Conditional expression of a constitutively active aryl hydrocarbon receptor in MCF-7 human breast cancer cells.
In addition to inducing transcription of a battery of target genes encoding drug-metabolizing enzymes, the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to induce antiestrogenic responses. However, the mechanisms underlying such complex biologic responses affecting growth and differentiation remain unclear. In the present study we have investigated biological effects of a constitutively active mutant of the aryl hydrocarbon (Ah) receptor (CA-AhR), in particular whether it modulates estrogen receptor function in human MCF-7 breast cancer cells. To this end, the CA-AhR protein was conditionally expressed using the tet repressor. Expression of CA-AhR resulted in constitutive formation of a DNA-binding AhR-aryl hydrocarbon receptor nuclear translocator heterodimeric complex and enhanced expression of the Ah receptor target gene CYP1A1 in the absence of TCDD. Moreover, expression of CA-AhR inhibited estrogen-dependent cathepsin D expression and growth of these cells. Thus, the present model system conditionally expressing the CA-AhR protein provides a novel tool for the investigation of AhR-mediated signaling pathways.
Köhle
Christoph
C
Institute of Toxicology, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany.
Hassepass
Ingo
I
Bock-Hennig
Barbara S
BS
Walter Bock
Karl
K
Poellinger
Lorenz
L
McGuire
Jacqueline
J
D001943:Breast Neoplasms; D002402:Cathepsin D / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D004958:Estradiol; D019363:Cytochrome P-450 CYP1A1; D002402:Cathepsin D