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Activity by ERß in the Uterus
Departments of Molecular and Integrative Physiology (J.F., J.M.D., B.S.K.), Cell and Structural Biology (D.H.B., B.S.K.), and Veterinary Medicine (R.H.), University of Illinois, Urbana, Illinois 61801; and Department of Obstetrics and Gynecology (A.F.P.), Pituitary Hormone Center, Harbor-University of California, Los Angeles Medical Center, Torrance, California 90509
Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, University of Illinois, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}life.uiuc.edu
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Abstract |
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and ERß, and their potential comodulatory effects on gene expression and uterine growth using recently developed ER subtype-selective agonist ligands. The use of ER subtype-selective ligands provides an alternative, complementary approach to the use of receptor knockout mice. Administration of the ER-selective ligand propyl pyrazole triol (PPT) to immature mice resulted in a significant increase in uterine weight, as well as bromodeoxyuridine incorporation and proliferating cell nuclear antigen expression in luminal epithelial cells. PPT also increased complement component 3, lactoferrin, and glucose-6-phosphate dehydrogenase (G6PDH), and decreased androgen receptor (AR) and progesterone receptor (PR) mRNA levels in uterine tissue, as did estradiol (E2). However, when compared with E2, PPT was less effective in stimulating uterine weight, complement component 3, and G6PDH expression but was as effective as E2 in regulating lactoferrin, AR, and PR expression. In contrast to the action of the ER agonist PPT, the ERß agonist diarylpropionitrile (DPN) did not increase uterine weight or luminal epithelial cell proliferation at a dose that reduced G6PDH and elicited a decrease in PR and AR mRNA and protein expression. Interestingly, DPN reduced the uterine weight stimulation by PPT, and enhanced the effect of PPT in decreasing uterine PR and AR mRNA. These findings with ER subtype-selective ligands indicate that ER is the major regulator of estrogen function in the uterus, but that ERß does exert effects on some uterine markers of estrogen action. In addition, ERß can modulate ER activity in a response-specific and dose-dependent manner. |
Introduction |
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and ERß (1, 2, 3, 4, 5, 6), the specific roles of ER and ERß in mediating estrogen action in the uterus are only partially understood. What is currently known derives almost exclusively from ER knockout mouse models (ERKO and ßERKO). Based on these models, it appears that ER plays the predominant role in mediating the effects of E2 on the uterus. In the ERKO mouse, E2 failed to elicit an increase in uterine weight, uterine cell proliferation, water imbibition, and hyperemia, all of which are known markers of E2 action in the uterus (4). Interestingly, E2 did increase progesterone receptor (PR) expression specifically in uterine stromal cells of the ERKO mouse, suggesting that ERß may be capable of mediating some of E2 effects in the uterus (7). In contrast, initial reports on the ßERKO mouse suggested that their subfertility was due to an ovarian defect; the uterus in these animals appeared to respond fully to E2 with an increase in uterine weight and water imbibition and was capable of carrying fetuses to full gestation (8). However, it has recently been suggested that the subfertility of ßERKO mice may be the result of both ovarian and uterine defects (6). This would be supported by the findings of several groups showing the presence of ERß protein in all cell types of the uterus (7, 9). Treatment of immature ßERKO mice with E2 resulted in a uterine hyperresponsiveness to E2 compared with wild-type animals, suggesting that ERß may play a role in the uterus as a negative modulator of ER activity (9).
Although very valuable, these knockout mouse models have some limitations that can complicate the interpretation of findings. For example, the absence of one receptor or the other may result in unrecognized differences in development or potential compensatory mechanisms, such as the increased number of glands in the ßERKO uterus, which may mask the true physiological roles of ER and ERß (9). It is also possible that the altered hormonal profiles in these mice can influence their responses to E2. In fact, circulating E2 levels in the ERKO mouse are ten times higher than in the wild-type mouse (10). Furthermore, splice variants of ER have been identified in the original ERKO mice, which appear to be functional in some tissues examined (10, 11, 12, 13, 14).
