S. Safe et al., Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells, J MAMMARY G, 5(3), 2000, pp. 295-306
The aryl hydrocarbon receptor (AhR)(3) is a ligand-activated transcription
factor that forms a functional heterodimeric complex with the AhR nuclear t
ranslocator (Arnt) protein. The environmental toxin, 2,3,7,8-tetrachlorodib
enzo-p-dioxin (TCDD), is a high affinity ligand for the AhR and has been ex
tensively used to investigate AhR-mediated biochemical and toxic responses.
TCDD modulates several endocrine pathways including inhibition of 17 beta
-estradiol-induced responses in the immature and ovariectomized rodent uter
us and mammary gland and in human breast cancer cell lines. TCDD inhibits f
ormation and growth of mammary tumors in carcinogen-induced rodent models a
nd relatively nontoxic selective AhR modulators (SAhRMs) are being develope
d for treatment of breast cancer. The mechanisms of inhibitory AhR-estrogen
receptor (ER) crosstalk have been investigated in MCF-7 breast cancer cell
s by analysis of promoter regions of genes induced by E2 and inhibited by T
CDD. AhR-mediated inhibition of E2-induced cathepsin D, pS2, c-fos, and hea
t shock protein 27 gene expression involves direct interaction of the AhR c
omplex with inhibitory pentanucleotide (GCGTG) dioxin responsive elements (
iDREs) resulting in disruption of interactions between proteins binding DNA
elements required for ER action and the basal transcription machinery. Mec
hanisms of inhibitory AhR-ER crosstalk indicate that functional iDREs are r
equired for inhibition of some genes; however, results indicate that other
interaction pathways are important including AhR-mediated proteasome-depend
ent degradation of the ER.