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

Departments of Biochemistry (P.J.A., C.E.-N., B.J.P., M.H., D.B.L.), Veterinary Pathobiology (E.M.C., B.M.J.), Child Health (D.B.L.), and Animal Sciences (D.B.L.), MU Center for Phytonutrient and Phytochemical Studies (P.J.A., C.E.-N., E.M.C., B.M.J., B.J.P., D.B.L.), University of Missouri, Columbia, Missouri 65211

Address all correspondence and requests for reprints to: Dennis B. Lubahn, Ph.D., Room 110A, Animal Sciences Research Center, 920 East Campus Drive, University of Missouri, Columbia, Missouri 65211. E-mail: lubahnd{at}missouri.edu.

	Abstract

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Understanding estrogen’s regulation of phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers. Phase II enzymes such as glutathione-S-transferases (GST) and quinone reductase protect against developing chemically induced cancers by metabolizing reactive oxygen species. Phase II enzyme expression is regulated by a cis-acting DNA sequence, the antioxidant response element (ARE). It has previously been reported that several antiestrogens, but not 17ß-estradiol, could regulate ARE-mediated gene transcription. Our goal was to determine whether additional estrogenic compounds could regulate ARE-mediated gene expression both in vitro and in vivo. We discovered that physiological concentrations (10 nM) of 17ß-estradiol repressed GST Ya ARE-dependent gene expression in vitro. Treatment with other endogenous and anti-, xeno-, and phytoestrogens showed that estrogen receptor/ARE signaling is ligand, receptor subtype, and cell type specific. Additionally, GST and quinone reductase activities were significantly lowered in a dose-dependent manner after 17ß-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17ß-estradiol, and other estrogens, down-regulate phase II enzyme activities. We propose estrogen-mediated repression of phase II enzyme activities may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in some estrogen-responsive tissues.

	Introduction

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THE EXPOSURE TO cytotoxic chemicals capable of causing oxidative stress can greatly impact the development of many diseases including cancer. The metabolism of many cytotoxic chemicals has proven to be effective in modulating the degree of oxidative damage incurred on exposure. The metabolism of many chemicals involves two distinct phases, phase I and phase II. In this report, we investigate the effects of estrogen exposure on the regulation phase II enzyme expression.

Phase I enzymes, which are members of the cytochrome P450 superfamily, metabolically oxidize many xenochemicals thereby forming electrophilic intermediates (1, 2, 3). Because of the ability to induce DNA damage and mutations, the electrophilic intermediates formed by phase I metabolism are responsible for the carcinogenic activity of many chemicals including dimethylbenz[a]anthracene and benzo(a)pyrene (4). Phase II detoxification enzymes, which are responsible for metabolizing the products of phase I metabolic reactions, degrade these reactive intermediates by conjugation or reduction reactions, thereby protecting cells from oxidative DNA damage. The most common conjugation reactions are catalyzed by glutathione-S-transferases (GST) (5), uridine 5' diphosphoglucuronosyl transferases (6) and sulfotransferases (7), whereas the reduction reactions are catalyzed by epoxide hydrolase (8) and quinone reductase (QR) (9).

It has been demonstrated that chemical carcinogenesis can be inhibited by the consumption of electrophilic agents, commonly referred to as chemoprotective agents (10). This process, referred to as the electrophilic counter response (11), has been attributed to the ability of the electrophilic agents to enhance the metabolism of the carcinogen by inducing phase II drug metabolism genes, thereby combating oxidative stress and DNA damage (12, 13, 14, 15). Chemoprotective agents can increase phase II gene expression through a cis-acting DNA element referred to as the antioxidant/electrophile response element (ARE) in the promoter of target genes (16, 17). The primary pathway known to induce phase II gene expression through the ARE is through activation of the bzip transcription factor Nrf2 (18).