As a complementary, alternative approach, we have in this study used two recently developed, novel ER subtype-selective ligands to investigate the independent and possible comodulatory actions of ER and ERß in the uterus of normal wild-type mice. The compound propyl pyrazole triol (PPT) is a potent ER agonist, which does not activate ERß. This results from the fact that it binds with high affinity and 400-fold preference to ER, and demonstrates almost no binding to ERß (15, 16). In contrast, the compound diarylpropionitrile (DPN) is a potency-selective agonist for ERß with a more than 70-fold higher binding affinity for ERß than ER (17). In this study, immature female mice were treated with these compounds, either separately or in combination, and their effects on uterine cell proliferation and gene expression were examined. Herein, we report our findings that while the majority of E2 actions in the uterus are mediated by ER, ERß does play a role in modulating ER effectiveness in a response-specific and ligand dose-dependent manner.
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Materials and Methods |
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selective ligand PPT (from 20–500 µg/animal·d), the ERß-selective ligand DPN (10–250 µg/animal·d), or a combination of PPT and DPN for 1 or 4 d. Injections consisted of compound dissolved in DMSO then diluted 1:10 in corn oil. As 1 d findings were similar, but were less definitive because the response magnitude was generally lower, we present only the 4 d data. At 22 h following the final injection, bromodeoxyuridine (BrdU) (60 mg/kg in PBS; Sigma, St. Louis, MO) was administered ip. Two hours later, animals were killed by CO2 sedation and cervical dislocation. Uteri were removed, washed in cold PBS, and weighed after removal of associated fat and expressing any luminal fluid. One uterine horn was then snap-frozen in liquid nitrogen for RNA isolation and the other was fixed for immunocytochemistry. The experiment was repeated three times with two to five animals per group per replicate.
RNA isolation and real-time PCR
Total RNA was isolated from whole uterine tissue using Trizol Reagent (Invitrogen, Carlsbad, CA) according to the manufacturer’s instruction. One microgram of total RNA was reverse transcribed in a total volume of 20 µl using 200 U reverse transcriptase, 50 pmol random hexamer, and 1 mM deoxynucleotide triphosphate (New England Biolabs, Inc., Beverly, MA). The resulting cDNA was then diluted to a total volume of 100 µl with sterile H2O. Each real-time PCR consisted of 1 µl of diluted reverse transcriptase product, 1x SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA), and 50 nM of forward and reverse primer. Reactions were carried out in an ABI Prism 7700 Sequence Detection System (Applied Biosystems) for 40 cycles (95 C for 15 sec, 60 C for 1 min) following an initial 10 min incubation at 95 C. Primers used for real-time PCR are listed in Table 1
. The fold change in expression was calculated using the 
cycle threshold method with the ribosomal protein 36B4 mRNA as an internal control.
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Serum prolactin (PRL) assay
Trunk blood was collected following cardiac puncture at the time of the animals were killed. Serum was collected following centrifugation (14,000 rpm, 4 C, 10 min) and stored at -80 C. RIA for mouse PRL was carried out using reagents of the National Hormone and Peptide Program.
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Results |
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and ERß in estrogen-induced uterine growth were examined in immature female mice injected with the ER or the ERß subtype-selective ligand. PPT, the ER ligand, induced a dose-dependent increase in uterine weight, whereas DPN, the ERß selective ligand, had no effect at any of the doses tested (Fig. 1). It is of note that higher doses of PPT than E2 are required to elicit uterine weight gain, as noted previously in studies in rats (18).
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activity, we examined whether administration of DPN had any effect on the stimulation by PPT. For this, we used two doses of PPT (100 and 500 µg), together with one dose of DPN (100 µg). With the highest dose of PPT, DPN had no modulatory effect on PPT activity. However, with the lower dose of PPT (100 µg), DPN caused a statistically significant, 30% reduction in the stimulation of uterine weight by PPT (Fig. 1
). These data suggest that ER plays the major role in estrogen-induced uterine weight gain but that ERß is capable of moderating ER signaling in a dose-dependent manner.
