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      Induction of quinone reductase by tamoxifen or DPN protects against mammary tumorigenesis

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          Abstract

          We have previously shown that estrogen receptor β (ERβ)-mediated up-regulation of quinone reductase (QR) is involved in the protection against estrogen-induced mammary tumorigenesis. Our present study provides evidence that the ERβ agonist, 2,3- bis-(4-hydroxy-phenyl)-propionitrile (DPN), and the selective estrogen receptor modulator tamoxifen (Tam), inhibit estrogen-induced DNA damage and mammary tumorigenesis in the aromatase transgenic (Arom) mouse model. We also show that either DPN or Tam treatment increases QR levels and results in a decrease in ductal hyperplasia, proliferation, oxidative DNA damage (ODD), and an increase in apoptosis. To corroborate the role of QR, we provide additional evidence in triple transgenic MMTV/QR/Arom mice, wherein the QR expression is induced in the mammary glands via doxycycline, causing a decrease in ductal hyperplasia and ODD. Overall, we provide evidence that up-regulation of QR through induction by Tam or DPN can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a novel mechanism of prevention against breast cancer. Thus, our data have important clinical implications in the management of breast cancer; our findings bring forth potentially new therapeutic strategies involving ERβ agonists. Krishnamurthy, N., Hu, Y., Siedlak, S., Doughman, Y. Q., Watanabe, M., Montano, M. M. Induction of quinone reductase by tamoxifen or DPN protects against mammary tumorigenesis.

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          Author and article information

          Journal
          FASEB J
          FASEB J
          fasebj
          fasebj
          fasebj
          The FASEB Journal
          Federation of American Societies for Experimental Biology (Bethesda, MD, USA )
          0892-6638
          1530-6860
          October 2012
          October 2012
          : 26
          : 10
          : 3993-4002
          Affiliations
          [ * ]Department of Pharmacology,
          [ ]Department of Pediatrics, and
          [ ]Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
          Author notes
          [1 ]Correspondence: Case Western Reserve University School of Medicine, Department of Pharmacology, H. G.Wood Bldg. W305, 2109 Adelbert Rd., Cleveland, OH 44106, USA. E-mail: mxm126@ 123456case.edu
          Article
          PMC6190799 PMC6190799 6190799 12-208330
          10.1096/fj.12-208330
          6190799
          22700872
          e0b55128-607a-43db-bba6-8bbde8dce1cb
          © FASEB
          History
          : 13 March 2012
          : 5 June 2012
          Categories
          Research Communications

          aromatase,hyperplasia,oxidative DNA damage
          aromatase, hyperplasia, oxidative DNA damage

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