β-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast

Abstract

Wnt signalling pathway is known to have a critical role in carcinogenesis and in epithelial-to-mesenchymal transition. Upon Wnt activation, b-catenin is translocated from the membrane to the cytoplasm and nucleus, where it interacts with transcriptional activators. It has been suggested that various spindle cell lesions of the breast may harbour Wnt pathway activation. Given that b-catenin nuclear localization constitutes a good surrogate marker of Wnt canonical pathway activation, we have investigated the distribution of b-catenin in spindle cell lesions of the breast and whether it could be employed in the differential diagnosis of these lesions. A total of 52 metaplastic breast carcinomas, eight fibromatoses and 23 phyllodes tumours were retrieved from our institutions' archives. We performed immunohistochemistry using two anti-b-catenin antibodies. In all, three fibromatoses and 21 metaplastic breast carcinomas were subjected to CTNNB1 (b-catenin encoding gene) mutation analysis by direct gene sequencing. A good correlation between the two antibodies was observed (Spearman's r40.82, Po0.001). All fibromatoses and 23% of metaplastic breast carcinomas expressed nuclear b-catenin. In fibromatosis, b-catenin was more often diffusely expressed, whereas in metaplastic breast carcinomas, expression was more frequently focal. Membranous b-catenin expression was significantly lower in spindle cell carcinomas than in other subtypes of metaplastic breast carcinomas. In phyllodes tumours, stromal cells of benign and malignant subtypes displayed nuclear b-catenin expression in 94 and 57% of cases, respectively. No CTNNB1 mutation was identified in any of the 21 metaplastic carcinomas analysed, whereas the mutations 45S4S/P and 41T4T/A were found in samples of fibromatosis. In conclusion, b-catenin nuclear expression is a common feature in fibromatoses and in the stromal component of phyllodes tumours, but may also be observed in metaplastic breast carcinomas. b-catenin nuclear expression should not be used as a single marker to differentiate fibromatosis from other spindle cell tumours of the breast.

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

“…Owing to lost/fragmented cores or cores without invasive tumour on tissue microarray sections, b-catenin expression data with both antibody clones were available in 221 out of 245 tumours. As previously described, 18 a good correlation between the two commercially available antibodies raised against b-catenin, clones 14/b-catenin and 17C2, was found. We observed statistically significant correlations between both antibodies for the semiquantitative assessment of b-catenin membranous (Spearman's r ¼ 0.863, Po0.0001), cytoplasmic (Spearman's r ¼ 0.620, Po0.0001), and nuclear expression (Spearman's r ¼ 0.676, Po0.0001) ( Table 1).…”

“…For b-catenin immunohistochemistry, two commercially available monoclonal antibodies raised against the C-terminal domain of b-catenin were used, clone 14/b-catenin (BD Transduction Laboratories, San Jose, CA, USA) and 17C2 (Novocastra/Leica, Newcastle Upon Tyne, UK), which were used in 1:6000 and 1:100 dilutions, respectively, as previously described 18 and summarized in Supplementary Table 1. Immunohistochemical analysis with the 14/b-catenin clone was performed with the observers blinded to the results of the analysis of 17C2 clone.…”

“…As previously described, 18 positive controls (ie, DNA samples of the HCT116 colon cancer cell line 36 and of one formalinfixed paraffin-embedded breast fibromatosis, which harbored an exon 3 CTNNB1 mutation) were included in each experiment. The primers used for CTNNB1 sequencing were previously described.…”

“…3,[10][11][12][13][14][15][16][17] Our previous study on spindle lesions of the breast demonstrated that aberrant b-catenin expression is often observed in metaplastic carcinomas of the breast, indicating that Wnt canonical pathway activation is found in at least a subset of breast cancers. 18 Expression of b-catenin in breast cancer and its association with outcome have been a matter of controversy. Although some have reported that aberrant b-catenin expression is found in breast cancers of poor outcome 3,13,15 and of the basal-like phenotype, 19 others have failed to demonstrate a correlation between b-catenin aberrant expression and outcome.…”

“…The prevalence of these molecular abnormalities is highly debated in breast cancer. [21][22][23][24] Although some authors have described CTNNB1 mutations in up to 26% of metaplastic carcinomas of the breast, 25 we 18 and others 7 have failed to confirm the presence of CTNNB1 mutations in this histological type of breast tumours. Notwithstanding the fact that most recent studies agree in that b-catenin/ Wnt pathway is activated in at least a subset of breast cancers, 15,18,19 the molecular alterations underlying aberrant b-catenin expression are yet to be elucidated.…”