α-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-κB signalling

Basal-like breast cancer is a highly aggressive tumour subtype associated with poor prognosis. Aberrant activation of NF-kappa B signalling is frequently found in triple-negative basal-like breast cancer cells, but the cause of this activation has remained elusive. Here we report that alpha-catenin functions as a tumour suppressor in E-cadherin-negative basal-like breast cancer cells by inhibiting NF-kappa B signalling. Mechanistically, alpha-catenin interacts with the I kappa B alpha protein, and stabilizes I kappa B alpha by inhibiting its ubiquitylation and its association with the proteasome. This stabilization in turn prevents nuclear localization of RelA and p50, leading to decreased expression of TNF-alpha, IL-8 and RelB. In human breast cancer, CTNNA1 expression is specifically downregulated in the basal-like subtype, correlates with clinical outcome and inversely correlates with TNF and RELB expression. Taken together, these results uncover a previously undescribed mechanism by which the NF-kappa B pathway is activated in E-cadherin-negative basal-like breast cancer.