Signaling and Regulation FOXA1 Is Essential for Aryl Hydrocarbon Receptor–Dependent Regulation of Cyclin G2

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recently, AHR has emerged as a potential therapeutic target for breast cancer by virtue of its ability tomodulate estrogen receptor-a (ERa) signalling and/or its ability to block cell proliferation.Our previous studies identified cyclinG2 (CCNG2), an inhibitor of cellcycle progression, as an AHR target gene; however, the mechanism of this regulation is unknown. Chromatin immunoprecipitation assays in T-47D human breast cancer cells revealed a TCDD-dependent recruitment of AHR, nuclear co-activator 3 (NCoA3) and the transcription factor forkhead box A1 (FOXA1), a key regulator of breast cancer cell signaling, toCCNG2 resulting in increases inCCNG2mRNA and protein levels.Mutation of the AHR response element (AHRE) and forkhead-binding sites abolishedTCDD-inducedCCNG2-regulated reporter gene activity. RNA interference–mediated knockdown of FOXA1 prevented the TCDD-dependent recruitment of AHR and NCoA3 to CCNG2 and reduced CCNG2 mRNA levels. Interestingly, knockdown of FOXA1 also caused a marked decrease in ERa, but not AHR protein levels. However, RNA interference–mediated knockdown of ERa, a negative regulator of CCNG2, had no effect on TCDD-dependent AHR or NCoA3 recruitment to or expression ofCCNG2. These findings show that FOXA1, but not ERa, is essential for AHR-dependent regulation of CCNG2, assigning a role for FOXA1 in AHR action. Mol Cancer Res; 10(5); 636–48. 2012 AACR.