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Br J Cancer. Jan 2001; 84(2): 209–217.
PMCID: PMC2363713

β-Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis

Abstract

To clarify the possible role of aberrant β-catenin expression during endometrial tumorigenesis, a total of 199 cases of endometrial carcinomas (endometrioid type), as well as 37 cases of simple/complex and 32 of atypical hyperplasias, was consecutively investigated for immunohistochemistry, along with 141 normal endometrial samples distant from carcinomas. Of 199 carcinoma cases, 73 tumours as well as 44 normal samples were also analysed using a combination of RT-PCR and Southern blot hybridization, Western blot, and mutation gene assays. Cell membrane β-catenin immunoreactivity showed a stepwise decrease from normal, through atypical hyperplasia, to grade 3 carcinomas. In contrast, the nuclear accumulation in atypical hyperplasias and grade 1 or 2 tumours was higher than in simple/complex hyperplasias. Mutations in exon 3 of the β-catenin gene involving codons 33, 34, 37, 41, and 45 were observed in 16 (22.9%) of 70 endometrial carcinomas, as well as 3 (12.5%) of 24 atypical hyperplasias, the results being significantly related to low membrane and high nuclear immunoreactivity but not relative mRNA expression levels, suggesting that the gene mutations may be closely associated with changes in subcellular distribution. In addition to significant association between β-catenin mutation and low grade histological malignancy (P = 0.048), the mutations were detected in none of 15 and 13 (26%) of 50 tumours with or without lymph node metastasis, the difference being significant (P = 0.027). These findings suggest that β-catenin abnormalities may play an important role in a relatively early event during the endometrial hyperplasia-carcinoma sequence. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Selected References

