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

Basal-like breast cancer is a highly aggressive tumor subtype associated with poor prognosis. Aberrant activation of NF-κB signaling is frequently found in triple-negative basal-like breast cancer cells, but the cause of this activation has remained elusive. Here we report that α-catenin functions as a tumor suppressor in E-cadherin-negative basal-like breast cancer cells by inhibiting NF-κB signaling. Mechanistically, α-catenin interacts with IκBα protein and stabilizes IκBα by inhibiting its ubiquitination and its association with the proteasome. This stabilization in turn prevents nuclear localization of RelA and p50, leading to decreased expression of TNFα, 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-κB pathway is activated in E-cadherin-negative basal-like breast cancer.