Gene: CTNNB1 maps to 3p22-p21. This region is frequently affected by somatic alterations in a variety of tumors (Kraus C. et al., 1994; Trent J.M. et al., 1995). The CTNNB1 gene has 16 exons and spans 23.2 kb (Nollet F. et al., 1996). The promoter region is GC-rich.
mRNA: size: 3.4 kb (Nollet F. et al., 1996).
Protein:
- In colon carcinoma cells, it has been shown that beta-catenin regulates expression of
cyclin D1 (Tetsu O. and McCormick F., 1999).
- It was shown that glycogen synthase kinase 3beta (GSK3beta) decreases the interaction of
MUC1 with beta-catenin and that overexpression of
MUC1 in the absence of GSK3beta activity inhibits formation of the
E-cadherin-beta-catenin complex (Li Y. et al., 1998).
-
Mucin-1 (MUC-1) was shown to associate with beta-catenin. The interaction was dependent on cell adhesion.
MUC-1, like
E-cadherin and the adenomatous polyposis coli gene product, contains an SXXXXXSSL site that is responsible for direct binding to beta-catenin (Yamamoto M. et al., 1997).
Cell lines:
- Studies of
E-cadherin and alpha- and beta-catenin were carried out in 18 breast cancer cell (BCC) lines to determine the prevalence and nature of alterations in these genes in breast cancer. Ten lines failed to express
E-cadherin protein at detectable levels and seven failed to produce detectable levels of
E-cadherin transcripts. In a line lacking
E-cadherin expression (SK-BR-3) a homozygous deletion of a large portion of the
E-cadherin gene was noted. Localized sequence alterations in
E-cadherin transcripts were not identified in any lines. Two of the 18 lines had no detectable alpha-catenin protein and six others had reduced levels. The two lines lacking alpha-catenin protein had reduced or undetectable levels of alpha-catenin transcripts, while no consistent changes in alpha-catenin transcript levels were seen in the lines with reduced, but detectable, levels of alpha-catenin protein. Similarly, although two lines lacked beta-catenin protein, in most lines the levels of beta-catenin transcripts and protein were not well correlated with one another. Our findings suggest that alterations in
E-cadherin and alpha- and beta-catenin expression are frequent in human BCC lines, and that in some cases the decreased expression may result from mutations in the genes (Pierceall W.E. et al., 1995).
- The BCC line SKBR-3 was shown to contain beta-catenin mRNA but no protein. When
E-cadherin was transfected into these cells, the beta-catenin was produced and was stabilized in the adherens junction and not degraded (Lipschutz J.H. and Kissil J.L., 1998).
-
Wnt-1 expression in the mouse mammary epithelial cell lines RAC311 and C57MG was shown to induce stabilization of cytosolic beta-catenin and morphological transformation. Expression of Wnt-1 in these cells caused transcriptional up-regulation of the
cyclooxygenase-2 gene, resulting in increased levels of
cyclooxygenase-2 mRNA and protein. Prostaglandin E2 production was increased as a consequence of the elevated
cyclooxygenase-2 activity and could be decreased by treatment with a selective
cyclooxygenase-2 inhibitor.
Cyclooxygenase-2 thus appears to be a common downstream target for APC mutation and
Wnt-1 expression (Howe L.R. et al., 1999).
Tumors:
- In lobular carcinomas, simultaneous loss of
E-cadherin and alpha- and beta-catenin expression was found. Lobular carcinoma in situ adjacent to invasive lobular carcinoma showed simultaneous loss of
E-cadherin and catenins in all the cases studied--remarkably, also, in four cases positive for
E-cadherin and catenin expression in the invasive component. These results indicate that simultaneous loss of
E-cadherin and alpha-, beta- and gamma-catenin may be an important step in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer (De Leeuw W.J.F. et al., 1997).
- In a series of 55 breast typical medullary carcinomas diagnosed according to the strict use of Ridolfi et al (Cancer 40: 1365-1385, 1977) criteria,
E-cadherin and beta-catenin were investigated using quantitative (SAMBA 2005 system) immunocytochemical assays on frozen sections. Results were compared to that obtained on paraffin sections and in a series (n=55) of grade 3 ductal carcinomas. It was shown that medullary carcinomas significantly (p<0.001) expressed more
E-cadherin and beta-catenin than grade 3 ductal carcinomas.
