NF-ĸB as Node for Signal Amplification During Weaning

Post-lactational involution has been reported to share common features with breast tumor development. A deep characterization of the signaling triggered after weaning would help to unveil the complex relationship between involution and breast cancer. NF-ĸB, a crucial factor in the involuting gland, might be an important regulatory node for signal amplification after weaning; however there is limited information about the identity of NF-ĸB-target genes and the molecular mechanisms leading to the selection of genes involved in a particular biological process. We identified 4532 target genes in mammary gland at 48h weaning, by genome-wide analysis of regions bound by RelA(p65)-NF-ĸB in vivo. It was found that among total RelA(p65)-NF-ĸB-enriched genes, only 268 bound the trans-activating complex p65/p300. Our results suggest that the latter represents a major complex preferentially involved in the modulation of the inflammatory response at 48h of mammary gland involution. A genome-wide factor location analysis revealed that p65-binding had a heterogeneous distribution while the complex of p65 and its co-activator p300 were mainly bound to proximal promoters near transcription start sites. Moreover, our computational analysis predicts the existence of cooperating elements on RelA-NF-ĸB/p300-enriched genes that could explain preferential binding and modulation of gene expression during mammary gland involution.