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Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis

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). Further studies on the functional role of ERβ-mediated upregulation of antioxidative enzymes indicated protective effects against estrogen-induced oxidative DNA damage (ODD). We now report on in vivo and in vitro studies that show that ERβ-mediated upregulation of QR are involved in the protection against estrogen-induced mammary tumorigenesis. Using the August Copenhagen Irish (ACI) model of estrogen-induced carcinogenesis, we observed that increased ODD and decreased QR expression occur early in the process of estrogen-induced mammary tumorigenesis. Prevention of ACI mammary gland tumorigenesis by tamoxifen was accompanied by decreased ODD and increased QR levels. These correlative findings were supported by our findings that downregulation of QR levels led to increased levels of estrogen quinone metabolites and enhanced transformation potential of 17β-estradiol treated MCF10A non-tumorigenic breast epithelial cells. Concurrent expression of ERβ and treatment with 4-hydroxytamoxifen decreased tumorigenic potential of these MCF10A cells. We conclude that upregulation of QR, through induction by tamoxifen, can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a possible novel mechanism of tamoxifen prevention against breast cancer.

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Abbreviations

COMT:

catechol-O-methyltransferase

E2:

17β-estradiol

ER:

estrogen receptor

ERα:

estrogen receptor α

ERβ:

estrogen receptor β

GST-Pi:

glutathione S-transferase Pi

ODD:

oxidative DNA damage

QR or NQO1:

quinone reductase

siRNA:

short interfering RNAs

TAM:

tamoxifen

TOT:

4-hydroxytamoxifen

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Acknowledgements

We thank Dr Sara Li (University of Kansas) for some of the ACI rat tissues, Dr Anil Jaiswal (Baylor College of Medicine) for the pMT2-QR vector and Dr Alan Wolfman (Lerner Research Institute, Cleveland Clinic) for Ha-RAS expression vector. This work was supported by the National Institute of Health Grants CA80959 and CA92440 to MMM, P01-CA49210 from the NIH and DAMD17-03-01-0229 from the US Army Breast Cancer Research Program to EC and ER, and ES05022 from the NIH to SMS.

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Correspondence to M M Montano.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Montano, M., Chaplin, L., Deng, H. et al. Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis. Oncogene 26, 3587–3590 (2007). https://doi.org/10.1038/sj.onc.1210144

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