RelB NF-kappaB represses estrogen receptor alpha expression via induction of the zinc finger protein Blimp1.
Aberrant constitutive expression of NF-kappaB 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 (ERalpha)-negative breast cancers versus ERalpha-positive ones, due in part to repression of RelB synthesis by ERalpha signaling. Notably, RelB promoted a more invasive phenotype in ERalpha-negative cancers via induction of the BCL2 gene. We report here that RelB reciprocally inhibits ERalpha 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 B- and T-cell development, which is transcribed from the PRDM1 gene. Blimp1 protein repressed ERalpha (ESR1) gene transcription. Commensurately higher Blimp1/PRDM1 expression was detected in ERalpha-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-kappaB subunit mediates repression, specifically of ERalpha, thereby promoting a more migratory phenotype.
Department of Biochemistry K615, Boston University School of Medicine, 72 E. Concord Street, Boston, MA 02118, USA.
Xiaobo
X
Wang
Karine
K
Belguise
Christine F
CF
O'Neill
Nuria
N
Sánchez-Morgan
Mathilde
M
Romagnoli
Sean F
SF
Eddy
Nora D
ND
Mineva
Ziyang
Z
Yu
Chengyin
C
Min
Vickery
V
Trinkaus-Randall
Dany
D
Chalbos
Gail E
GE
Sonenshein
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D017931:DNA Primers / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D019254:Genes, bcl-2; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D000074462:Positive Regulatory Domain I-Binding Factor 1; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D017931:DNA Primers; D047628:Estrogen Receptor alpha; D019253:Proto-Oncogene Proteins c-bcl-2; C497593:RELB protein, human; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D051841:Transcription Factor RelB; D000074462:Positive Regulatory Domain I-Binding Factor 1; D018631:ras Proteins