Estrogen exposure is an important risk factor for the induction of breast, ovarian, and uterine cancers. However, the mechanisms that underlie cancer formation remain elusive. There are currently several mechanisms used to explain the cancer promoting actions of estrogens. One mechanism proposed is that cancer formation may result from excessive estrogen exposure in tissues in which estrogen acts as a potent mitogenic agent stimulating cellular growth and differentiation. This mitogenic activity occurs through the regulation of estrogen responsive target genes such as cyclin D1, c-myc, cathepsin D, and TGF, which stimulate cell proliferation (19). In the classical estrogen-signaling pathway, the receptor-ligand complex can bind directly to estrogen response elements (EREs) in the promoter of target genes and regulate gene transcription. Additionally, estrogen receptors (ERs) regulate gene transcription by binding to other transcription factors, which are already bound to DNA. For example, ER is known to regulate activator protein-1 (AP-1)-mediated (20) gene expression through this tethering mechanism.

Another mechanism proposed to contribute to estrogen-induced cancers is the metabolism of 17ß-estradiol (E2) to 4-hydroxyestradiol (4OHE2) (21). After formation, 4OHE2 undergoes metabolic redox cycling generating mutagenic hydroxy radicals as well as quinone derivatives of 4OHE2, which are capable of forming DNA adducts (22).

It has recently been shown that anti-estrogens, but not E2, regulate expression of the phase II enzyme QR through an ARE mediated pathway (23, 24, 25). Given that the activities of phase II enzymes activity alter cancer susceptibility through the metabolism of intracellular reactive oxygen species (ROS) and that estrogen exposure induces cancer formation possibly through the production of ROS, we wanted to further characterize estrogenic regulation of the ARE. In vitro ER regulation of a mouse GST Ya reporter gene by ER and ERß was determined in two cell lines in the presence of various endogenous estrogenic agonists, antagonists, xenoestrogens, and phytoestrogens.

Our results showed that ER/ARE regulation was tissue specific, ligand specific, receptor and subtype specific and could be repressed by low levels of E2. To determine in vivo effects, the activities of GST and QR were measured in mice after estrogen exposure. Our results demonstrate that E2 exposure causes a decrease in GST and QR activities in the uterus. The ability of estrogens to down-regulate protective phase II detoxification enzymes, thereby exposing cells to increased oxidative DNA damage, presents a novel mechanism by which estrogens could promote cancer formation. The implications of estrogen regulation of ARE-mediated gene expression with regard to estrogen-induced cancer are discussed.

	Materials and Methods

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Chemicals
All chemicals and hormones were obtained from Sigma Chemical Co. (St. Louis, MO) unless otherwise stated. ICI 182 780 was obtained from TOCRIS (Ellisville, MO). Dr. William Kelce generously provided HPTE.

Plasmids
Complementary DNA sequences encoding the human ER, generously provided by Dr. Stuart Alder, were subcloned into pcDNAZeo3.1(+) (Invitrogen, Carlsbad, CA). cDNA sequences encoding human ERß were amplified by RT-PCR using primers (sense 5' CTTGCA AGGTGTTTTCTCAGCTG 3'; antisense 5' GTTCACCTCAGGGCCAG GCGTCA 3') from human bladder total RNA (Invitrogen) and subcloned into pcDNA Zeo 3.1(+). The sequences of all constructs were confirmed by automated sequencing (DNA core, University of Missouri-Columbia).

The mouse GST Ya ARE luciferase reporter used was kindly provided by W. Fahl (McArdle Laboratory for Cancer Research, University of Wisconsin) as previously described (17).

Cell culture and transfection experiments
ER-negative MCF-7 cells (C4–12-5) were maintained in complete medium consisting of phenol red-free Eagle’s MEM supplemented with insulin (6 ng/ml), HEPES (10 mM), and 5% charcoal-stripped calf serum (Life Technologies, Inc., Gaithersburg, MD) (26). COS 1 cells were maintained in DMEM (Mediatech, Inc., Herndon, VA) containing 10% fetal bovine serum (Life Technologies, Inc.). For transient transfection experiments, cells were plated in 24-well plates and transiently transfected using Plus and lipofectamine reagents (Invitrogen). Cells were transfected with 50 ng ER or ERß plasmids, 400 ng ARE reporter vector. Transfection experiments were normalized to cotransfected renilla control vectors. The SV-40 renilla vector (Promega, Madison, WI) was used in COS 1 cells; the PHRG-TK renilla vector was used in C4–12-5 cells. Luciferase assays were done using dual luciferase assay kit (Promega). Statistical significance was determined using a t test.

