25 years of ERβ: a personal journey

in Journal of Molecular Endocrinology
View More View Less
  • 1 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
  • | 2 Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing, People’s Republic of China
  • | 3 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

Correspondence should be addressed to J-Å Gustafsson: jgustafs@central.UH.EDU
Free access

Summary

After the discovery of ERβ, a novel role for dihydrotestosterone (DHT) in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), an estrogen which does not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus is a potential target for treatment of prostate cancer. ERβ was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases (Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease), ERβ agonists are very effective in relieving symptoms and improving pathologies, this has not proven to be the case in humans. In this review we will focus on the main differences in ERβ signaling between rodents and humans and will make the point that a very important difference between the two species is in the splice variants which are expressed in humans and not rodents. The main conclusion at this point is that before we think of using ERβ agonists clinically, much more work on ERβ signaling in the human or in primates needs to be done.

Abstract

Summary

After the discovery of ERβ, a novel role for dihydrotestosterone (DHT) in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), an estrogen which does not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus is a potential target for treatment of prostate cancer. ERβ was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases (Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease), ERβ agonists are very effective in relieving symptoms and improving pathologies, this has not proven to be the case in humans. In this review we will focus on the main differences in ERβ signaling between rodents and humans and will make the point that a very important difference between the two species is in the splice variants which are expressed in humans and not rodents. The main conclusion at this point is that before we think of using ERβ agonists clinically, much more work on ERβ signaling in the human or in primates needs to be done.

A short history

Many years ago (1969) in the lab of the great American endocrinologist, Jean Wilson, steroid 5α-reductase was identified as the enzyme which catalyzes the conversion of testosterone to dihydrotestosterone (DHT). DHT was found to be a better binder to the androgen receptor (AR) than testosterone but not by much (two-fold). Yet, absence of 5α-reductase has severe consequences in genital development (ambiguous genitals), micropenis, and loss of secondary sexual characteristics (lack of facial hair). What was known since 1981, is that there is a second estrogen in the body which is synthesized, not from testosterone via aromatase (Muthusamy et al. 2011), but from DHT via a member of the hydroxysteroid dehydrogenases (HSD) superfamily of enzymes (Thieulant et al. 1981). This steroid is 5α-androstane-3β, 17β-diol (3β-Adiol) and its level in the prostate is regulated by an enzyme, first described in the ventral prostate in the lab of another great American cell biologist, Donald Coffey (Isaacs et al. 1979). The enzyme which degrades 3β-Adiol was identified by our team in Stockholm (Sundin et al. 1987). The question that we were addressing at the time was, why is it that, with its abundance, cytochromes P450 (CYP450) in the liver does not degrade 3β-Adiol but the prostate, brain, and pituitary with very low levels of CYP450, degrade it very rapidly. Our team isolated the 3β-Adiol hydroxylase, and it was later identified as CYP7β1 (Stapleton et al. 1995, Sundin et al. 1987). Such a (non-liver-expressed) organ-specific, abundant expression of a CYP450 is characteristic of an endocrine pathway. The question that was raised at the time was what is the relationship between the brain, the prostate, and the pituitary. There was no logical answer until 1996 when our team discovered the second estrogen receptor, ERβ (Kuiper et al. 1996). This was a receptor abundantly expressed in the prostate and the fetal brain but not in the pituitary. And with this one discovery, everything about DHT, 3β-Adiol, CYP7β1, and ERβ fell into place and a new endocrine pathway was unveiled (Fig. 1) (Weihua et al. 2002).

Figure 1
Figure 1

A novel role for dihydrotestosterone (DHT) in estrogen signaling.

Citation: Journal of Molecular Endocrinology 68, 1; 10.1530/JME-21-0121

How does scientific discovery occur?

