PT - JOURNAL ARTICLE AU - Kah Poh Tan AU - Bernice Wang AU - Mingdong Yang AU - Paul C Boutros AU - Jane MacAulay AU - Haibo Xu AU - Andrew I Chuang AU - Kosuge Kazuhiro AU - Mika Yamamoto AU - Shinichiro Takahashi AU - Alex ML Wu AU - Patricia A Harper AU - Douglas D Ross AU - Shinya Ito TI - Aryl Hydrocarbon Receptor (AHR) is A Transcriptional Activator of Human Breast Cancer Resistance Protein (BCRP/ABCG2) AID - 10.1124/mol.110.065078 DP - 2010 May 11 TA - Molecular Pharmacology PG - mol.110.065078 4099 - http://molpharm.aspetjournals.org/content/early/2010/05/11/mol.110.065078.short 4100 - http://molpharm.aspetjournals.org/content/early/2010/05/11/mol.110.065078.full AB - Breast cancer resistance protein (BCRP/ABCG2) is a membrane-bound efflux transporter important in cellular detoxification and multidrug resistance. Some aryl hydrocarbon receptor (AHR) agonists were reported to induce BCRP expression in human colon carcinoma cells. However, a direct involvement of AHR transcriptional regulation remains unexplored. In this study, we show that BCRP induction by AHR ligands occurs in human intestinal, liver and mammary carcinoma cells, and in primary colonocytes and hepatocytes. Increased BCRP transporter activity consistent with gene induction was also evident in the Caco2 subclone C2bbe1 cells. Utilizing RNA interference and ectopic expression techniques to manipulate cellular AHR status, we confirmed AHR dependency of ABCG2 gene regulation. By gene promoter analysis, chromatin immunoprecipitation and electrophoretic mobility shift assays, an active, proximal dioxin response element (DRE) at -194/-190 bp upstream of the transcription start site of the human ABCG2 gene was identified. Despite a common observation in human-derived cells, our in vitro and in vivo studies supported by pylogenetic footprinting analysis did not find that mouse Abcg2 is subject to AHR regulation. We conclude that AHR is a direct transcriptional regulator of human BCRP and provide an unprecedented role of AHR in cellular adaptive response and cytoprotection by upregulating an important ATP-binding cassette efflux transporter.The American Society for Pharmacology and Experimental Therapeutics