Animals and treatment
Adult virgin female C57BL/6J mice were maintained in the same room but in different cages than male animals, in accordance with the University of Missouri Animal Care and Use Committee Guidelines. All experimental procedures were approved by the University of Missouri Animal Care and Use Committee guidelines. The mice were fed Purina Laboratory mouse chow soy-based formulation 5008 (Ralston-Purina Co., St. Louis, MO) until weaning and then fed soy-based formulation 5001 (Ralston-Purina Co.). Mice were provided water ad libitum and exposed to a daily 12-h light,12-h dark cycle.

Mice were ovariectomized and allowed to recover for 10 d before treatment was started. During this time they were fed a phytoestrogen-free, casein-based diet (27). Mice then were either implanted with an E2 pellet (Innovative Research, Sarasota, FL) or subjected to a sham operation and treatment continued for 14 d. For tissue distribution studies, mice were implanted with 0.25 mg E2/21-d release pellets. For the dose-response studies, pellet sizes were 0.001, 0.01, 0.025, 0.05, 0.1, and 0.18 mg E2/21-d release pellets. After 14 d of treatment, mice were killed by CO₂ asphyxiation and tissues removed and stored at -80 C until use. RIA was used to measure E2 levels in the blood as previously reported (28). Blood levels of E2 in mice implanted with 0.25-mg pellets were measured as 800 pg/ml. E2 levels in sham-operated mice and mice implanted with 0.001-, 0.01-, 0.025-, 0.05-, 0.1-, and 0.18-mg pellets were measured to be 4.6, 6.1, 71.3, 86.6, 159.5, 430.9, and 241.5 pg/m, respectively.

Cytosol preparation
For tissue distribution studies, mouse tissue high-speed cytosols/lysates were prepared by differential centrifugation using pooled tissue samples (n = 5 per mouse treatment). Tissues were homogenized in TEG buffer (10 mM Tris-HCl, 1.5 mM EDTA, 10% glycerol, 3 mM sodium azide, pH 7.4) on ice, employing a Tissue Tearor (Biospec Products Inc., Racine, WI). The homogenized solution was centrifuged at 10,000 x g for 15 min at 4 C, and the resulting supernatant was then centrifuged at 100,000 x g for 2 h at 4 C. Cytosol was stored at -80 C until use. For the dose-response experiment, two animals per treatment were used. The uterus was homogenized in TEG buffer as above and then centrifuged at 10,000 x g at 4 C for 15 min in a microcentrifuge. The resulting supernatant was isolated and stored at -80 C until use.

GST and QR assays
Total GST and nicotinamide adenine dinucleotide phosphate reduced QR activities were measured in high-speed tissue cytosol as reported previously (23, 29). Briefly, for GST determination, reactions contained 1–60 µg cytosolic protein depending on tissue type, 2.5 mM glutathione, and 1 mM chlorodinitrobenzene (CDNB) in a total volume of 1 ml in 0.1 M potassium phosphate buffer and 1 mM EDTA (pH 6.5). The change in absorbance was monitored at 340 nM in a dual-beam spectrophotometer using a complete assay mixture without cytosolic protein as a blank. The change in absorbance at 340 nM was used to determine GST activity for each tissue type, and numbers were normalized to protein added. For QR assays, 10 µM menadione, 70 µM cytochrome C, and cytosolic protein was mixed in 0.1 M potassium phosphate buffer, pH 7.5. Nicotinamide adenine dinucleotide phosphate reduced was added at a final concentration of 0.5 mM, and the change in absorbance at 550 nM was measured to determine QR rates and the results were normalized to protein added. Protein concentrations were determined using BCA protein reagent (Pierce Chemical, Rockford, IL) and the BSA protein standard set (Sigma) as standards.

