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

Aberrant constitutive expression of c-Rel, p65 and p50 NF-kappa B subunits has been reported in over 90% of breast cancers(1,2). Recently, we characterized a de novo RelB NF-kappa B subunit synthesis pathway, induced by the cytomegalovirus (CMV) IE1 protein, in which binding of p50-p65 NF-kappa B and c-Jun-Fra-2 AP-1 complexes to the RELB promoter work in synergy to potently activate transcription(3). Although RelB complexes were observed in mouse mammary tumours induced by either ectopic c-Rel expression(4) or carcinogen exposure(5), 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 (ER alpha)-negative breast cancer cells. ERa signalling reduced levels of functional NF-kappa B and Fra-2 AP-1 and inhibited de novo RelB synthesis, leading to an inverse correlation between RELB and ERa gene expression in human breast cancer tissues and cell lines. Induction of Bcl-2 by RelB promoted the more invasive phenotype of ER alpha-negative cancer cells. Thus, inhibition of de novo RelB synthesis represents a new mechanism whereby ERa controls epithelial to mesenchymal transition (EMT).