Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis.
We previously reported that antiestrogen-liganded estrogen receptor beta (ERbeta) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:quinone oxidoreductase). Further studies on the functional role of ERbeta-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 ERbeta-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 17beta-estradiol treated MCF10A non-tumorigenic breast epithelial cells. Concurrent expression of ERbeta 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.
Montano
M M
MM
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA. mxm126@po.cwru.edu
Chaplin
L J
LJ
Deng
H
H
Mesia-Vela
S
S
Gaikwad
N
N
Zahid
M
M
Rogan
E
E
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001943:Breast Neoplasms / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D008321:Mammary Glands, Animal / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000502:physiology*; D018384:Oxidative Stress; D051381:Rats; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; D004967:Estrogens; D013629:Tamoxifen; C016601:afimoxifene; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016660:NAD(P)H Dehydrogenase (Quinone); D003849:Deoxyguanosine