The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jan-ake Gustafsson - One of the best experts on this subject based on the ideXlab platform.
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Estrogen Receptor Beta and neural development
Vitamins and Hormones Series, 2021Co-Authors: Ivan Nalvarte, Jan-ake Gustafsson, Mukesh Varshney, Jose InzunzaAbstract:Abstract The female sex hormone estradiol (E2, 17β-estradiol) has important functions in the developing brain. In addition to regulating sexual differentiation of the brain, E2 participates in the development of brain areas involved in functions unrelated to reproduction, such as cognition. E2 signals mainly thorough two Estrogen Receptors; Estrogen Receptor alpha (ERα) and Beta (ERβ). While ERα has distinct functions for sexual imprinting of the developing brain, ERβ is considered to participate in the development of brain areas related to cognitive function. In this chapter we will focus on ERβ's role during neural development. We will discuss the contributions of sex chromosomal and sex hormonal effects in this process and place it in relation to recent data on ERβ obtained from stem cell models. Finally, we will discuss the lessons learned from mouse and stem cell models in understanding ERβ's role in neural development and how new stem cell models, by addressing the human relevance, may help to advance our progress in this field.
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motor function deficits in the Estrogen Receptor Beta knockout mouse role on excitatory neurotransmission and myelination in the motor cortex
Neuroendocrinology, 2021Co-Authors: Mukesh Varshney, Jan-ake Gustafsson, Jose Inzunza, Shintaro Katayama, Tianyao Liu, Virpi Tohonen, Kaarel Krjutskov, Juha Kere, Xiaotang Fan, Ivan NalvarteAbstract:Background: Male Estrogen Receptor Beta (ERβ) knockout (BERKO) mice display anxiety and aggression linked to, among others, altered serotonergic signaling in the basolateral amygdala and dorsal raphe, impaired cortical radial glia migration, and reduced GABAergic signaling. The effects on primary motor cortex (M1 cortex) and locomotor activity as a consequence of ERβ loss have not been investigated. Objective: The aim of this study was to determine whether locomotor activity is altered as a consequence of the changes in the M1 cortex. Methods: The locomotor activity of male wild-type (WT) and BERKO mice was evaluated using the open-field and rotarod tests. Molecular changes in the M1 cortex were analyzed by RNA sequencing, electron microscopy, electrophysiology, and immunohistological techniques. In addition, we established oligodendrocyte (OL) cultures from WT and BERKO mouse embryonic stem cells to evaluate OL function. Results: Locomotor profiling revealed that BERKO mice were more active than WT mice but had impaired motor coordination. Analysis of the M1 cortex pointed out differences in synapse function and myelination. There was a reduction in GABAergic signaling resulting in imbalanced excitatory and inhibitory neurotransmission as well as a defective OL differentiation accompanied by myelin defects. The effects of ERβ loss on OL differentiation were confirmed in vitro. Conclusion: ERβ is an important regulator of GABAergic interneurons and OL differentiation, which impacts on adult M1 cortex function and may be linked to increased locomotor activity and decreased motor coordination in BERKO mice.
