero A, Carcangiu ML, Rimm DL, Tallini G . 2001 Am. J. Pathol. 158: 987–996
Gras E, Catasus L, Argüelles R, Moreno-Bueno G, Palacios J, Gamallo C, Matías-Guiu X, Prat J . 2001 Cancer 92: 2829–2836
He T-C, Spark AB, Rago C, Hemerking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW . 1998 Science 281: 1509–1512
Hsu W, Zeng L, Constantini F . 1999 J. Biol. Chem. 294: 3439–3445
Ikeda T, Yoshinaga K, Semba S, Kondo E, Ohmori H, Horii A . 2000 Oncol. Rep. 7: 323–326
Jin Z, Tamura G, Tsuchiya T, Sakata K, Kashiwaba M, Osakabe M, Motoyama T . 2001 Br. J. Cancer 85: 69–73
Jones MH, Koi S, Fujimoto I, Hasumi K, Kato K, Nakamura Y . 1994 Genes Chromosomes Cancer 9: 119–123
Kawakami K, Branbender J, Lord RV, Groshen S, Greenwald BD, Krasna MJ, Yin J, Fleisher S, Abraham JM, Beer D, Sidransky D, Huss HT, Demeester DR, Eads C, Laird PW, Ilson DH, Kelsen DP, Harpole D, Moore MB, Danenberg KD, Danenberg PV, Meltzer SJ . 2000 J. Natl. Cancer Inst. 92: 1805–1811
Kirchner T, Brabletz T . 2000 Am. J. Pathol. 157: 1113–1121
Kobayashi K, Sagae S, Nishioka Y, Tokino T, Kudo R . 1999 Jpn. J. Cancer Res. 90: 55–59
Kolligs FT, Kolligs B, Hajra KM, Hu G, Tani M, Cho KR, Fearon ER . 2000 Gen. Dev. 14: 1319–1331
Korinek V, Barker N, Morin PJ, Van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H . 1997 Science 275: 1784–1787
Lin YM, Kato T, Satoh S, Nakamura Y, Furukawa Y . 2000 J. Hum. Genet. 45: 254–256
Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Quian C, Christensen E, Roche PC, Smith DI, Thibodeau SN . 2000 Nat. Genet. 26: 146–147
Matias-Gviu X, Catasus L, Bussaglia E, Lagarda H, Garcia A, Pons C, Munoz J, Arguelles R, Machin P, Prat J . 2001 Human Pathol. 32: 569–577
Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri D, Dale D, Holowaty E, Bapap B, Gallinger S, Redston M . 1999 Cancer 59: 3346–3351
Moreno-Bueno G, Gamallo C, Perez-Gallego L, de Mora JC, Suarez A, Palacios J . 2001 Diag. Mol. Pathol. 10: 116–122
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW . 1997 Science 275: 1787–1790
Nei H, Saito T, Yamasaki H, Mizumoto H, Ito E, Kudo R . 1999 Mol. Carcinog. 25: 207–218
Palacios J, Gamallo C . 1998 Cancer Res. 58: 1344–1347
Palacios J, Catasús L, Moreno-Bueno G, Matías-Guiu X, Prat J, Gamallo C . 2001 Virchows Arch. 438: 464–469
Perucho M . Correspondence re: CR Boland et al 1999 Cancer Res. 59: 249–256
Reinacher-Schick A, Gumbiner BM . 2001 J. Cell Biol. 152: 491–502
Rubinfeld BI, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P . 1996 Science 272: 1023–1026
Saegusa M, Okayasu I . 2001 J. Pathol. 194: 59–67
Saegusa M, Hashimura M, Yoshida T, Okayasu I . 2001 Br. J. Cancer 84: 209–217
Samowitz WS, Holden JA, Curtin K, Edwards SL, Walker AR, Lin HA, Robertson MA, Nichols MF, Gruenthal KM, Lynch BJ, Leppert MF, Slattery M . 2001 Am. J. Pathol. 158: 1517–1524
Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishikawi T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamoka Y, Nakamura Y . 2000 Nat. Genet. 24: 245–250
