Previously, we reported that BRCA1 regulates the expression of various classes of genes, including genes involved in xenobiotic stress responses [I. Bae et al., Cancer Research (2004), 64: 7893-7909]. In this study, we investigated the effects of BRCA1 on xenobiotic stress-inducible gene expression. In response to aryl hydrocarbon receptor (AhR) ligands, cytoplasmic AhR becomes activated and then translocates to the nucleus where it forms a complex with the aryl hydrocarbon receptor nuclear translocator (ARNT). Subsequently, the AhR•ARNT complex binds to the enhancer or promoter of genes containing a xenobiotic stress responsive element (XRE) and regulates the expression of multiple target genes, including cytochrome P450 subfamily polypeptide I (CYP1A1). In this study, we found that endogenous and overexpressed exogenous wild-type BRCA1 affect xenobiotic stress-induced CYP1A1 gene expression. Using a standard chromatin immunoprecipitation (ChIP) assay, we demonstrate that BRCA1 is recruited to the promoter regions of CYP1A1 and CYP1B1 along with ARNT and/or AhR following xenobiotic exposure. Our findings suggest that BRCA1 may be physiologically important for mounting a normal response to xenobiotic insults and that it may function as a coactivator for ARNT activity. Using immunoprecipitation (IP)-Western blotting (WB) and GST-capture assays, a xenobiotic-independent interaction between BRCA1 and ARNT has been identified, although it is not yet known whether this is a direct or indirect interaction. We also found that the inducibility of CYP1A1 and CYP1B1 transcripts following xenobiotic stress was significantly attenuated in BRCA1 knockdown cells. This reduced inducibility is associated with an altered stability of ARNT. This reduced inducibility was almost completely reversed in cells transfected with an ARNT expression vector. Finally, we found that xenobiotic (TCDD) treatments of breast cancer cells containing reduced levels of BRCA1 cause the transcription factor ARNT to become unstable.