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abstract 2081 intestinal Estrogen Receptor Beta suppresses colon inflammation and tumorigenesis in both sexes
Epidemiology, 2020Co-Authors: Linnea Hases, Jan-ake Gustafsson, Ashish Saxena, Rajitha Indukuri, Madeleine Birgersson, Trang Nguyenvu, Rodrigo Lozano, Johan Hartman, Jonna Frasor, Pekka KatajistoAbstract:Estrogen has been shown to protect women against colorectal cancer (CRC). In this study, using tissue-specific knockout mice, we characterize the role for intestinal Estrogen Receptor Beta (ERβ) and, for the first time, demonstrate a direct preventive role against colitis-induced colon tumors in both sexes. By inducing colitis and CRC using azoxymethane and dextran sodium sulfate in intestine-specific ERβ knockout mice, we observe an increase in colon ulceration in addition to an enhanced development of neoplasms, with increased number of tumors in males and increased tumor size in females. We identify a local increase in TNFα expression and deregulation of NFκB targets. We note that males exhibit especially strong effects following intestinal ERβ knockout. The protection by intestinal ERβ against TNFα-induced damage is corroborated using ex vivo organoid culture, where we observe that activation of ERβ protects against TNFα-induced epithelial cell damage. Further, we characterize an underlying mechanism of action, using CRC cell lines with re-introduced ERβ, where ERβ binds to cis-regulatory chromatin areas of key NFκB regulators BCL3, BIRC3 and ATF3, and thereby modulates TNFα-induced signaling. With these results we define a clear role for intestinal ERβ and demonstrate an underlying mechanism, strongly supporting the notion that selective activation of intestinal ERβ has potential to prevent CRC in both sexes. Citation Format: Linnea Hases, Rajitha Indukuri, Madeleine Birgersson, Trang Nguyen-Vu, Rodrigo Lozano, Ashish Saxena, Johan Hartman, Jonna Frasor, Jan-Ake Gustafsson, Pekka Katajisto, Amena Archer, Cecilia Williams. Intestinal Estrogen Receptor Beta suppresses colon inflammation and tumorigenesis in both sexes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2081.
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motor function deficits in the Estrogen Receptor Beta knockout mouse role on excitatory neurotransmission and myelination in the motor cortex
Neuroendocrinology, 2020Co-Authors: Mukesh Varshney, Jan-ake Gustafsson, Jose Inzunza, Shintaro Katayama, Tianyao Liu, Virpi Tohonen, Kaarel Krjutskov, Juha Kere, Xiaotang Fan, Ivan NalvarteAbstract:Introduction Male Estrogen Receptor Beta (ERβ) knockout (BERKO) mice display anxiety and aggression linked to, among others, altered serotonergic signaling in the basolateral amygdala and dorsal raphe, impaired cortical radial glia migration and reduced GABAergic signaling. Effects on primary motor cortex (M1 cortex) and locomotor activity as a consequence of ERβ loss have not been investigated. Objective The aim of this study was to determine whether locomotor activity is altered as a consequence of the changes in the M1 cortex. Methods Locomotor activity of WT and BERKO male mice was evaluated using the open-field and rotarod tests. Molecular changes in the M1 cortex were analyzed by RNA-sequencing, electron microscopy, electrophysiology, and immunohistological techniques. In addition, we established oligodendrocyte cultures from WT and BERKO mouse embryonic stem cells to evaluate oligodendrocyte function. Results Locomotor profiling revealed that BERKO mice were more active than WT mice but had impaired motor coordination. Analysis of the M1 cortex pointed out differences in synapse function and myelination. There was a reduction in GABAergic signaling resulting in imbalanced excitatory and inhibitory neurotransmission, as well as a defective oligodendrocyte differentiation accompanied by myelin defects. The effects of ERβ loss on oligodendrocyte differentiation was confirmed in vitro. Conclusion ERβ is an important regulator of GABAergic interneurons and oligodendrocyte differentiation, which impacts on adult M1 cortex function, and may be linked to increased locomotor activity and decreased motor coordination in BERKO mice.
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colitis induced colorectal cancer and intestinal epithelial Estrogen Receptor Beta impact gut microbiota diversity
International Journal of Cancer, 2019Co-Authors: Jan-ake Gustafsson, Ashish Saxena, Linnea Hases, Ahmed Ibrahim, Luisa W Hugerth, Maike Seifert, Quentin Thomas, Lars EngstrandAbstract:Chronic inflammation of the colon (colitis) is a risk factor for colorectal cancer (CRC). Hormone-replacement therapy reduces CRC incidences, and the Estrogen Receptor Beta (ERβ/ESR2) has been implicated in this protection. Gut microbiota is altered in both colitis and CRC and may influence the severity of both. Here we test the hypothesis that intestinal ERβ impacts the gut microbiota. Mice with and without intestine-specific deletion of ERβ (ERβKOVil ) were generated using the Cre-LoxP system. Colitis and CRC were induced with a single intraperitoneal injection of azoxymethane (AOM) followed by administration of three cycles of dextran sulfate sodium (DSS) in drinking water. The microbiota population were characterized by high-throughput 16S rRNA gene sequencing of DNA extracted from fecal samples (N = 39). Differences in the microbiota due to AOM/DSS and absence of ERβ were identified through bioinformatic analyses of the 16S-Seq data, and the distribution of bacterial species was corroborated using qPCR. We demonstrate that colitis-induced CRC reduced the gut microbiota diversity and that loss of ERβ enhanced this process. Further, the Bacteroidetes genus Prevotellaceae_UCG_001 was overrepresented in AOM/DSS mice compared to untreated controls (3.5-fold, p = 0.004), and this was enhanced in females and in ERβKOVil mice. Overall, AOM/DSS enriched for microbiota impacting immune system diseases and metabolic functions, and lack of ERβ in combination with AOM/DSS enriched for microbiota impacting carbohydrate metabolism and cell motility, while reducing those impacting the endocrine system. Our data support that intestinal ERβ contributes to a more favorable microbiome that could attenuate CRC development.
