In the present study we examined the ability of 3,3′,4,4′,5-pentachlorinated biphenyl [PCB126 (polychlorinated biphenyl 126)], a prototypical AHR (aryl hydrocarbon receptor) agonist, and 2,2′,4,6,6′-PCB (PCB104), which does not activate AHR, to induce the recruitment of ERα (oestrogen receptor α) to CYP1A1 (cytochrome P4501A1 gene) and CYP1B1 promoters in T-47D human breast cancer cells and other cell lines. PCB126 treatment strongly induced CYP1A1 and CYP1B1 mRNA expression that was unaffected by co-treatment with E2 (17β-oestradiol). PCB104 failed to induce changes in either CYP1A1 or CYP1B1 expression levels. ChIP (chromatin immunoprecipitation) assays show that PCB126, but not PCB104, increased the promoter occupancy by ERα to CYP1A1 and CYP1B1 promoters. Co-treatment with PCB126+E2 significantly enhanced the promoter occupancy of ERα at CYP1A1, whereas co-treatment with PCB126+4-hydroxytamoxifen or ICI182,780 did not. Competitive binding studies revealed that neither PCB126 nor PCB104 bound to ERα. HEK-293 cells (human embryonic kidney-293 cells) stably transfected with ERα showed significantly higher PCB126-induced CYP1A1 expression compared with empty vector controls, whereas no increase was observed in cells stably transfected with ERα lacking its N-terminal AF1 (activation function-1) domain (ERαΔAF1). Despite no increase in AHR-mediated gene expression, ChIP assays revealed that ERαΔAF1 was present at CYP1A1 and CYP1B1 promoters. HC11 mouse mammary cells stably expressing shRNA (small-hairpin RNA) against ERα showed an 8-fold reduction in PCB126-dependent Cyp1a1 expression. Our results provide further evidence that AHR agonists induce ERα promoter occupancy at AHR target genes through indirect activation of ERα, and support a role for ERα in AHR transactivation.
Co-planar 3,3′,4,4′,5-pentachlorinated biphenyl and non-co-planar 2,2′,4,6,6′-pentachlorinated biphenyl differentially induce recruitment of oestrogen receptor α to aryl hydrocarbon receptor target genes
- Views Icon Views
- Share Icon Share
- Cite Icon Cite
Jason Matthews, Björn Wihlén, Nina Heldring, Laura MacPherson, Luisa Helguero, Eckardt Treuter, Lars-Arne Haldosén, Jan-Åke Gustafsson; Co-planar 3,3′,4,4′,5-pentachlorinated biphenyl and non-co-planar 2,2′,4,6,6′-pentachlorinated biphenyl differentially induce recruitment of oestrogen receptor α to aryl hydrocarbon receptor target genes. Biochem J 1 September 2007; 406 (2): 343–353. doi: https://doi.org/10.1042/BJ20070585
Download citation file: