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

Abstract

Aberrant constitutive expression of NF-?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?)-negative breast cancers versus ER?-positive ones, due in part to repression of RelB synthesis by ER? signaling. Notably, RelB promoted a more invasive phenotype in ER?-negative cancers via induction of the BCL2 gene. We report here that RelB reciprocally inhibits ER? 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? (ESR1) gene transcription. Commensurately higher Blimp1/PRDM1 expression was detected in ER?-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-?B subunit mediates repression, specifically of ER?, thereby promoting a more migratory phenotype. Copyright ? 2009, American Society for Microbiology. All Rights Reserved.