Peter Kraft - One of the best experts on this subject based on the ideXlab platform.
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haplotypes of Estrogen Receptor Beta and risk of non small cell lung cancer in women
Lung Cancer, 2011Co-Authors: Jessica K Paulus, Peter Kraft, Wei Zhou, Bruce E Johnson, Xihong Lin, David C ChristianiAbstract:Epidemiologic and biologic evidence suggests that lung cancer has different clinical and biological characteristics in women, and that Estrogen may contribute to the pathogenesis of non-small cell lung cancer (NSCLC). We investigated whether germline variation in the Estrogen Receptor-Beta gene (ESR2) is associated with lung cancer risk among 1021 female cases and 826 female controls enrolled in the Lung Cancer Susceptibility Study at the Massachusetts General Hospital from 1992 to 2004. Four haplotype-tagging polymorphisms (htSNPs) (rs3020450, rs1256031, rs1256049, rs4986938) captured the common genetic variation across the ESR2 locus from a set of markers culled from healthy controls from a public database and sequencing the coding regions of 95 breast cancer cases. Using the expectation-maximization algorithm, five common haplotypes were resolved (CCGC (43%), TCAT (287%), TCAC (11%), CCAC (9%) and CCAT (6%)). Multivariate logistic regression was used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) for individual htSNPs and haplotype scores. Neither the four individual htSNPs nor their resolved haplotypes were associated with lung cancer risk in the entire population, nor in strata defined by parity (yes versus no), age (<50 years versus ≥50 years) or smoking history (current-, former-, never-smokers). Our findings indicate that ESR2 is not associated with risk of lung cancer in women.
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haplotypes of the Estrogen Receptor Beta gene and breast cancer risk
International Journal of Cancer, 2008Co-Authors: David G Cox, Peter Kraft, Philip Bretsky, Demetrius Albanes, David Altshuler, Heiner Boeing, Paul D P Pharoah, Pilar Amiano, Goran Berglund, Julie E BuringAbstract:Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen Receptors are the first step along the path of signaling cell growth and development upon stimulation with Estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the Estrogen Receptor Beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.
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Sequence variants of Estrogen Receptor Beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
Cancer Epidemiology Biomarkers & Prevention, 2007Co-Authors: Yen-ching Chen, Peter Kraft, Philip Bretsky, Shamika Ketkar, David J. Hunter, Demetrius Albanes, David Altshuler, Gerald L. Andriole, Christine D. Berg, Heiner BoeingAbstract:Sequence variants of Estrogen Receptor Beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
David C Christiani - One of the best experts on this subject based on the ideXlab platform.
