Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2

Abstract

Aberrant constitutive expression of c-Rel, p65 and p50 NF-κB subunits has been reported in over 90% of breast cancers^1,2. Recently, we characterized a de novo RelB NF-κB subunit synthesis pathway, induced by the cytomegalovirus (CMV) IE1 protein, in which binding of p50–p65 NF-κB and c-Jun–Fra-2 AP-1 complexes to the RELB promoter work in synergy to potently activate transcription³. Although RelB complexes were observed in mouse mammary tumours induced by either ectopic c-Rel expression⁴ or carcinogen exposure⁵, little is known about RelB in human breast disease. Here, we demonstrate constitutive de novo RelB synthesis is selectively active in invasive oestrogen receptor alpha (ERα)-negative breast cancer cells. ERα signalling reduced levels of functional NF-κB and Fra-2 AP-1 and inhibited de novo RelB synthesis, leading to an inverse correlation between RELB and ERα gene expression in human breast cancer tissues and cell lines. Induction of Bcl-2 by RelB promoted the more invasive phenotype of ERα-negative cancer cells. Thus, inhibition of de novo RelB synthesis represents a new mechanism whereby ERα controls epithelial to mesenchymal transition (EMT).