Supplementary Figure Legends 1-2 from 15-Deoxy-Δ<sup>12,14</sup>-Prostaglandin J<sub>2</sub> Inhibits Transcriptional Activity of Estrogen Receptor-α via Covalent Modification of DNA-Binding Domain
Han‐Jong KimJoon‐Young KimZhaojing MengLihua WangFa LiuThomas P. ConradsTerrence R. BurkeTimothy D. VeenstraWilliam L. Farrar
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Supplementary Figure Legends 1-2 from 15-Deoxy-Δ<sup>12,14</sup>-Prostaglandin J<sub>2</sub> Inhibits Transcriptional Activity of Estrogen Receptor-α via Covalent Modification of DNA-Binding DomainEstrogen receptor beta
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Abstract Human breast cancer can be divided into a group that contains specific receptor sites for estrogen and a group without such specific estrogen‐binding sites. The presence of specific estrogen receptors in some tumors indicating hormonal dependency has been shown to be of predictive value for endocrine treatment. This would greatly improve therapeutic planning for patients with breast cancer. Tumor tissue from 52 patients was investigated for content of both cytosol estrogen and estrogen receptor. In addition, the total tumor estrogen was also determined in 14 of these tumors. The results of this investigation show two distinct groups: one group containing both estrogen receptor and estrogen and a second group with no receptor but with measurable amount of estrogen. Tumors with estrogen receptors have higher tissue levels of estrogen than tumors without specific estrogen receptor. Even in the absence of estrogen receptor, however, most tumor tissue examined contained a measurable amount of estrogen.
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Estrogen receptor alpha
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Basal (medicine)
Vasomotor
Knockout mouse
Estrogen receptor beta
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The proper level of estrogen-estrogen receptor (ER) signaling is important for the maintenance of epithelial homeostasis in the breast. In a previous study we demonstrated that ATBF1, which has been suggested as a tumor suppressor in breast cancer, inhibited estrogen-mediated cell proliferation by selectively competing with AIB1 for binding to the ER. However, the expression of ATBF1 mRNA was shown to positively correlate with ER in breast cancer specimens. We, therefore, examined whether estrogen regulates ATBF1. We demonstrated that estrogen up-regulated the transcription of ATBF1, which was mediated by the direct binding of the ER onto the ATBF1 promoter, and that a half-estrogen-responsive element in the ATBF1 promoter was essential for ER direct binding. Furthermore, we found that estrogen at lower levels increased, but at higher levels decreased the expression of ATBF1 protein, which involved the degradation of ATBF1 protein by the estrogen-responsive proteasome system. ATBF1 protein levels fluctuate with estrogen levels. Although lower levels of estrogen increased ATBF1 protein expression, ATBF1 still inhibited cell proliferation caused by lower levels of estrogen. These findings not only reveal an autoregulatory feedback loop between ATBF1 and estrogen-ER signaling but also suggest that ATBF1 plays a role in both the maintenance of breast epithelial homeostasis and breast tumorigenesis caused by elevated estrogen levels. The proper level of estrogen-estrogen receptor (ER) signaling is important for the maintenance of epithelial homeostasis in the breast. In a previous study we demonstrated that ATBF1, which has been suggested as a tumor suppressor in breast cancer, inhibited estrogen-mediated cell proliferation by selectively competing with AIB1 for binding to the ER. However, the expression of ATBF1 mRNA was shown to positively correlate with ER in breast cancer specimens. We, therefore, examined whether estrogen regulates ATBF1. We demonstrated that estrogen up-regulated the transcription of ATBF1, which was mediated by the direct binding of the ER onto the ATBF1 promoter, and that a half-estrogen-responsive element in the ATBF1 promoter was essential for ER direct binding. Furthermore, we found that estrogen at lower levels increased, but at higher levels decreased the expression of ATBF1 protein, which involved the degradation of ATBF1 protein by the estrogen-responsive proteasome system. ATBF1 protein levels fluctuate with estrogen levels. Although lower levels of estrogen increased ATBF1 protein expression, ATBF1 still inhibited cell proliferation caused by lower levels of estrogen. These findings not only reveal an autoregulatory feedback loop between ATBF1 and estrogen-ER signaling but also suggest that ATBF1 plays a role in both the maintenance of breast epithelial homeostasis and breast tumorigenesis caused by elevated estrogen levels.