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haplotypes of Estrogen Receptor Beta and risk of non small cell lung cancer in women
Lung Cancer, 2011Co-Authors: Jessica K Paulus, Peter Kraft, Wei Zhou, Bruce E Johnson, Xihong Lin, David C ChristianiAbstract:Epidemiologic and biologic evidence suggests that lung cancer has different clinical and biological characteristics in women, and that Estrogen may contribute to the pathogenesis of non-small cell lung cancer (NSCLC). We investigated whether germline variation in the Estrogen Receptor-Beta gene (ESR2) is associated with lung cancer risk among 1021 female cases and 826 female controls enrolled in the Lung Cancer Susceptibility Study at the Massachusetts General Hospital from 1992 to 2004. Four haplotype-tagging polymorphisms (htSNPs) (rs3020450, rs1256031, rs1256049, rs4986938) captured the common genetic variation across the ESR2 locus from a set of markers culled from healthy controls from a public database and sequencing the coding regions of 95 breast cancer cases. Using the expectation-maximization algorithm, five common haplotypes were resolved (CCGC (43%), TCAT (287%), TCAC (11%), CCAC (9%) and CCAT (6%)). Multivariate logistic regression was used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) for individual htSNPs and haplotype scores. Neither the four individual htSNPs nor their resolved haplotypes were associated with lung cancer risk in the entire population, nor in strata defined by parity (yes versus no), age (<50 years versus ≥50 years) or smoking history (current-, former-, never-smokers). Our findings indicate that ESR2 is not associated with risk of lung cancer in women.
Benita S. Katzenellenbogen - One of the best experts on this subject based on the ideXlab platform.
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contrasting activities of Estrogen Receptor Beta isoforms in triple negative breast cancer
Breast Cancer Research and Treatment, 2021Co-Authors: Shunchao Yan, John A. Katzenellenbogen, Parama Dey, Yvonne S Ziegler, Xin Jiao, Sung Hoon Kim, Benita S. KatzenellenbogenAbstract:Triple negative breast cancer (TNBC), an aggressive subtype of breast cancer, lacks the three major Receptors for predicting outcome or targeting therapy. Hence, our aim was to evaluate the potential of Estrogen Receptor Beta (ERβ) as a possible endocrine therapy target in TNBC. The expression and prognostic effect of ERβ isoforms were analyzed using TCGA breast tumor data, and the expression of ERβ isoform mRNA and protein in TNBC cell lines was assayed. Endogenous ERβ2 and ERβ5 were knocked down with siRNA, and ERβ2, ERβ5, and ERβ1 were upregulated using a doxycycline-inducible lentiviral system. Cell proliferation, migration and invasion, and specific gene expressions were evaluated. ERβ2 and ERβ5 were the predominant endogenous forms of ERβ in TNBC tumors and cell lines. High ERβ2 predicted worse clinical outcome. Knockdown of endogenous ERβ2/ERβ5 in cell lines suppressed proliferation, migration and invasion, and downregulated proto-oncogene survivin expression. ERβ2/ERβ5 upregulation did the reverse, increasing survivin and these cell activities. ERβ1 was barely detectable in TNBC cell lines, but its upregulation reduced survivin, increased tumor suppressor expression (E-cadherin and cystatins), and suppressed proliferation, migration and invasion in both ligand-independent and dependent manners, suggesting the possible translational benefit of ERβ ligands. ERβ2/ERβ5 and ERβ1 exhibit sharply contrasting activities in TNBC cells. Our findings imply that delineating the absolute amounts and relative ratios of the different ERβ isoforms might have prognostic and therapeutic relevance, and could enable better selection of optimal approaches for treatment of this often aggressive form of breast cancer.
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the androgen derivative 5alpha androstane 3Beta 17Beta diol inhibits prostate cancer cell migration through activation of the Estrogen Receptor Beta subtype
Cancer Research, 2005Co-Authors: Vittoria Guerini, Benita S. Katzenellenbogen, Daniela Sau, Paola Rusmini, Paolo Ciana, Adriana Maggi, Eugenia Scaccianoce, Paolo Martini, L Martini, Marcella MottaAbstract:Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5alpha-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen Receptor-independent mechanism. We have shown that the dihydrotestosterone metabolite 5alpha-androstane-3Beta,17Beta-diol (3Beta-Adiol), a steroid which does not bind androgen Receptors, but efficiently binds the Estrogen Receptor Beta (ERBeta), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERBeta signaling. Very surprisingly, estradiol is not active, suggesting the existence of different pathways for ERBeta activation in prostate cancer cells. Moreover, 3Beta-Adiol, through ERBeta, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3Beta-Adiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that (a) circulating testosterone may act with Estrogenic effects downstream in the catabolic process present in the prostate, and (b) that the Estrogenic effect of testosterone derivatives (ERBeta-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estradiol on the same Receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3Beta-hydroxysteroid dehydrogenases (the enzymes responsible for 3Beta-Adiol formation) are strongly correlated with hereditary prostate cancer.
