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Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications

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Abstract

We previously reported that antiestrogen-liganded estrogen receptor β (ERβ) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:quinone oxidoreductase). Our studies also indicate that upregulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites. We now report on the upregulation of glutathione S-transferases Pi (GST-Pi) and gamma-glutamylcysteine synthetase heavy subunit (GCSh) expression by antiestrogens. Studies indicate the regulation of GST-Pi and GCSh transcriptional activity by ER. While ER regulation is mediated by an electrophile response element (EpRE), we identified mechanistic differences in the involvement of other transcription factors. Regardless of these differences, ERβ-mediated regulation of GST-Pi and GCSh point towards an important role for ERβ in cellular protection against oxidative stress. A protective role is supported by our observation of inhibition of estrogen-induced DNA damage upon upregulation of GST-Pi and GCSh expression.

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Abbreviations

ERβ:

estrogen receptor β

ERα:

estrogen receptor α

E2:

17β-estradiol

TOT:

trans-hydroxytamoxifen

QR:

quinone reductase

GST-Pi:

glutathione S-transferases Pi

GCSh:

gamma-glutamylcysteine synthetase heavy subunit

ARE/EpRE:

antioxidant/electrophile response element

8-OHdG:

8-hydroxydeoxyguanine

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Acknowledgements

We thank Dr Steven A Reeves (Massachusetts General Hospital) for the pBPSTR1 retroviral vector, Dr Henry Forman (University of Alabama) for the GCSh antibody, and Dr R Timothy Mulchay (University of Wisconsin) for the GCSh-pGL3 reporter.

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Correspondence to Monica M Montano.

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This work was supported by National Institute of Health Grant CA80959 to MMM

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Montano, M., Deng, H., Liu, M. et al. Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications. Oncogene 23, 2442–2453 (2004). https://doi.org/10.1038/sj.onc.1207358

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  • DOI: https://doi.org/10.1038/sj.onc.1207358

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