Journal
TOXICOLOGICAL SCIENCES
Volume 138, Issue 1, Pages 89-103Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kft274
Keywords
aryl hydrocarbon receptor; aryl hydrocarbon receptor nuclear translocator; estrogen receptor; cytochrome P4501A1; cytochrome P4501B1; 2; 3; 7; 8-tetrachlorodibenzo-p-dioxin; zinc finger nucleases
Categories
Funding
- Canadian Institute of Health Research (CIHR) [MOP-82715]
- DOW Chemical Co.
- CIHR New Investigator Award
- Early Researcher Award from the Ontario Ministry of Innovation
- CIHR Doctoral Research Award
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In this study, we used zinc finger nucleasemediated knockout of the aryl hydrocarbon receptor (AHR) or AHR nuclear translocator (ARNT) in MCF7 and AHR knockout in MDA-MB-231 human breast cancer cells to investigate cross talk among AHR, ARNT, and estrogen receptor (ER). Knockout of AHR or ARNT prevented the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-dependent induction of all AHR target genes examined. Knockout of AHR or ARNT also significantly reduced basal cytochrome P4501B1 (CYP1B1) expression levels, which were restored with overexpression of either protein but not with a DNA bindingdeficient AHR mutant. Basal and TCDD-, 17-estradiol (E2)-, or TCDD E2-dependent recruitment of AHR, ARNT, ER, NCoA3, and RNA polymerase II to CYP1B1 as well as CYP1B1 mRNA levels were abolished in MCF7-AHR(ko) and MDA-MB-231 AHR(ko) cells. However, reduced but significant E2-dependent recruitment of ER, NCoA3, and RNA polymerase II to CYP1B1 and weak increases in CYP1B1 mRNA levels were observed in MCF7 ARNT(ko) cells. Interestingly, E2-dependent increases in trefoil factor 1, but not growth regulation by estrogen in breast cancer 1 (GREB1) mRNA levels, were dependent on ARNT expression. Moreover, the TCDD-dependent increases in the proteolytic degradation of ER were prevented by the loss of AHR or ARNT. Our data show that AHR and ARNT play critical roles in the basal, TCDD, and E2-induced regulation of CYP1B1 but also reveal distinct roles for both proteins in ER transactivation.
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