Carcinogenesis Advance Access originally published online on February 10, 2006
Carcinogenesis 2006 27(8):1567-1578; doi:10.1093/carcin/bgi339
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Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse Winterthurerstrasse 260, 8057 Zürich, Switzerland
*To whom correspondence should be addressed. Tel: +41 1 635 87 63; Fax: +41 1 635 89 10; Email: naegelih{at}vetpharm.unizh.ch
Estrogen receptors display high levels of promiscuity in accommodating a wide range of ligand structures, but the functional consequence of changing receptor conformations in complex with distinct agonists is highly controversial. To determine variations in the transactivation capacity induced by different estrogenic agonists, we assessed global transcriptional profiles elicited by natural or synthetic xenoestrogens in comparison with the endogenous hormone 17ß-estradiol. Human MCF7 and T47D carcinoma cells, representing the most frequently used model systems for tumorigenic responses in the mammary gland, were synchronized by hormone starvation during 48 h. Subsequently, a 24 h exposure was carried out with equipotent concentrations of the selected xenoestrogens or 17ß-estradiol. Analysis of messenger RNA was performed on high-density oligonucleotide microarrays that display the sequences of 33 000 human transcripts, yielding a total of 181 gene products that are regulated upon estrogenic stimulation. Surprisingly, genistein (a phytoestrogen), bisphenol-A and polychlorinated biphenyl congener 54 (two synthetic xenoestrogens) produced highly congruent genomic fingerprints by regulating the same range of human genes. Also, the monotonous genomic signature observed in response to xenoestrogens is identical to the transcriptional effects induced by physiological concentrations of 17ß-estradiol. This striking functional convergence indicates that the transcription machinery is largely insensitive to the particular structure of estrogen receptor agonists. The occurrence of such converging transcriptional programs reinforces the hypothesis that multiple xenoestrogenic contaminants, of natural or anthropogenic origin, may act in conjunction with the endogenous hormone to induce additive effects in target tissues.
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