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the androgen derivative 5alpha androstane 3Beta 17Beta diol 3Beta adiol inhibits migration of prostate cancer cell by activation of the Estrogen Receptor Beta
Cancer Research, 2005Co-Authors: Vittoria Guerini, Benita S. Katzenellenbogen, Daniela Sau, Paola Rusmini, Paolo Ciana, Adriana Maggi, Paolo G V Martini, Marcella Motta, Angelo PolettiAbstract:297 In earlier stages, prostate cancer (PC) depends on androgens and may be reduced with androgen blockade. Androgen-ablation therapy often induces androgen-independent PC, characterized by an increased invasiveness. We have found that the the testosterone derivative, dihydrotestosterone inhibits cell migration with an androgen Receptor (AR)-independent mechanism. This effect has been linked to its metabolite 5alpha-androstane-3Beta,17Beta-diol (3Beta-Adiol), a steroid which does not bind AR, but interact with the Estrogen Receptor Beta (ERBeta). 3Beta-Adiol inhibits cell migration of PC through the activation of the ERBeta signalling, while estradiol is not active, suggesting the existence of different pathways for ERBeta activation in PC cells. Moreover, 3Beta-Adiol induces the expression of E-cadherin, a protein known to be capable to reduce metastasis formation of breast cancer and PC cells. The inhibitory effects of 3Beta-Adiol on PC cell migration is counteracted by siRNA against E-cadherin. The present data demonstrated that 1) testosterone may exert an Estrogenic effects downstream in the catabolic process present in the prostate; 2) the Estrogenic effect of testosterone derivatives (ERBeta-dependent) inhihits cell migration, although it is apparently different from that linked to estradiol on the same Receptor and may be protective against PC invasion and metastasis. These results may help to explain some clinical observations which reported that alterations in gene coding for 3Beta-HSDs (the enzymes responsible for 3Beta-Adiol formation) are strongly correlated with hereditary PC.
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Isocoumarins as Estrogen Receptor Beta selective ligands: Isomers of isoflavone phytoEstrogens and their metabolites.
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Meri De Angelis, Michael Waibel, Fabio Stossi, Benita S. Katzenellenbogen, John A. KatzenellenbogenAbstract:Abstract In a search for new ligands selective for the Estrogen Receptor Beta (ERβ), we prepared a series of non-steroidal compounds having an isocoumarin core structure. An interesting feature of these derivatives is that they bear the same functionalities as the well-known ERβ -selective, isoflavone phytoEstrogens daidzein and genistein, but in an isomeric arrangement. These compounds could be prepared efficiently by electrophilic cyclization of acetylenic ester precursors, followed by simple manipulations to introduce additional substituents. Through a reduction of some of the isocoumarins, we also obtained isomeric analogs of the isoflavone metabolites equol and dehydroequol. The compounds we prepared were evaluated in ER binding assays, and selected compounds were studied further in cell-based gene transcription assays. Several of the isocoumarins and their analogs are high-affinity ligands that show considerable selectivity for ERβ in terms of binding affinity, and strikingly high ERβ selectivity in terms of potency in gene transcription assays. Two of the best compounds, which combine high transcriptional potency with an ERβ selectivity greater than 1000, should prove to be excellent probes of ERβ function in vivo.
Karin Dahlmanwright - One of the best experts on this subject based on the ideXlab platform.