For each sample, triplicate measures of each enzyme activity were performed. For tissue distribution studies, treatment experiments were repeated for a total of two times with five animals in each treatment group. For the dose-response curve, two animals were used for each pellet size and the experiment was performed once. For each enzyme assay, the nontreated (control) group results were set at 100%, and the enzyme activity for the treated groups was expressed as a percent of the control animals. The graphs listed mean with SD as the error bars. For tissue distribution experiments, statistical significance was determined using a t test. For the uterine dose-response curve, linear regression analysis was used to calculate a confidence interval of P < 0.05 for the GST activities of the untreated animals. Then each sample point on the dose-response curve was then compared with the calculated confidence interval of the untreated animals. All points on the dose-response curve that did not overlap the calculated confidence interval were determined to be statistically significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Note Added in Proof References

 
Activation of an ARE by estrogens and phytoestrogens in COS I cells
Comparison of the DNA sequences from three different EREs is shown in Fig. 1 along with the ARE from the GST Ya gene. Although the sequence requirements of an AP-1 site, ERE, and ARE are distinct due to the high sequence similarity, it is possible to have one or more of these EREs overlapping in an ARE. To study estrogenic regulation of an ARE alone, a construct containing the GST Ya gene promoter-controlling expression of the luciferase reporter gene was used in transient transfection experiments. The GST Ya ARE lacks an AP-1 motif and an ERE, which are present in the ARE of other genes such as NADP(H) QR (24).

View larger version (10K): [in this window] [in a new window]   FIG. 1. Sequence comparison of several response elements known to be estrogen responsive. The classical ERE, AP-1 sites, and ARE core sequence are listed. N, Any four nucleotides. Due to sequence homology, it is possible to have several of these EREs that overlap.

View larger version (18K): [in this window] [in a new window]   FIG. 2. Effect of various estrogens on expression of an ARE reporter gene in COS I cells. Cells were treated for 24 h with either 10 nm E2, 10 nM 4-OHE2 or 1 µM of the other estrogens. Cells were then lysed and analyzed for luciferase activity. Asterisks, P < 0.05.

View larger version (19K): [in this window] [in a new window]   FIG. 3. Effect of various estrogens on expression of an ARE reporter gene in ER-negative C4-12-5 cells. Cells were treated for 24 h with 10 nM E2, 10 nM 4-OHE2, or 1 µM of the other estrogens. Cells were then lysed and analyzed for luciferase activity. Asterisks, P < 0.05.

View larger version (28K): [in this window] [in a new window]   FIG. 4. Estrogenic regulation of total GST and QR activities in mouse tissues. Animals were treated with 0.25 mg/21-d release estrogen pellets for 14 d at which time mice were killed and tissues dissected. A, GST levels were quantified by CDNB conjugation. B, QR levels were quantified using menadione as a substrate. Asterisks, P < 0.05.

Because the dose administered to the wild-type animals was supraphysiological, a dose-response curve was performed to determine what levels of E2 were needed to elicit the decrease in ARE-mediated gene expression. E2 serum concentrations of less than 100 pg/ml were capable of repressing ARE-mediated gene transcription (Fig. 5).

View larger version (14K): [in this window] [in a new window]   FIG. 5. Effect of varying E2 doses on GST activity in mouse uterus. Animals were treated with varying sizes of 21-d release E2 pellets for 14 d at which time mice were killed and tissues dissected. GST levels were quantified by CDNB conjugation. E2 concentrations as measured in blood by RIA as described in Materials and Methods are plotted on the x-axis. Each dose point represents duplicate animals. Asterisks, P < 0.05.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Note Added in Proof References

To determine whether E2 treatment would alter GST or QR activities in vivo, mice were either implanted with E2 pellets or sham implanted, and total GST and QR levels were measured. Multiple isoforms of GSTs exist that are detected with the CDNB assay (30), but this assay was used instead of a more specific mRNA assay to determine what affect estrogen treatment would have on total GST activity. This was done because total GST activity would give a better indication of susceptibility to oxidative stress. If E2 treatment would down-regulate just one particular GST isoform, the change in total GST activity may not significantly alter the ability to protect against oxidative stress. Because the CDNB assay is not specific for GST Ya, we then decided to assay for QR to confirm our results with an independent ARE-regulated enzyme. QR was chosen because it is ARE regulated and the assay we used to detect its activity is specific for this enzyme (23, 24).

