Estrogen represses CXCR7 gene expression by inhibiting the recruitment of NFκB transcription factor at the CXCR7 promoter in breast cancer cells.
Although many studies reported mechanisms involved in the positive regulation of estrogens (E2) target genes, very little is known concerning the repressive effect of E2. In this study, we explored the molecular mechanisms by which E2 regulates CXCR7 expression in breast cancer cells. Our results show that E2-mediated down-regulation of CXCR7 occurs at the transcriptional level as demonstrated using actinomycin D and requires estrogen receptor alpha (ERα). In addition, CXCR7 is a primary ERα-target gene because the effect of E2 does not require the synthesis of an intermediary protein as revealed by the translational inhibitor cycloheximide treatment. Using an inhibitor of the NFκB pathway and chromatin immunoprecipitation assays, we demonstrated that NFκB is necessary for the high expression of CXCR7 gene and is recruited to the proximal promoter of the CXCR7 gene. Interestingly, the chromatin immunoprecipitation analyses also showed that E2-treatment significantly prevented the recruitment of NFκB to the promoter. Altogether, our results demonstrate that E2, through ERα, directly down-regulates CXCR7 expression by interfering with NFκB transcription factor at the promoter level.
University of Rennes 1, Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Rennes, France. gwenneg.kerdivel@univ-rennes1.fr
Gwenneg
G
Kerdivel
Antoine
A
Boudot
Farzad
F
Pakdel
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors* / Q000235:genetics
C501896:ACKR3 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D054387:Receptors, CXCR; D004958:Estradiol