E-cadherin and beta-catenin correlated with high expression of p53, of
c-erbB, and of Ki-67 antigens, and with lack of hormone receptors antigenic sites (p<0.001) (Charpin C. et al., 1999).
- A study of 142 routinely processed breast tissue samples including normal breast, benign lesions, in situ and invasive carcinomas indicated that changes in
E-cadherin, beta-catenin and
CD44 expression occur early in breast carcinogenesis, but events additional to their deranged expression are needed to acquire an invasive phenotype (Bànkfalvi A. et al., 1999).
- In a series of 183 cases of invasive breast carcinoma examined by immunohistochemistry on paraffin sections, expression of beta-catenin did not correlate with patient survival (Peralta Soler A. et al., 1999).
- Protein expression of p53,
bcl-2, p21,
cyclin D1,
E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin was investigated in both primary tumours and metastatic lesions from 34 breast cancer patients by immunohistochemistry (IHC) using monoclonal antibodies. Metastatic tissue showed a different expression profile from the primary tumour in most patients. The most significant finding was the re-expression of
E-cadherin, alpha-catenin, and beta-catenin, and increased down-regulation of gamma-catenin, in metastatic lesions (Bukholm I.K. et al., 2000).
Bànkfalvi A. et al. (1999) Immunophenotypic and prognostic analysis of
E-cadherin and beta-catenin expression during breast carcinogenesis and tumour progression: a comparative study with
CD44. Histopathology 34, 25-34.
Bukholm I.K. et al. (2000) Re-expression of
E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients. J. Pathol. 190, 15-19.
Charpin C. et al. (1999)
E-cadherin and beta-catenin expression in breast medullary carcinomas. Int. J. Oncol. 15, 285-292.
De Leeuw W.J.F. et al. (1997) Simultaneous loss of
E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma
in situ. J. Pathol. 183, 404-411.
Howe L.R. et al. (1999) Transcriptional activation of
cyclooxygenase-2 in
Wnt-1-transformed mouse mammary epithelial cells. Cancer Res. 59, 1572-1577.
Kraus C. et al. (1994) Localization of the human beta-catenin gene (CTNNB1) to 3p21: a region implicated in tumor development. Genomics 23, 272-274.
Li Y. et al. (1998) Interaction of glycogen synthase kinase 3beta with the
DF3/MUC1 carcinoma-associated antigen and beta-catenin. Mol. Cell. Biol. 18, 7216-7224.
Lipschutz J.H. and Kissil J.L. (1998) Expression of beta-catenin and gamma-catenin in epithelial tumor cell lines and characterization of a unique cell line. Cancer Lett. 126, 33-41.
McCrea P.D. et al. (1991) A homolog of the armadillo protein in Drosophila (plakoglobin) associated with
E-cadherin. Science 254, 1359-1361.
Nollet F. et al. (1996) Genomic organization of the human beta-catenin gene (CTNNB1). Genomics 32, 413-424.
Peifer M. (1993) Cancer, catenins, and cuticle pattern: a complex connection. Science 262, 1667-1668 (
Review).
Peralta Soler A. et al. (1999) P-cadherin expression in breast carcinoma indicates poor survival. Cancer 86, 1263-1272.
Pierceall W.E. et al. (1995) Frequent alterations in
E-cadherin and alpha- and beta-catenin expression in human breast cancer cell lines. Oncogene 11, 1319-1326.
Tetsu O. and McCormick F. (1999) Beta-catenin regulates expression of
cyclin D1 in colon carcinoma cells. Nature 398, 422-426.
Trent J.M. et al. (1995) The gene for the APC-binding protein beta-catenin (CTNNB1) maps to chromosome 3p22, a region frequently altered in human malignancies. Cytogenet. Cell Genet. 71, 343-344.
Yamamoto M. et al. (1997) Interaction of the
DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J. Biol. Chem. 272, 12492-12494.