How do scientists make their ground-breaking discoveries? Were they looking for what they found, or did they blindly stumble upon them? Discoveries do not happen by accident, but because of open minds and keen powers of observation. What is clear is that scientists do not make their discoveries in isolation. What was happening in bits and pieces in different labs around the world was the discovery of a pathway for the synthesis of the second estrogen in the body. In each case there were key postdoctoral fellows who were instrumental in the discoveries and who went on to be scientists of distinction reflective of their individual talents. In the case of Jean Wilson it was Nick Bruchovsky, for Don Coffey it was John Isaacs and for Jan-Ake Gustafsson, George Kuiper. All three labs were trying to understand the complex endocrinology of androgen signaling in the prostate. Indeed, androgen signaling is complex and at the time that Jean Wilson and Don Coffey were making their discoveries, the androgen receptor (AR) had not yet been cloned and the concept of steroid hormone receptors as a family of ligand-activated transcription factors was many years into the future.

Cloning and nuclear receptors

The advent of cloning in the 1980’s created a tsunami of information which swept over biology and with this, a quantum leap occurred in Endocrinology. All of the mysteries of steroid receptors, known only as very complex proteins, began to dissolve and a gene family to which all steroid hormone receptors belonged was revealed. Their architecture, and mechanisms of action were elucidated, and new family members were revealed by cloning of homologous genes. This was the technique used to clone ERβ.

How was ERβ received by endocrinologists

Very surprisingly, many endocrinologists did not welcome ERβ as an estrogen receptor because it was not expressed in the pituitary and had no proliferative effects in the uterus. It was thought of as a 'vestigial receptor'. One of the most convincing pieces of evidence for a lack of function of ERβ was the lack of phenotype in the prostates of knockout (ko) mouse created by the Chambon lab in Strasbourg (Dupont et al. 2000) and the Wyeth lab in upstate New York (Harris et al. 2002, Harris 2007). The ERβ ko mouse created in the lab of Oliver Smithies (Krege et al. 1998) did show epithelial hyperplasia, increased androgen signaling, and increase in expression of genes associated with prostate cancer, as well as development abnormalities in the brain and an overactive immune system. Despite the differences in prostate phenotype in the different ko mice, all of the female ERβ knockout mice were infertile suggesting an important role for this receptor in survival of the species. It was not until 2020 with the complete removal of the ERβ gene in mice (Warner et al. 2020) that it became very clear that ERβ was indeed a functional receptor in the prostate and mammary gland and many other organs. The controversy had all been caused by the method used to create knockout mice. To create their knockout mice both Chambon and Wyeth removed the DNA-binding domain (DBD) from the ERβ gene. Oliver Smithies inserted a neocassette into the DBD and disrupted the gene. In the Oliver Smithies mouse, no ERβ protein was detectable but in the Chambon and Wyeth mouse there was ERβ detected with an antibody directed against the C-terminus of the protein. Because of this, the phenotype of the Oliver Smithies mouse was deemed an artifact due to the presence of the neo-cassette, which was left in the mouse genome. In retrospect, the lack of phenotype in the Chambon and Wyeth KO mice should not have been surprising because ERβ does not use binding to DNA as its major mode of action (Zhao et al. 2010). It uses tethering to other transcription factors without itself binding to DNA. The reason for the female infertility remains to be explained. It appears not to be due to a defect in the ovary itself but at the level of the CNS (Wolfe & Wu 2012).

Mistakes created by poor quality antibodies

One problem in the ERβ story is the poor quality of many commercial antibodies. This has led to all kinds of misleading conclusions about the expression of ERβ. In an attempt to clarify this issue, Nelson et al. published a study advising about which antibodies are acceptable (Nelson et al. 2016).

Although the intent was laudable, it has created a new difficulty for researchers in the field: reviewers now will not accept studies done with antibodies, which are not recommended or tested in the review. We suggest that instead of rejecting antibodies, two controls should be done in papers reporting on ERβ. One control that should be essential for evaluation of ERβ on Western blots is a standard curve with ERβ in the femtomole range. The reason for this is that steroid hormone receptors are present in cells in the fmol/mg protein range. If 20 µg protein is loaded in the well, is the sensitivity of the assay high enough to detect the ERβ? Could this amount of ERβ possibly produce those very strong bands shown in so many publications?