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Estrogen increases the permeability of cultured human cervical epithelia (Gorodeski, GI. Am J Physiol Cell Physiol 275: C888–C899, 1998), and the effect is blocked by the estrogen receptor modulators ICI-182780 and tamoxifen. The objective of the study was to determine involvement of estrogen receptor(s) in mediating the effects on permeability. In cultured human cervical epithelial cells estradiol binds to high-affinity, low-capacity sites, in a specific and saturable manner. Scatchard analysis revealed a single class of binding sites with a dissociation constant of 1.3 nM and binding activity of ∼0.5 pmol/mg DNA. Estradiol increased the density of estrogen-binding sites in a time- and dose-related manner (half time ≈ 4 h, and EC 50 ≈ 1 nM). RT-PCR assays revealed the expression of mRNA for the estrogen receptor α (αER) and estrogen receptor β (βER). Removal of estrogen from the culture medium decreased and treatment with estrogen increased the expression of αER and βER mRNA. In cells not treated with estrogen, ICI-182780 and tamoxifen increased βER mRNA. In cells treated with estrogen, neither ICI-182780 nor tamoxifen had modulated significantly the increase in αER or βER mRNA. The transcription inhibitor actinomycin D blocked the estrogen-induced increase in permeability, and it abrogated the estradiol-induced increase in estrogen binding sites. These results suggest that the estrogen-dependent increase in cervical permeability is mediated by an αER-dependent increase in transcription.
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It is well known that hearing loss is more profound in elderly males than females, regardless of noise exposure. Also, an age-related hearing decline starts much earlier in males, already after the age of 30, while in women, the decline does not start until the age of 50. This coincides with the menopausal transition in most women, when endogenous circulating levels of estrogen in the body are reduced. It is also well known that women with Turner syndrome who are estrogen deficient suffer from early onset of age-related hearing loss already at the age of 35. The overall aim of this thesis was to investigate whether the female sex steroid hormone, estrogen, and its receptors are important in maintaining hearing. The effects of estrogen, estrogen-modulators and anti-estrogen on the estrogen receptors (ERs) in the inner ear were investigated. The expression pattern of estrogen receptors during periods of maximum and minimum hormonal levels such as pregnancy, maturation and development was characterized. The experimental studies were performed using rat and mice animal models. We found that ERs are up and down-regulated in the inner ear depending on the stage of maturation, development and pregnancy. In post-natal rats, ER expression levels appear to be inversely correlated to estrogen levels (e.g. when high levels of estrogen are present, ERs are expressed less in the inner ear). At the time points measured in non-fetal rats, ERα and ERβ expression was highest in three-week-old rats (a known period of fairly low estrogen levels). ER expression reached the lowest levels in pregnant mother rats in late pregnancy (a known period of high estrogen levels). There was no ERα or ERβ identified in the inner ears of the fetuses, at either E8 or E18. No estrogen receptors were found in the cochlea of the developing fetus. These findings suggest that estrogen may have an effect on the cochlea during various stages of life, but seems not to be active during gestation. Treatment of ovariectomized rats with estradiol, tamoxifen, anti-estrogen or vehicle only, did not alter the ER expression pattern significantly in the inner ear. However, a slight down regulation of ERα in the marginal cells of the stria vascularis (involved in ion regulation) was seen in rats that were injected with pure anti-estrogen, suggesting that ERα may be involved in the ion regulation in the cochlea. When investigating estrogen receptor β deficient mice, altered inner ear morphology was found, corresponding to deafness already by one year of age. Also, both ERs are present in the inner ear of wild type (WT) mice at specific localizations suggesting subtype-specific functionality. All together the findings of this thesis strengthen the hypothesis that estrogen has a direct effect on hearing functions and may imply that ERβ is important for the prevention of age-related hearing loss. This study provides a better understanding of the observed positive hearing effects of hormone replacement therapy in patients with low estrogen levels (e.g. postmenopausal women). Several interesting areas for further investigation arose from the work of this thesis including: the protective role of ERβ on hearing along with its possible interactions with ERα; the complex interactions of the reproductive hormones in the inner ear along with their effects on target organ morphology and hearing, and localization and functionality of other reproductive hormone receptors. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals. I. Simonoska R, Stenberg AE, Masironi B, Sahlin L and Hultcrantz M. (2009) Estrogen receptors in the inner ear during different stages of pregnancy and development in the rat. Acta Oto-Laryngologica Feb 13: 1-7. II. Stenberg AE, Simonoska R, Stygar D, Sahlin L and Hultcrantz M. (2003) Effect of estrogen and antiestrogens on the estrogen receptor content in the inner ear of ovariectomized rats. Hearing Research 182: 19-23. III. Simonoska R, Stenberg AE, Duan M, Yakimchuk K, Fridberger A, Sahlin L, Gustafsson JA and Hultcrantz M. (2009) Inner ear pathology and loss of hearing in estrogen receptor beta deficient mice. Journal of Endocrinology. In press.
