β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation

Aberrant beta-catenin expression as determined by assessment of its subcellular localization constitutes a surrogate marker of Wnt signalling pathway activation and has been reported in a subset of breast cancers. The association of beta-catenin/Wnt pathway activation with clinical outcome and the mechanisms leading to its activation in breast cancers still remain a matter of controversy. The aims of this study were to address the distribution of beta-catenin expression in invasive breast cancers, the correlations between beta-catenin expression and clinicopathological features and survival of breast cancer patients, and to determine whether aberrant beta-catenin expression is driven by CTNNB1 (beta-catenin encoding gene) activating mutations. Immunohistochemistry was performed on a tissue microarray containing 245 invasive breast carcinomas from uniformly treated patients, using two anti-beta-catenin monoclonal antibodies. Selected samples were subjected to CTNNB1 exon 3 mutation analysis by direct gene sequencing. A good correlation between the two beta-catenin antibodies was observed (Spearman's r > 0.62, P < 0.001). Respectively, 31 and 11% of the cases displayed lack/reduction of beta-catenin membranous expression and nuclear accumulation. Complete lack of beta-catenin expression was significantly associated with invasive lobular carcinoma histological type. Subgroup analysis of non-lobular cancers or non-lobular grade 3 carcinomas revealed that lack/reduction of beta-catenin membranous expression and/or nuclear accumulation were significantly associated with oestrogen receptor negativity, absence of HER2 gene amplification and overexpression, lack/reduction of E-cadherin expression and tumours of triple-negative and basal-like phenotype. Univariate survival analysis revealed a significant association between beta-catenin nuclear expression and shorter metastasis-free and overall survival in the whole cohort; however, beta-catenin nuclear expression was not an independent predictor of outcome in multivariate analysis. No CTNNB1 mutations were identified in the 28 selected breast carcinomas analysed. In conclusion, beta-catenin/Wnt pathway activation is preferentially found in triple-negative/basal-like breast carcinomas, is associated with poor clinical outcome and is unlikely to be driven by CTNNB1 mutations in breast cancer. Modern Pathology (2011) 24, 209-231; doi:10.1038/modpathol.2010.205; published online 12 November 2010