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.NF-B is a structurally and evolutionary conserved family of dimeric transcription factors with subunits having an N-terminal region of approximately 300 amino acids that shares homology with the v-Rel oncoprotein (17, 44). The conserved Rel homology domain is responsible for DNA binding, dimerization, nuclear translocation, and interaction with inhibitory proteins of NF-B (IBs). Mammals express five NF-B members, including c-Rel, RelB, RelA (p65), p50, and p52, which can form either homo-or heterodimers. RelB differs from the other members in that it only binds DNA as a heterodimer with either p52 or p50 and interacts only poorly with the inhibitory protein IB␣. In most untransformed cells, other than B lymphocytes, NF-B complexes are sequestered in the cytoplasm bound to specific IB proteins.

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

“…Transrepression of ER by NF-kB has been proposed as a mechanism by which ER-positive breast tumor cells lose ER expression and, hence, gives rise to a subpopulation of tumor cells that are resistant to endocrine treatment (38,39). Furthermore, we provide evidence that increased NF-kB signaling leading to ERa alterations are mediated via RRM2 overexpression and can be reversed using didox through its ability to inhibit NF-kB activation (Fig.…”

Identification of p130Cas/ErbB2-dependent invasive signatures in transformed mammary epithelial cells

“…Among them, PRDM1 that encodes the transcriptional repressor Blimp-1 28 was recently described as a potent repressor of ER-α synthesis, which is induced by activation of the NFκB member RelB, leading to a migratory phenotype. 29 Moreover, Blimp1 is emerging as a crucial downstream effector of RelB/Bcl-2/ Ras pathway that promotes EMT signature and breast cancer cell migration. 30 In addition, we observed increased expression of ITPKA and HEY1 genes previously described to promote cell motility, EMT, and migration.…”

The immune system and inflammation in breast cancer

“…Therefore, activation of NF-κB by inflammation may negate the effect of its suppression by ERα, which ultimately induces a more aggressive breast cancer phenotype. It has also been shown that NF-κB can suppress ERα activity in several experimental models (Bodine et al, 1999; Feldman et al, 2007; Wang et al, 2009). NF-κB and ERα can also synergistically induce expression of target genes which are involved in inflammation (Frasor et al, 2008), apoptosis (Stanculescu et al, 2010; Pradhan et al, 2012), proliferation (Tu et al, 2006) and drug-resistance (Pradhan et al, 2010).…”