In most tissues, GST and QR activities were not significantly altered despite the presence of ERs in many of these tissues (31). In the uterus, however, estrogen treatment resulted in a marked decrease in ARE-dependent, phase II enzyme activities. The dose-response curve showed that E2 concentrations of less than 100 pg/ml were sufficient to decrease GST activity. Serum E2 concentrations reach 200 pg/ml in some mouse strains (32) and 500 pg/ml in humans (33) at various stages of the menstrual cycle, indicating that the concentrations of E2 necessary to regulate ARE-mediated gene expression in vivo occur under normal physiological conditions.

The effect that repressing phase II detoxification enzyme activities has on the development of chemically induced cancers has recently been studied by creating mice deficient of the transcription factor NRF2 (34). NRF2 is the primary transcription factor responsible for the binding to the ARE in the promoter of phase II genes and inducing their expression. NRF2-deficient mice express lower levels of the phase II enzyme activities of GST and QR. NRF2-deficient animals were more susceptible to chemically induced cancer because of the decreased phase II enzyme activities (35). This work illustrates that repression of phase II enzyme activities leads to increased cancer susceptibility.

The data presented here might help explain why increased estrogen exposure is a known risk factor for the induction of uterine cancer. Uterine exposure to E2 decreases phase II enzyme activity through an ARE mediated pathway, in effect mimicking the situation observed in NRF2 knockout animals. Decreased phase II enzyme activity would slow the metabolism of ROS generated by either endogenous sources such as 4OHE2 as well as exogenous sources such as environmental chemicals. This alteration in ROS metabolism would then result in increased oxidative DNA damage, which would eventually lead to the development of cancer. This alteration in carcinogen metabolism through ARE-mediated gene regulation represents a novel mechanism to help explain why increased estrogen exposure is a known risk factor for the induction of certain types of cancers.

It has recently been reported that treatment of physiological concentrations of E2 can induce oxidative DNA damage in breast cancer cells (36). In this study by Bianco et al. (36), E2 was metabolized to the catechol estrogen 4OHE2, which then directly damaged DNA through ROS generation. We propose an additional second, genomic pathway by which E2 exposure can promote DNA damage by working through the ERs to repress enzymes that protect against oxidative stress. Although the genomic and direct mechanisms that E2 could use to promote DNA damage are distinct, these pathways also overlap. By repressing QR through an ARE-mediated process, E2 exposure could inhibit the metabolism and clearance of 4OHE2. By inhibiting the metabolism of 4OHE2, this compound could then induce increased amounts of DNA damage.

Due to the potential importance of ARE signaling with regard to cancer, it is important to carefully define which ligands act through this pathway as well as characterize cell-specific and tissue-specific responses. In COS I cells, we identified several differences between ER- and ERß-mediated gene transcription, indicating ER/ARE signaling is receptor subtype specific. Specifically, tam, 4OH-tam, methoxychlor, and its metabolite HPTE all repressed ARE-mediated gene transcription through ER in COS I cells. In the presence of ERß, however, tam, 4OH-tam, and methoxychlor induced ARE-mediated transcription. Therefore, in the presence of certain estrogens, whether ARE-mediated gene expression is induced or repressed is dependent on which ER is present. Additionally, the compounds tam, 4OH-tam, methoxychlor, and HPTE also showed cell type differences by generally increasing ARE-mediated gene transcription in C4-12-5 breast cancer cells but repressing transcription through ER in COS I cells. The induction transcription by ICI at the ARE is similar to what is observed for other antiestrogens at other nonclassical estrogen-regulated response elements. Both ER and ERß have been shown to induce transcription at an AP-1 site in the presence of the antiestrogen ICI 164,384 (20). At promoter-specific transcription factor-1 sites, ICI was able to stimulate gene transcription in a cell-specific and a receptor subtype fashion (37).

