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Pathology Division, National Cancer Center Research Institute, Tokyo 104 [T. F., M. S., H. T., K. M., S. H.]; and Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160 [T. F., S. N.], Japan
ß-Catenin forms complexes with Tcf and Lef-1 and functions as a transcriptional activator downstream of the Wnt signaling pathway. Activation of the pathway by stabilization of ß-catenin has been shown to be important in the development of colorectal carcinoma, which is mainly caused by inactivating mutations of the adenomatous polyposis coli tumor suppressor gene or by activating mutations in exon 3 of the ß-catenin gene. Here, we analyzed mutations in exon 3 of the ß-catenin gene in endometrial carcinoma cases in which loss of heterozygosity at the adenomatous polyposis coli tumor suppressor gene locus has been rarely reported. We found that 10 of 76 cases had ß-catenin gene mutations. All mutations identified were single-base missense mutations on serine/threonine residues (codons 33, 37, 41, and 45), altering the glycogen synthase kinase-3ß phosphorylation consensus motif, which participates in the degradation of ß-catenin. To determine whether these ß-catenin mutations actually led to stabilization of this protein, expression of ß-catenin was analyzed immunohistochemically, and 9 of 10 cases with the ß-catenin mutation and 20 of 66 cases without it showed accumulation of ß-catenin in the cytoplasm and/or nucleus. In total, 38% of cases showed accumulation of ß-catenin. These data indicate that stabilization of ß-catenin due to mutations in exon 3 of the ß-catenin gene and other mechanisms may have an important role in development of endometrial carcinomas.
1 Supported by a Grant-in-Aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control and a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan. T. F. is an awardee of Research Resident Fellowships from the Foundation for Promotion of Cancer Research (Tokyo, Japan).
2 To whom requests for reprints should be addressed, at Pathology Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104, Japan.
Received 4/29/98. Accepted 6/29/98.
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