RelB NF-κB Represses Estrogen Receptor α Expression via Induction of the Zinc Finger Protein Blimp1

Aberrant constitutive expression of NF-kappa B subunits, reported in more than 90% of breast cancers and multiple other malignancies, plays pivotal roles in tumorigenesis. Higher RelB subunit expression was demonstrated in estrogen receptor alpha (ER alpha)-negative breast cancers versus ER alpha-positive ones, due in part to repression of RelB synthesis by ER alpha signaling. Notably, RelB promoted a more invasive phenotype in ER alpha-negative cancers via induction of the BCL2 gene. We report here that RelB reciprocally inhibits ER alpha synthesis in breast cancer cells, which contributes to a more migratory phenotype. Specifically, RelB is shown for the first time to induce expression of the zinc finger repressor protein Blimp1 (B-lymphocyte-induced maturation protein), the critical mediator of Band T-cell development, which is transcribed from the PRDM1 gene. Blimp1 protein repressed ER alpha (ESR1) gene transcription. Commensurately higher Blimp1/PRDM1 expression was detected in ER alpha-negative breast cancer cells and primary breast tumors. Induction of PRDM1 gene expression was mediated by interaction of Bcl-2, localized in the mitochondria, with Ras. Thus, the induction of Blimp1 represents a novel mechanism whereby the RelB NF-kappa B subunit mediates repression, specifically of ER alpha, thereby promoting a more migratory phenotype.