Satyamoorthy K, Li G, Vaidya B, Patel D, Herlyn M . 2001 Cancer Res. 61: 7318–7324
Schosshauer PW, Pirog EC, Levine RL, Elleson LH . 2000 Mod. Pathol. 13: 1066–1071
Sharpe C, Lawrence N, Martinez Arias A . 2001 BioEssays 23: 311–318
Spark AB, Morin PJ, Vogelstein B, Kinzler KW . 1998 Cancer Res. 58: 1130–1134
Staal FJ, Burgering BM, van de Wetering M, Clevers HC . 1999 Int. Immunol. 11: 317–323
Tetsu O, McCormick F . 1999 Nature 398: 422–426
Tsuchiya T, Tamura G, Sato K, Sakata K, Jin Z, Motoyama T, Usuba O, Kimura W, Nishizuka S, Wilson KT, James SP, Yin J, Fleisher AS, Zou T, Silverberg SG, Kong D, Meltzer SJ . 2000 Oncogene 19: 3642–3646
Ueda M, Gemmill RM, West J, Winn R, Sugita M, Tanaka N, Ueki M, Drabkin HA . 2001 Br. J. Cancer 85: 64–68
Valizadeh A, Karayiannakis AJ, El-Hariry I, Kmiot W, Pignatelly M . 1997 Am. J. Pathol. 150: 1977–1984
Virmani AK, Rathi A, Sathyanarayama UG, Padar A, Huang CX, Cunningham HT, Farinas AJ, Milchgrub S, Euhus DM, Gilcrease M, Herman J, Minna JD, Gazdar AF . 2001 Clin. Cancer Res. 7: 1998–2004
Voeller HJ, Truica CI, Gelman EP . 1998 Cancer Res. 58: 2520–2523
Webster M-T, Rozycka M, Sara E, Davis E, Smalley M, Young N, Dale TC, Wooster R . 2000 Genes Chromosomes Cancer 28: 443–453
Willert K, Nusse R . 1998 Curr. Opin. Gen Development 8: 95–102
Wu R, Zhai Y, Fearon ER, Cho KR . 2001 Cancer Res. 61: 8247–8255
Yuan H, Mao J, Li L, Wu D . 1999 J. Biol. Chem. 274: 30419–30423
Zhou XP, Hoang JM, Li YJ, Seruca R, Carneiro F, Sobrinho-Simoes M, Lothe RA, Gleeson CM, Russel SEH, Muzeau F, Fléjou JF, Hoang-Zuang K, Lidereau R, Thomas G, Hamelin R . 1998 Genes Chromosomes Cancer 21: 101–107
Zysman M, Saka A, Millar A, Knight J, Chapman W, Bapat B . 2002 Cancer Res. 62: 3663–3666
Acknowledgements
Supported in part by grants FIS 01/0037-01 and SAF2001-0065. G Moreno-Bueno is a recipient of a postdoctoral research grant from the Centro Nacional de Investigaciones Oncológicas, Spain, and D Sarrió is a recipient of a BEFI grant from the Fondo de Investigaciones Sanitatias (01/9132), Spain.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Moreno-Bueno, G., Hardisson, D., Sánchez, C. et al. Abnormalities of the APC/β-catenin pathway in endometrial cancer. Oncogene 21, 7981–7990 (2002). https://doi.org/10.1038/sj.onc.1205924
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205924
Keywords
This article is cited by
-
Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma
Virchows Archiv (2021)
-
β-catenin activates TGF-β-induced epithelial–mesenchymal transition in adenomyosis
Experimental & Molecular Medicine (2020)
-
Crosstalk of estrogen receptors and Wnt/β-catenin signaling in endometrial cancer
Journal of Cancer Research and Clinical Oncology (2020)
-
Eukaryotic elongation factor-2 kinase expression is an independent prognostic factor in colorectal cancer
BMC Cancer (2019)
-
Transcriptional regulation of P63 on the apoptosis of male germ cells and three stages of spermatogenesis in mice
Cell Death & Disease (2018)