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The definition of the role of estrogen is a long-date scientific preoccupation. On the basis of the studies carried out in the last twenty years, it is now well accepted that estradiol and its cognate receptors are relevant transcription regulators in reproductive as well as non-reproductive tissues. Models of estrogen (E2) insufficiency (ArKO) and estrogen receptors (ER) dysfunction (ERKOs) have revealed new and unexpected roles of estradiol and its receptors both in female and male. The purpose of this study is to use mouse models of estrogen insufficiency (ArKO) and estrogen receptors dysfunction (ERKOs) to provide a genomic insight in the multiple and complex mechanisms defining estrogenic signaling to help understanding its role in physiological and pathological conditions. In particular the objective was to identify the genes responsive to estrogen signaling according to various possible mechanisms: 1) estrogen and estrogen receptordependent actions; 2) estrogen-independent and estrogen-receptor-dependent actions; 3) estrogen receptor-independent estrogen-dependent actions. To reach this aim, estrogen and estrogen receptors dependent genes expression profiling were performed by microarray analysis in ventral and dorso-lateral prostate and gonadal white adipose tissue from mouse models of impaired estrogen synthesis (ArKO) and ER action (ERKOs). The experimental and biological reproducibility of microarray data was first verified and confirmed providing a correlation between real-time PCR and microarrays in fold change measurements and in expression profiles across all tissues. The results obtained from the analysis of the expression profiles indicate that the classical and the non-genomic actions of estrogen are not to represent the main mechanisms of estrogenic signaling in prostate and adipose tissue. Conversely it appears that the estrogenic signaling in these tissues is exerted via estrogen receptors with an estrogen-independent mechanism of action. ERa appear to be the main mediator of the observed estrogenic effects, with mechanisms that differ according to the specific tissue. In ventral and dorso-lateral prostates, ERa seems to have inhibitory effects on transcription of target genes, supporting the hypothesis of its implication as a tumor suppressor in the prostate gland. Additional studies need to be performed to permit the identification of genes whose regulation can be directly modulated by ERs.
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AIM:To investigate the expression of estrogen receptors in myocardium of ovariectomized female rats.METHODS:One week after bilateral ovariectomy,the female SD rats were divided into 3 groups randomly:OVX +estrogen(0.15 mg/kg,s.c.),OVX + normal sodium and control.After 4 weeks of treatment,the expression of estrogen receptors in the myocardium were evaluated by Western blotting.RESULTS:After ovariectomy,serum estrogen decreased significantly,compared with control[(88±22 vs 403±59)pmol/L,P0.05],the expression of estrogen receptors decreased(P0.05).After estrogen replacement therapy,serum estrogen increased[(3864±105)pmol/L],estrogen upregulated the expression of ERβ receptor(P0.05)and downregulated ERα receptor(P0.05)in myocardium.CONCLUSION:Estrogen replacement modifies the expression of estrogen receptors in myocardium of ovariectomized female rats.
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Understanding of the mechanisms of estrogen action in the brain has always been poor. Neurons in several brain regions do not harbor estrogen receptor α (ERα) and yet are estrogen responsive. It was formerly thought that these responses represented indirect actions of estrogen. It is now evident that these neurons express ERβ and that estrogen receptors have diverse actions in the central nervous system. By clear delineation of the cellular expression and function of the two estrogen receptors, it is likely that, in the future, selective ERα and ERβ ligands will be developed and used for treatment of depression and behavioral disorders and may be useful in preventing degenerative diseases, such as Alzheimer's and Parkinson's disease.
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