To examine whether the changes observed in uterine weight correlated with epithelial cell proliferation, we used two different indices of proliferation, BrdU incorporation (as an indicator of DNA synthesis) and PCNA expression (as an indicator of proliferation-related gene expression). These two were examined in luminal epithelial cells by immunocytochemistry. Both E2 and PPT induced a significant increase in BrdU incorporation and PCNA expression. By contrast, DPN had no effect on either marker when administered alone or in combination with PPT (Fig. 2). These data imply that the reduction observed in uterine weight by DPN in combination with PPT is not associated with a decrease in luminal epithelial cell proliferation. Because luminal epithelial cells represent only a small proportion of the overall uterine cell population, the uterine weight effects observed may rather reflect changes in other uterine cell components (stroma and/or myometrium) or in immune cell infiltration.
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). PPT, at either dose, also stimulated C3 mRNA but was only one-third as effective as E2. Lactoferrin mRNA levels, on the other hand, showed a dose-dependent increase in response to PPT, with the highest dose of PPT being as stimulatory as E2 (Fig. 3B). G6PDH mRNA expression was stimulated 3-fold by E2, whereas PPT had no effect at the lower dose and was only 25% as effective as E2 at the higher dose. In contrast to PPT, DPN had no stimulatory effect on any of these three genes. When administered along with PPT, DPN had no effect on the C3 or lactoferrin gene expression response to PPT. On the other hand, DPN alone significantly inhibited G6PDH expression, and this inhibition was reversed by coadministration of PPT (Fig. 3C).
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). For both of these genes, DPN also exhibited a weak suppressive effect when administered alone. Furthermore, DPN appeared to work cooperatively with PPT, with DPN enhancing the suppression of PR mRNA by the lower dose of PPT, and DPN enhancing the suppression of AR mRNA expression by the higher dose of PPT.
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and 6). PR protein was strongly decreased by E2 in the luminal epithelium, as previously demonstrated (21, 22). As seen with E2, PPT down-regulated PR protein at both doses examined (Fig. 5, C and D). This effect was restricted to the luminal epithelial cells and was not observed in the stroma. Consistent with only modest effects on PR mRNA, DPN had little discernable effect on PR protein levels based on IHC (Fig. 5G). Because PPT alone suppressed PR protein to very low levels in the luminal epithelium, an additive effect of DPN and PPT, as observed at the mRNA level, could not be detected by IHC (Fig. 5, E and F). These results suggest that ER is the predominant regulator of PR levels in the uterus.
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, B–D). DPN alone had only a modest effect on AR protein with a slight but consistent decrease in staining intensity of the stromal cells (Fig. 6G). As was the case with PR, additive effects of PPT and DPN were difficult to detect due to the strong suppressive effect of PPT alone but the number of cells staining positive for AR, particularly in the luminal epithelial cells, was decreased by the combination of PPT and DPN (Fig. 6, E and F). Hence, AR expression is predominantly regulated by ER but can be modulated by ERß.
Effects of PPT and DPN on serum PRL
It is well established that both synthesis and secretion of pituitary PRL are stimulated by E2, so we were interested to examine the effects of PPT and DPN on serum PRL levels. Like E2, PPT induced a significant increase in serum PRL, whereas DPN alone had no effect (Fig. 7). The combination of PPT with DPN further increased serum PRL to levels equivalent to that seen with E2. Thus, our data suggest that the effects of estrogen on the levels of serum PRL are largely ER-mediated, consistent with findings in ER knockout animals (23).
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Discussion |
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and ERß-selective ligands can be useful in beginning to elucidate the respective roles of ER and ERß in estrogen functions in target tissues. Our findings in intact animals provide evidence that the ERß ligand, DPN, evokes distinct effects, sometimes different from those evoked through ER alone (by PPT), in addition to modulating some actions mediated by ER. The effects of ER-selective ligand, PPT, were overall of greater magnitude, with PPT having marked estrogenic effects on uterine weight gain, luminal epithelial cell proliferation, and complement C3, lactoferrin, G6PDH, PR, and AR expression. The ERß-selective ligand, DPN, appeared to predominantly play a modulatory role in uterine function. DPN reduced PPT-induced uterine weight gain and inhibited G6PDH gene expression, had no effect on C3 or lactoferrin expression, but had an additive effect with PPT on PR and AR mRNA down-regulation and enhanced the stimulatory effect of PPT on serum PRL levels. Thus, based on these results using subtype-selective ligands, ERß modulation of ER activity appears to be response specific.
ER subtype-selective ligands exhibit gene-specific and ligand dose-dependent regulatory effects
Of note, our studies in intact animals indicate not only gene-specific but also dose-dependent effects of the ERß agonist on ER mediation of estrogenic responses. Hence, the antiuterotropic and suppressive effect of DPN on PR mRNA was observed with the lower dose of PPT, whereas the effect of DPN on AR mRNA down-regulation was significant only when given with the higher dose of PPT. This may be explained by the complex cross-regulation of these two ERs by estrogen ligand and by the presence or absence of the other receptor subtype in different cell types (4, 6, 7, 8, 10, 11, 14), as well as by the ability of these receptors to act on genes as homodimers as well as heterodimers (24, 25). Possible differences in the gene promoters and their responsiveness to the different dimer species might underlie the intriguing dose-dependent effects on gene regulation we have observed with our ER- and ERß-selective ligands. It is of interest that Hall and McDonnell (26) observed a related, dose-dependent effect of E2 on the ability of ERß to modulate ER activity on transfected reporter genes, suggesting that the relative level of activity of each receptor may influence how effective ERß is in modulating ER.
Our data confirm that AR is down-regulated by E2 and demonstrate that this down-regulation can be evoked individually via either ER or ERß, with this effect operating more conspicuously through ER. Interestingly, the effects of ER and ERß agonists were additive in eliciting this down-regulation in the uterus. Similarly, studies in rat and mouse ventral prostate have revealed that ERß is involved in regulating the AR content of this tissue (27). Also, ERß agonist reduced the uterine weight increase in response to PPT, an antiproliferative function also implied for this ER subtype based on findings in the uterus and ventral prostate of ERß knockout mice (9, 27). Our findings support the conclusions from ER knockout mice that the primary uterotrophic stimulus is ER but also provide data to support a moderate inhibitory effect of the ERß-selective ligand on uterine growth stimulation by ER, an effect that does not appear to be secondary to ERß-dependent inhibition of epithelial cell proliferation. In this respect, our results appear to differ from those of Weihua et al. (9). We examined BrdU incorporation and PCNA levels in the luminal epithelium, whereas Weihua et al. used Ki67 as the marker. It is possible that ERß might modulate Ki67 in the epithelium without actually affecting cell proliferation because Ki67 is required for proliferation, but cells expressing Ki67 will not necessarily undergo proliferation.
In addition to modulating some of the effects of PPT, DPN alone also affected the levels of uterine PR and AR mRNA. Intriguingly, DPN markedly reduced uterine G6PDH expression, whereas E2 and PPT increased G6PDH, revealing that the effects of ER and ERß may be opposite to one another at some genes. There is already precedence for the opposite regulation of genes by ER and ERß through work of Paech et al. (28) on the activator protein-1-regulated gene, collagenase.
ER ligand effectiveness is dependent on the endpoint assessed
An interesting aspect of our studies was the demonstration that the magnitude of effectiveness of the PPT ligand was very dependent on the endpoint examined. Whereas PPT was as effective as E2 in altering lactoferrin and PR expression, PPT was less effective than E2 in modulating the expression of complement C3, G6PDH, AR, and in stimulating uterine weight gain. This suggests that, although PPT clearly puts ER into an agonist conformation, the conformation induced may not be identical to that of the E2-ER complex. This is consistent with current thinking regarding the tripartite nature of ligand-receptor-coregulator and promoter regulation of receptor activity (29, 30, 31, 32). More direct evidence may become available in the future from x-ray crystallographic structures that would compare the PPT-ER vs. E2-ER receptor complexes and also from further studies comparing the regulation of global gene expression by PPT vs. E2 in various estrogen target cells and tissues.
ER subtype-selective ligands provide insights complementary to those obtained from studies in ER knockout mice
Using ER knockout mice, it has been demonstrated in bone that ERß can stimulate, in the absence of ER, some of the same genes as does ER, whereas ERß almost always reduced the magnitude of gene stimulation by ER when both receptors were present (33). We likewise observed that the ERß agonist, DPN, could stimulate some of the same activities as did ER in the uterus, yet stimulation via ERß was always much weaker compared with that via ER, as observed in bone also by Lindberg et al. (33). However, in our studies, we note that the results of costimulation of gene expression by ER and ERß, using PPT and DPN, varied greatly, depending on the particular response being assessed. Thus, the effect of DPN on PPT-stimulation of the endpoints we examined—uterine weight gain, C3, lactoferrin, G6PDH, AR and PR—was either suppressive, stimulatory or without effect, depending on the particular endpoint examined.
The use of ER-selective ligands to understand the respective biological roles of ER and ERß serves as a valuable alternative, complementary approach to the use of knockout animals. While both approaches have their strengths and limitations (18), it is gratifying to find that by each method ER appears to be the predominant regulator of estrogen function in the uterus. Our studies with these selective ligands highlight the complex manner in which the two ERs work alone and together to regulate a variety of estrogen actions in the uterus. They also illustrate that the manner in which the two ERs interact with one another is dependent both on the specific response parameter or gene target that is being monitored and on the relative activity of the two receptors, as modulated by the dose of ER-subtype specific ligand. These observations, as well as those of others (9, 26, 27), suggest that pharmaceuticals that act as specific ligands for ER and ERß may prove useful clinically for modulating in a controlled fashion the activities of these receptors in normal and cancerous target tissues.
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Acknowledgments |
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Footnotes |
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Abbreviations: BrdU, Bromodeoxyuridine; C3, component 3; DPN, diarylpropionitrile; E2, estradiol; ER, estrogen receptor; ERKO and ßERKO, ER knockout mouse models; G6PDH, glucose-6-phosphate dehydrogenase; PCNA, proliferating cell nuclear antigen; PPT, propyl pyrazole triol; PR, progesterone receptor; PRL, prolactin.
Received December 16, 2002.
Accepted for publication March 28, 2003.
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 V. Krishnan, H. A. Bullock, B. C. Yaden, M. Liu, R. J. Barr, C. Montrose-Rafizadeh, K. Chen, J. A. Dodge, and H. U. Bryant The Nongenotropic Synthetic Ligand 4-Estren-3{alpha}17{beta}-diol Is a High-Affinity Genotropic Androgen Receptor Agonist Mol. Pharmacol., March 1, 2005; 67(3): 744 - 748. [Abstract] [Full Text] [PDF]
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T. D. Lund, T. Rovis, W. C. J. Chung, and R. J. Handa Novel Actions of Estrogen Receptor-{beta} on Anxiety-Related Behaviors Endocrinology, February 1, 2005; 146(2): 797 - 807. [Abstract] [Full Text] [PDF]
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 M. Zaitseva, D. S. Yue, J. A. Katzenellenbogen, P. A. W. Rogers, and C. E. Gargett Estrogen Receptor-{alpha} Agonists Promote Angiogenesis in Human Myometrial Microvascular Endothelial Cells Reproductive Sciences, December 1, 2004; 11(8): 529 - 535. [Abstract] [PDF]
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 H.V.O. Carswell, I.M. Macrae, L. Gallagher, E. Harrop, and K.J. Horsburgh Neuroprotection by a selective estrogen receptor {beta} agonist in a mouse model of global ischemia Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1501 - H1504. [Abstract] [Full Text] [PDF]
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A. Hillisch, O. Peters, D. Kosemund, G. Muller, A. Walter, B. Schneider, G. Reddersen, W. Elger, and K.-H. Fritzemeier Dissecting Physiological Roles of Estrogen Receptor {alpha} and {beta} with Potent Selective Ligands from Structure-Based Design Mol. Endocrinol., July 1, 2004; 18(7): 1599 - 1609. [Abstract] [Full Text] [PDF]
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M. Tena-Sempere, V.M. Navarro, A. Mayen, C. Bellido, and J.E. Sanchez-Criado Regulation of Estrogen Receptor (ER) Isoform Messenger RNA Expression by Different ER Ligands in Female Rat Pituitary Biol Reprod, March 1, 2004; 70(3): 671 - 678. [Abstract] [Full Text] [PDF]
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 S. E. Domino and E. A. Hurd LacZ expression in Fut2-LacZ reporter mice reveals estrogen-regulated endocervical glandular expression during estrous cycle, hormone replacement, and pregnancy Glycobiology, February 1, 2004; 14(2): 169 - 175. [Abstract] [Full Text] [PDF]
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, significantly different from the same dose of PPT alone (P < 0.05).