The cell type selectivity and differing responses by ER and ERß to the same ligands at an ARE reveals additional control mechanisms for estrogen regulation of ARE-mediated gene expression. Additionally, the ability of tam and 4OH-tam to activate ARE in breast cancer cells while repressing in COS 1 cells could partially explain the selective ER modulator effect of these estrogens. Specifically, Montano and Katzenellenbogen (23) hypothesized that the ability of tam and 4OH-tam to activate ARE-mediated gene expression in breast cancer cells could explain why tam is an effective breast cancer therapeutic. However, the ability of tam and 4OH-tam to repress ARE-mediated gene transcription through ER in another tissue could help explain why long-term tam therapy is associated with an increased risk of uterine cancer (38). Determining the effects of tam and 4OH-tam exposure on ARE mediated gene expression in vivo and in uterine cell lines is currently being investigated.

The inability of E2 to alter phase II enzyme activity in mouse mammary tissue observed in the present report mimics what has been reported previously using breast cancer cell lines (23, 24) and is curious given that estrogen exposure is a known risk factor for the induction of breast cancer. This observation could have several alternate explanations. One explanation is that E2 regulation of phase II enzyme activities in breast occurs only in certain cell types. In this experiment whole mammary tissue was used instead of specific cell types. Alternatively, E2 treatment could have failed to regulate ARE-mediated gene expression in the mammary because this tissue is not fully developed in virgin animals. Another explanation is that the regulation of phase II enzyme activities by E2 does not contribute to the formation of breast cancer.

The result of the ability of low E2 concentrations to repress ARE-mediated gene transcription in this report differs with previously reported data in which 10 nM estradiol treatment was unable to alter the expression of an ARE-driven reporter construct (23, 24). This difference could be explained by either cell type or promoter specific ARE activities. Previous experiments were done primarily using the QR ARE in MCF-7 cells, whereas we used the GST A1 ARE in COS I cells. To distinguish between the two possibilities, we determined the effect of various estrogens on signaling through the GST Ya ARE in an alternate cell line, the ER-negative breast cell line, C4-12-5, which was derived from the MCF-7 cell line. Signaling through an ARE was markedly different in C4-12-5 cells, compared with the signaling in COS 1 cells. The data obtained in this study in MCF-7 derived cells agree well with previously published results (23, 24), confirming that estrogen action through the ARE is highly dependent on cellular environment.

In conclusion, the results presented here show that E2 exposure decreases phase II enzyme activity in the mouse uterus, and this is likely to occur through an ARE-mediated pathway. Decreased phase II enzyme activity on exposure to estrogens could result in increased cellular oxidative stress because of slower metabolism of ROS. The elevated oxidative stress on estrogen exposure would lead to increased DNA damage and mutations, which would eventually contribute to the development of cancer. The alteration in carcinogen metabolism through ARE-mediated gene regulation potentially represents a novel mechanism to help explain why increased estrogen exposure is a known risk factor for the induction of certain types of cancers.

	Note Added in Proof

Top Abstract Introduction Materials and Methods Results Discussion Note Added in Proof References

 
After this paper was submitted, a related paper was published that examined ARE-mediated responses to estrogens (39).

	Acknowledgments

 
The authors are thankful to Dr. William Lamberson for helping with statistical analysis, Dr. Xiaohui Yuan for construction of the ERß expression plasmid, and Leslie Newton for maintenance of the animals used for the experiments reported in this manuscript.

	Footnotes

 
Present address for B.J.P.: Department of Pharmacology and Therapeutics, Roswell Cancer Institute, Buffalo, New York 14262.

This work was supported by a NIH predoctoral fellowship (to P.J.A.), NIH Grant ES 11721 (to M.H.), Army concept proposal award DAMD170110567, and National Institute of Environmental Health Sciences Grants P01 ES 10535 and ES 08272 (to D.B.L.).

Abbreviations: AP-1, Activator protein-1; ARE, antioxidant response element; CDNB, chlorodinitrobenzene; E2, 17ß-estradiol; ER, estrogen receptor; ERE, estrogen response element; GST, glutathione-S-transferases; ICI, ICI 182,780; 4OHE2, 4-hydroxyestradiol; 4OH-tam, 4-hydroxytamoxifen; QR, quinone reductase; ROS, reactive oxygen species; tam, tamoxifen.

Received June 30, 2003.

Accepted for publication September 26, 2003.

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