Induction of quinone reductase by tamoxifen or DPN protects against mammary tumorigenesis.
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.
Case Western Reserve University, School of Medicine, Department of Pharmacology, H. G.Wood Bldg. W305, 2109 Adelbert Rd., Cleveland, OH 44106, USA.
Nirmala
N
Krishnamurthy
Yanduan
Y
Hu
Sandra
S
Siedlak
Yong Qiu
YQ
Doughman
Michiko
M
Watanabe
Monica M
MM
Montano
D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D011422:Propionates
D001141:Aromatase; D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; D016660:NAD(P)H Dehydrogenase (Quinone); D009570:Nitriles; D013629:Tamoxifen; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates