The Ligand Status of the Aromatic Hydrocarbon Receptor Modulates Transcriptional Activation of BRCA-1 Promoter by Estrogen

Abstract

In sporadic breast cancers, BRCA-1 expression is downregulated in the absence of mutations in the BRCA-1 gene. This suggests that disruption of BRCA-1 expression may contribute to the onset of mammary tumors. Environmental contaminants found in industrial pollution, tobacco smoke, and cooked foods include benzo(a)pyrene [B(a)P] and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which have been shown to act as endocrine disruptors and tumor promoters. In previous studies, we documented that estrogen (E2) induced BRCA-1 transcription through the recruitment of an activator protein-1/estrogen receptor-A (ERA) complex to the proximal BRCA-1 promoter. Here, we report that activation of BRCA-1 transcription by E2 requires occupancy of the BRCA-1 promoter by the unliganded aromatic hydrocarbon receptor (AhR). The stimulatory effects of E2 on BRCA-1 transcription are counteracted by (a) cotreatment with the AhR antagonist 3V -methoxy-4V -nitroflavone; (b) transient expression in ERAnegative HeLa cells of ERA lacking the protein-binding domain for the AhR; and (c) mutation of two consensus xenobiotic-responsive elements (XRE, 5V -GCGTG-3V ) located upstream of the ERA-binding region. These results suggest that the physical interaction between the unliganded AhR and the liganded ERA plays a positive role in E2-dependent activation of BRCA-1 transcription. Conversely, we show that the AhR ligands B(a)P and TCDD abrogate E2-induced BRCA-1 promoter activity. The repressive effects of TCDD are paralleled by increased recruitment of the liganded AhR and HDAC1, reduced occupancy by p300, SRC-1, and diminished acetylation of H4 at the BRCA-1 promoter region flanking the XREs. We propose that the ligand status of the AhR modulates activation of the BRCA-1 promoter by estrogen. (Cancer Res 2006; 66(4): 2224-32)

Methylation Induced Gene Silencing of HtrA3 in Smoking-Related Lung Cancer

“…They bind aryl-hydrocarbon receptors, which are induced in response to xenobiotic factors, such as cigarette smoke (36). It has been proposed that sudden activation of the XRE pathway results in the rapid recruitment of transcription effectors away from other less crucial genes, downregulating their expression while the products of XRE responsive genes are upregulated (37,38). HtrA1 and HtrA2 transcriptional and protein upregulation may implicate their involvement in XRE-mediated response to xenobiotic stress.…”

The Active Form of Human Aryl Hydrocarbon Receptor (AHR) Repressor Lacks Exon 8, and Its Pro185 and Ala185 Variants Repress both AHR and Hypoxia-Inducible Factor

“…Although bHLH-PAS proteins are generally thought of as transcriptional activators, several are known to act as repressors: SIM2 (49, 66), NPAS1 (60), HIF-3␣ (41,44,67), and (in some circumstances) AHR (43,55,68). The mechanisms of repression are varied and include competition for ARNT (49,66,67), formation of abortive complexes with the target transcription factor (41,44), displacement of DNA-bound transcription factor complexes (17,37,49), and displacement of coregulatory proteins (24,43).…”

The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression

“…349 In fact, this model has been proposed to occur at the BRCA-1 promoter in the presence of estrogen. 312 Neither the AhR nor ARNT has been shown to directly interact with C/EBP. However, the presence and functional interplay between C/EBP and AhRC has been established at the promoter of glutathione S-transferase Ya (GST Ya) and CYP1A1 genes.…”