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  • Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997 Jul 1;16(13):3797–3804. [PMC free article] [PubMed]
  • Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996 Aug 15;382(6592):638–642. [PubMed]
  • Berchuck A, Boyd J. Molecular basis of endometrial cancer. Cancer. 1995 Nov 15;76(10 Suppl):2034–2040. [PubMed]
  • de Boer CJ, van Dorst E, van Krieken H, Jansen-van Rhijn CM, Warnaar SO, Fleuren GJ, Litvinov SV. Changing roles of cadherins and catenins during progression of squamous intraepithelial lesions in the uterine cervix. Am J Pathol. 1999 Aug;155(2):505–515. [PMC free article] [PubMed]
  • Deligdisch L, Cohen CJ. Histologic correlates and virulence implications of endometrial carcinoma associated with adenomatous hyperplasia. Cancer. 1985 Sep 15;56(6):1452–1455. [PubMed]
  • Fujimoto J, Ichigo S, Hori M, Morishita S, Tamaya T. Progestins and danazol effect on cell-to-cell adhesion, and E-cadherin and alpha- and beta-catenin mRNA expressions. J Steroid Biochem Mol Biol. 1996 Mar;57(5-6):275–282. [PubMed]
  • Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hirohashi S. Beta-catenin mutation in carcinoma of the uterine endometrium. Cancer Res. 1998 Aug 15;58(16):3526–3528. [PubMed]
  • Garcia-Rostan G, Tallini G, Herrero A, D'Aquila TG, Carcangiu ML, Rimm DL. Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res. 1999 Apr 15;59(8):1811–1815. [PubMed]
  • Gumbiner BM. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell. 1996 Feb 9;84(3):345–357. [PubMed]
  • Hao X, Tomlinson I, Ilyas M, Palazzo JP, Talbot IC. Reciprocity between membranous and nuclear expression of beta-catenin in colorectal tumours. Virchows Arch. 1997 Sep;431(3):167–172. [PubMed]
  • Hinck L, Nelson WJ, Papkoff J. Wnt-1 modulates cell-cell adhesion in mammalian cells by stabilizing beta-catenin binding to the cell adhesion protein cadherin. J Cell Biol. 1994 Mar;124(5):729–741. [PMC free article] [PubMed]
  • Horstmann MA, Pösl M, Scholz RB, Anderegg B, Simon P, Baumgaertl K, Delling G, Kabisch H. Frequent reduction or loss of DCC gene expression in human osteosarcoma. Br J Cancer. 1997;75(9):1309–1317. [PMC free article] [PubMed]
  • Ilyas M, Tomlinson IP, Rowan A, Pignatelli M, Bodmer WF. Beta-catenin mutations in cell lines established from human colorectal cancers. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10330–10334. [PMC free article] [PubMed]
  • Iwao K, Nakamori S, Kameyama M, Imaoka S, Kinoshita M, Fukui T, Ishiguro S, Nakamura Y, Miyoshi Y. Activation of the beta-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res. 1998 Mar 1;58(5):1021–1026. [PubMed]
  • Jones MH, Koi S, Fujimoto I, Hasumi K, Kato K, Nakamura Y. Allelotype of uterine cancer by analysis of RFLP and microsatellite polymorphisms: frequent loss of heterozygosity on chromosome arms 3p, 9q, 10q, and 17p. Genes Chromosomes Cancer. 1994 Feb;9(2):119–123. [PubMed]
  • Kimura Y, Shiozaki H, Doki Y, Yamamoto M, Utsunomiya T, Kawanishi K, Fukuchi N, Inoue M, Tsujinaka T, Monden M. Cytoplasmic beta-catenin in esophageal cancers. Int J Cancer. 1999 Apr 20;84(2):174–178. [PubMed]
  • Kobayashi K, Sagae S, Nishioka Y, Tokino T, Kudo R. Mutations of the beta-catenin gene in endometrial carcinomas. Jpn J Cancer Res. 1999 Jan;90(1):55–59. [PubMed]
  • Kondo Y, Kanai Y, Sakamoto M, Genda T, Mizokami M, Ueda R, Hirohashi S. Beta-catenin accumulation and mutation of exon 3 of the beta-catenin gene in hepatocellular carcinoma. Jpn J Cancer Res. 1999 Dec;90(12):1301–1309. [PubMed]
  • Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer. 1985 Jul 15;56(2):403–412. [PubMed]
  • Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri C, Dale D, Holowaty E, Bapat B, Gallinger S, Redston M. Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res. 1999 Jul 15;59(14):3346–3351. [PubMed]
  • Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destrée O, Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell. 1996 Aug 9;86(3):391–399. [PubMed]
  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997 Mar 21;275(5307):1787–1790. [PubMed]
  • Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999 Sep;155(3):703–710. [PMC free article] [PubMed]
  • Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW. Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. J Biol Chem. 1997 Oct 3;272(40):24735–24738. [PubMed]
  • Ozawa M, Baribault H, Kemler R. The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J. 1989 Jun;8(6):1711–1717. [PMC free article] [PubMed]
  • Palacios J, Gamallo C. Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res. 1998 Apr 1;58(7):1344–1347. [PubMed]
  • Peifer M, McCrea PD, Green KJ, Wieschaus E, Gumbiner BM. The vertebrate adhesive junction proteins beta-catenin and plakoglobin and the Drosophila segment polarity gene armadillo form a multigene family with similar properties. J Cell Biol. 1992 Aug;118(3):681–691. [PMC free article] [PubMed]
  • Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science. 1997 Mar 21;275(5307):1790–1792. [PubMed]
  • Saegusa M, Okayasu I. Down-regulation of bcl-2 expression is closely related to squamous differentiation and progesterone therapy in endometrial carcinomas. J Pathol. 1997 Aug;182(4):429–436. [PubMed]
  • Saegusa M, Hashimura M, Hara A, Okayasu I. Loss of expression of the gene deleted in colon carcinoma (DCC) is closely related to histologic differentiation and lymph node metastasis in endometrial carcinoma. Cancer. 1999 Jan 15;85(2):453–464. [PubMed]
  • Samowitz WS, Powers MD, Spirio LN, Nollet F, van Roy F, Slattery ML. Beta-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res. 1999 Apr 1;59(7):1442–1444. [PubMed]
  • Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 1998 Mar 15;58(6):1130–1134. [PubMed]
  • Woodman AC, Sugiyama M, Yoshida K, Sugino T, Borgya A, Goodison S, Matsumura Y, Tarin D. Analysis of anomalous CD44 gene expression in human breast, bladder, and colon cancer and correlation of observed mRNA and protein isoforms. Am J Pathol. 1996 Nov;149(5):1519–1530. [PMC free article] [PubMed]
  • Yoshinaga K, Sasano H, Furukawa T, Yamakawa H, Yuki M, Sato S, Yajima A, Horii A. The PTEN, BAX, and IGFIIR genes are mutated in endometrial atypical hyperplasia. Jpn J Cancer Res. 1998 Oct;89(10):985–990. [PubMed]
  • Zaino RJ, Kurman R, Herbold D, Gliedman J, Bundy BN, Voet R, Advani H. The significance of squamous differentiation in endometrial carcinoma. Data from a Gynecologic Oncology Group study. Cancer. 1991 Nov 15;68(10):2293–2302. [PubMed]

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