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Estrogen Receptor Beta in breast cancer
Molecular and Cellular Endocrinology, 2014Co-Authors: Larsarne Haldosen, Chunyan Zhao, Karin DahlmanwrightAbstract:Estrogen is essential for growth and development of the mammary glands and has been associated with the promotion and growth of breast cancer and in line with this, most human breast cancers are initially Estrogen-dependent and undergo regression when deprived of their supporting hormone. Estrogen exerts many of its effects via two nuclear Estrogen Receptors (ERs), ERα and ERβ. The discovery of a second ER, ERβ, demanded a full re-evaluation of Estrogen action in all target tissues and different Estrogen associated diseases, including human breast cancer. However, despite over 15 years of research, the exact role, if any, of ERβ in human breast cancer remains elusive. The main challenges now are to develop highly selective anti-ERβ antibodies that are applied to large well characterized human breast cancer samples to validate their diagnostic potential and to explore ERβ-selective agonists in animal models of breast cancer to validate their therapeutic potential.
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Estrogen Receptor Beta an overview and update
Nuclear Receptor Signaling, 2008Co-Authors: Chunyan Zhao, Karin Dahlmanwright, Jan-ake GustafssonAbstract:The discovery of a second Estrogen Receptor (ER), designated ERβ (NR3A2), has redefined our knowledge about the mechanisms underlying cellular signaling by Estrogens and has broad implications for our understanding of regulation of Estrogen-responsive tissues. Highly variable and even contrasting effects of Estrogens in different tissues seem to be at least partially explained by different Estrogen signaling pathways, involving ERα (NR3A1) and/or ERβ. To date, two key conclusions can be drawn from the significant body of work carried out on the specific roles of the two Receptor subtypes in diverse Estrogen target tissues. First, ERα and ERβ have different biological functions, as indicated by their specific expression patterns and the distinct phenotypes observed in ERα and ERβ knockout (αERKO and βERKO) mice. Second, ERα and ERβ appear to have overlapping but also unique sets of downstream target genes, as judged from a set of microarray experiments. Thus, ERα and ERβ have different transcriptional activities in certain ligand, cell-type, and promoter contexts, which may help to explain some of the major differences in their tissue-specific biological actions. The phenotypes observed for βERKO mice have suggested certain therapeutic areas to be further explored. The development of ERβ-selective ligands active in animal disease models indicates new avenues for clinical exploration. ERβ agonists are being explored and validated as drugs for a growing number of indications. Hopefully, some ERβ targeted drugs will prove to be efficient in enhancing human health.
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expression of Estrogen Receptor Beta isoforms in normal breast epithelial cells and breast cancer regulation by methylation
Oncogene, 2003Co-Authors: Chunyan Zhao, Jan-ake Gustafsson, Eric Lam, Andrew Sunters, Eva Enmark, Manuela Tamburo De Bella, Charles R Coombes, Karin DahlmanwrightAbstract:Two novel Estrogen Receptor Beta (ERBeta) mRNA isoforms that diverge in their 5'-untranslated regions, ERBeta mRNA (0K-1) and ERBeta mRNA (0N-1), have recently been identified. This indicates that transcription of the human ERBeta gene occurs from at least two different promoters, named promoter 0K and promoter 0N. The aim of this study was to investigate the expression of ERBeta isoforms in primary cultures of normal breast epithelial cells, a panel of breast cancer cell lines and in normal breast and breast cancer tissues; and to examine whether methylation of the two ERBeta promoters is involved in regulation of ERBeta gene expression. Using quantitative real-time PCR techniques, we found that ERBeta mRNA levels were significantly lower in breast cancer cell lines than in primary cultures of normal breast epithelial cells. Bisulfite genomic sequencing analysis revealed that two promoters of the ERBeta gene exhibit distinct methylation patterns. Promoter 0N was unmethylated in normal breast epithelial cells, but extensively methylated in breast cancer cell lines. In contrast, promoter 0K was unmethylated in both normal and malignant breast epithelial cells. We demonstrated a significant correlation between promoter 0N hypermethylation and loss of ERBeta mRNA expression in breast cancer cell lines. Treatment of breast cancer cells with demethylating agent effectively reactivated the expression of ERBeta mRNA. The observations from the cell lines were also reflected in primary breast cancer tumors. Thus, expression of ERBeta mRNA in breast tumors was found to be inversely associated with the degree of methylation of promoter 0N. Our results suggest that a decreased level of ERBeta mRNA may be associated with breast tumorigenesis, and that DNA methylation is an important mechanism for ERBeta gene silencing in breast cancer.