In Vitro and in Vivo Regulation of Antioxidant Response Element-Dependent Gene Expression by Estrogens

Ansell, Pete; Espinosa-Nicholas, C.; Curran, Edward M.; Judy, Barbara M.; Philips, Brian J.; Hannink, Mark; Lubahn, Dennis B.

doi:10.1210/en.2003-0817

Cited by 75 publications

(63 citation statements)

References 35 publications

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“…E 2 induced a 440% decrease in QR levels after 4 and 7 months of treatments ( Figure 1b). Although we have not observed E 2 -induced decrease in QR levels in breast epithelial cell lines (Montano et al, 1998), Ansell et al (2004) reported decreased QR expression in the uteri of E 2 -treated mice. Co-treatment with TAM led to an increase in QR levels in E 2 -treated animals, to levels similar to that observed in control (untreated) animals ( Figure 1b).…”

contrasting

confidence: 76%

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

et al. 2006

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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.

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contrasting

confidence: 76%

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

et al. 2006

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“…A study on NQO1 levels in the tissue of ovariectomized mice treated with E 2 over 14 days showed high tissue variability but significantly reduced uterine NQO1 (34). The observed enzyme activity was substantiated by immunoassay of NQO1 protein expression by Western blot (Fig.…”

Section: Induction Of Nqo1 In Liver Cellsmentioning

confidence: 81%

“…Nevertheless, one group has reported NQO1 induction by SERMs in MCF-7 cells, stating that HOT induced NQO1 via an ERhdependent pathway (36). Another group has reported NQO1 induction in both ERa-and ERh-transfected cell lines derived from MCF-7 cells by tamoxifen and HOT (34). Thus, we initially studied the MCF-7 cell line stably transfected with ERh, but observed only very weak induction of NQO1 by the X-DMA SERMs raloxifene and HOT (Supplementary data).…”

Section: Induction Of Nqo1in Breast Cancer Cellsmentioning

confidence: 99%

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

Dietz²,

Dunlap

et al. 2007

Molecular Cancer Therapeutics

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The benzothiophene selective estrogen receptor modulators (SERM) raloxifene and arzoxifene are in clinical use and clinical trials for chemoprevention of breast cancer and other indications. These SERMs are ''oxidatively labile'' and therefore have potential to activate antioxidant responsive element (ARE) transcription of genes for cytoprotective phase II enzymes such as NAD(P)Hdependent quinone oxidoreductase 1 (NQO1). To study this possible mechanism of cancer chemoprevention, a family of benzothiophene SERMs was developed with modulated redox activity, including arzoxifene and its metabolite desmethylarzoxifene (DMA). The relative antioxidant activity of these SERMs was assayed and correlated with induction of NQO1 in murine and human liver cells. DMA was found to induce NQO1 and to activate ARE more strongly than other SERMs, including raloxifene and 4-hydroxytamoxifen. Livers from female, juvenile rats treated for 3 days with estradiol and/or with the benzothiophene SERMs arzoxifene, DMA, and F-DMA showed substantial induction of NQO1 by the benzothiophene SERMs. No persuasive evidence in this assay or in MCF-7 breast cancer cells was obtained of a major role for the estrogen receptor in induction of NQO1 by the benzothiophene SERMs. These results suggest that arzoxifene might provide chemopreventive benefits over raloxifene and other SERMs via metabolism to DMA and stimulation of ARE-mediated induction of phase II enzymes. The correlation of SERM structure with antioxidant activity and NQO1 induction also suggests that oxidative bioactivation of SERMs may be modulated to enhance chemopreventive activity. [Mol Cancer Ther 2007;6(9):2418 -28]

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“…This transcription factor gives robust transcriptional activation so any alteration in its activity will readily be detected [22,28]. As shown in Figure 4, Dlk1 was unable to significantly repress transcription mediated by Nrf2, indicating that the ability of Dlk1 to repress Pit-1-induced transcription is specific.…”

Section: Dlk1 Regulates Pit-1-mediated Transcriptional Activationmentioning

confidence: 99%

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Ansell

Zhou

Schjeide

et al. 2007

Molecular and Cellular Endocrinology

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Delta-like protein 1 (Dlk1) is a transmembrane protein characterized by epidermal growth factor (EGF)-like repeats. Dlk1, which is also known as preadipocyte factor 1 (pref-1) because of its ability to inhibit preadipocyte differentiation, regulates the differentiation of several other cell types through unknown mechanisms. To elucidate Dlk1 functions, identification of Dlk1-regulated target genes is critical. The observation that Dlk1 is expressed in many endocrine tissues suggests that Dlk1 may have endocrine-related functions. Because Dlk1 is expressed in GH producing cells, we hypothesize that one function of Dlk1 is to regulate GH expression. We found that GH mRNA, protein, and secretion were significantly decreased in GH3 pituitary cell clones that stably express Dlk1. In contrast, Dlk1 expression was unable to alter prolactin expression. Co-transfection of GH3 cells with a GH promoter-regulated reporter gene showed that Dlk1 repressed GH promoter activity. Deletion and mutation analysis of the GH promoter indicated that Pit-1 binding sites in the GH promoter are required for Dlk1-mediated repression. Furthermore, Dlk1 expression represses Pit-1-mediated transcription when both proteins are co-expressed in MCF-7 cells. Deletion analysis of Dlk1 revealed that the ability of Dlk1 to regulate GH promoter activity is independent of both its EGF-like repeats and its ability to modulate MAP kinase activity. The observation that Dlk1 regulates GH expression identifies the first endocrine function of Dlk1, establishes GH as a Dlk1-regulated target gene, and provides a model system to facilitate studies of Dlk1-mediated signaling.

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In Vitro and in Vivo Regulation of Antioxidant Response Element-Dependent Gene Expression by Estrogens

Cited by 75 publications

References 35 publications

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

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

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

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