Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells

Citation
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
Citations number
75
Categorie Soggetti
da verificare
Journal title
JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA
ISSN journal
10833021 → ACNP
Volume
5
Issue
3
Year of publication
2000
Pages
295 - 306
Database
ISI
SICI code
1083-3021(200007)5:3<295:MOIAHR>2.0.ZU;2-U
Abstract
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.