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

Abstract

We previously reported that antiestrogen-liganded estrogen receptor b (ERb) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:-quinone oxidoreductase). Further studies on the functional role of ERb-mediated upregulation of antioxidative enzymes indicated protective effects against estrogeninduced oxidative DNA damage (ODD). We now report on in vivo and in vitro studies that show that ERbmediated 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 17b-estradiol treated MCF10A non-tumorigenic breast epithelial cells. Concurrent expression of ERb 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.

Inhibition of catechol-O-methyltransferase increases estrogen–DNA adduct formation

“…One is the reduction of the quinone to the CE catalyzed by quinone reductase (Fig. 1) [47,48]. The second pathway is the reaction of the quinone with GSH.…”

AberrantKeap1methylation in breast cancer and association with clinicopathological features

“…Anti-estrogens agents stimulate NQO1 transcription and protect against estrogen-induced DNA damage in estrogen-dependent breast cancer cells. 31,32 It has been observed that the Erα binding domain is required for estrogens inhibition of the NQO1 promoter activity leading to repression of homogenously treated will be needed to clarify the predictive role of KEAP1 genetic and epigenetic changes in breast cancer as well as in other tumor types. In summary, we show that the Nrf2-negative regulator KEAP1 is frequently methylated in breast cancer.…”

KEAP1 Genetic Polymorphisms Associate with Breast Cancer Risk and Survival Outcomes

“…SNP rs1048290 is a synonymous variant in the KEAP1 coding region, which is located in the sequence encoding the beta strand B of blade IV in the Kelch-1 domain, residing 33 bp (11 codons) from the codon for the amino acid whose side chain contacts the NRF2-derived peptide in the crystal structure (36). Antiestrogen agents have been reported to stimulate NAD(P) H:dehydrogenase, quinone 1 (NQO1) transcription and to protect against estrogen-induced DNA damage in estrogendependent breast cancer cells (41,42). Tamoxifen acts as a selective estrogen receptor modulator that binds the NQO1 promoter and activates NQO1 gene transcription in breast cancer cells (41,42).…”