Regulation of CEACAM1 transcription in human breast epithelial cells

Using in vivo footprinting and chromatin immunoprecipitation experiments we show that the CEACAM1 proximal promoter in breast cells is bound in its active state by SP1, USF1/USF2, and IRF1/2. When down-regulated the CEACAM1 promoter remains accessible to USF2 and partially accessible to USF1. Interferon-γ up-regulates CEACAM1 mRNA by a mechanism involving further induction of IRF-1 and USF1 binding at the promoter. As predicted by this analysis, silencing of IRF1 and USF1 but not USF2 by RNAi resulted in a significant decrease in CEACAM1 protein expression in MDA-MB-468 cells. The inactive CEACAM1 promoter in MCF7 cells exhibits decreased histone acetylation at the promoter region, with no evidence of H3K9 or H3K27 trimethylation, histone modifications often linked to condensed chromatin structure.Our data suggest that transcription activators USF1 and IRF1 interact to modulate CEACAM1 expression and that the chromatin structure of the promoter is likely maintained in a poised state that can promote rapid induction under appropriate conditions.Carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1) is a member of the immunoglobulin super family of glycoproteins [1,2]. It is expressed on the surface of epithelial and endothelial cells, as well as on cells from the immune system and plays a role in a variety of cellular processes like cell-cell adhesion, proliferation and differentiation, apoptosis and immune response. Several studies have reported down-regulation of CEACAM1 expression in cancers of epithelial origin, including colon [3], breast [4], liver [5], gastric [6] and prostate [7]. The degree of CEACAM1 down-regulation varies between different tissues: in colon cancer the protein is almost completely absent (90% down-regulation), while in breast cancer only about 30% of tumors exhibit a decrease in CEACAM1 expression. Importantly, forced over-expression of CEACAM1 in prostate, breast, colon or liver cell lines results in a decrease of the tu