- Paper Report
- Open Access
Beta-catenin in breast cancer
- Valerie Speirs1
© Current Science Ltd 2000
- Published: 1 December 2000
- cyclin D1
Overexpression of cyclin D1 is found in almost half of all breast tumours. However, amplification of the gene is seen in only 20% of cases, suggesting other pathways are involved in cyclin D1 overexpression. β-catenin was first described as a cell adhesion molecule but was later shown to additionally function as an oncogene when translocated to the nucleus. Within the nucleus, it binds to T cell factor (Tcf) or lymphoid enhancer factor (Lef) and can activate genes containing Tcf/Lef promoters. Reported mechanisms include deletion of the adenomatous polyposis coli (APC) gene, mutation of β-catenin or activation of the Wnt pathway. Expression of Wnt genes has been associated with breast cancer; although APC deletions and β-catenin mutations are common in other cancers (eg colorectal) so far they have not been associated with breast cancer.
This paper sets out to define the interaction of β-catenin with cyclin D1 in breast cancer progression.
Promoter activity was determined by transfection studies using a panel of breast cancer cell lines and the results were confirmed by gel shift analysis. Immunohistochemical analysis of the cellular distribution of cyclin D1 and β-catenin in archival breast tumours was also carried out.
Cyclin D1 promoter activity was significantly upregulated by β-catenin and could be blocked by addition of inhibitors of the β-catenin/Tcf4 pathway such as APC, the β catenin, GSK-3β, and a dominant-negative mutant of Tcf4. Using deletion constructs containing Tcf4 mutations, β-catenin was unable to activate the cyclin D1 promoter, identifying cyclin D1 as the target gene for β-catenin.Expression levels of β-catenin and cyclin D1 were compared in a panel of breast cancer cell lines. MCF-7 cells, which had highest cyclin D1 expression, also had the most significant levels of β-catenin whereas cell lines with no detectable cyclin D1 (HBL100 and BT549) expressed only background levels of β-catenin/Tcf4. Linear regression analysis showed a proportional correlation of cyclin D1 with β-catenin activity.
Immunohistochemical analysis of cyclin D1 and β-catenin in breast tumours revealed that, of the 53 samples positive for cyclin D1, 49 of these were also β-catenin positive. Both nuclear and cytoplasmic β-catenin was observed which is indicative of its activated form. Kaplan Meier and log rank analysis showed overexpression of both cyclin D1 and activated β-catenin were associated with poor prognosis and were negatively correlated with patient survival. Furthermore, high β-catenin activity was a strong independent prognostic factor.
This study has identified β-catenin as a marker for poor prognosis in breast cancer. Cyclin D1 has been identified as one of the targets of the β-catenin pathway. Thus, β-catenin may be involved in the progression of breast cancer and has potential as a novel therapeutic target.