The second control is a pre-adsorption of the antibody with ERβ protein. If the ERβ bands on the gel are lost after preadsorption, it is a good indication that the bands are specific. This will control for the presence of non-specific bands in different tissues and cells.

Mistakes associated with ERβ splice variants

Today there are still outstanding issues concerning ERβ in human disease. One of the most relevant issues concerns the translation of mouse data to humans. There are several ERβ splice variants in humans that do not exist in the mouse and one splice variant in the mouse that does not exist in humans. The role of the human splice variants is under investigation. They are named ERβ2, 3, 4, and 5 with the original ERβ now called ERβ1 (Table 1, Fig. 2). The first splice variant ERβcx now called ERβ2 (Inoue et al. 2000) was discovered only 2 years after the discovery of ERβ.

Table 1

ERβ splice variants in cancers.

Site of cancerSplice variant expressedOutcomeRef
BreastERβ2Less favorable(Fujimura et al. 2001)
ProstateERβ2Less favorable(Leung et al. 2010)
ColonERβ5Better prognosis(Campbell-Thompson et al. 2001)
PancreasERβ5Better prognosis(Konduri & Schwarz 2007)
GlioblastomaERβ5Less favorable(Liu et al. 2018)
Triple negative breast cancerERβ2Worse prognosis, chemotherapy resistance(Bialesova et al. 2017)
BreastERβ2Worse prognosis(Esslimani-Sahla et al. 2004)
Figure 2
Figure 2

Architecture of ERβ and its splice variants.

Citation: Journal of Molecular Endocrinology 68, 1; 10.1530/JME-21-0121

The ERβ splice variants are all truncated at the C-terminus after exon 7. Unlike ERβ1 which inhibits EMT (Mak et al. 2013), ERβ 2 induces EMT (Dey et al. 2015). In triple negative breast cancer cell lines ERβ2/5 also have effects opposite to those of ERβ1 and influence expression of the protooncogene survivin, migration, and invasiveness but not proliferation (Wu et al. 2013, Yan et al. 2021). The regulation of survivin is one of many genes which are regulated in opposite directions by ERβ1in mice (Wu et al. 2017) and ERβ2/5 in human cell lines.

One of the pitfalls of using antibodies directed against the N-terminus of ERβ is that they do not distinguish between ERβ1 and its splice variants and ERβ1 can be wrongly assigned functions which belong to the splice variants.

In triple negative breast cancer (TNBC) (Yan et al. 2021) and in prostate cancer (Fujimura et al. 2001, Vinayagam et al. 2007, Leung et al. 2010), ERβ2 and ERβ5 correlate with a less favorable prognosis. The situation is opposite in colon cancer (Campbell-Thompson et al. 2001) and in pancreatic cancer where expression of ERβ5 correlates to a better prognosis (Younes & Honma 2011). In breast cancer expressing ERα, the presence of ERβ2 correlates with a better response to endocrine therapy (Hamilton-Burke et al. 2010). In glioblastoma (Liu et al. 2018), ERβ5 is highly expressed and promotes oncogenicity via modulation of the mTOR and NFκB pathways. ERβ2 is associated with worse prognosis in TNBC and in breast cancer in general (Esslimani-Sahla et al. 2004, Bialesova et al. 2017).

What all these data suggest is that the activity of ERβ splice variants is dictated by the context of the cell and the pathways that drive the specific cancer (Table 1).

Diverse functions of the splice variants

One unanswered question is how do changes in the C-terminus of ERβ create proteins with (Sneddon et al. 2005) such diverse functions. The splice variants do not activate estrogen responsive elements (ERE) but can inhibit AP-1 activity. This indicates that the splice variants do not directly bind to DNA but rather, like ERβ1, tether to transcription factors. The binding to cell-specific transcription factors may explain why the functions of the splice variants appears to be cell-specific. In normal tissue, ERβ2 protein is expressed in the testis (Makinen et al. 2001, Zhou et al. 2002, Sneddon et al. 2005) and in B-cells (Yakimchuk et al. 2012). The significance of the cellular distributions of ERβ1 and 2 in the testis remains to be explained.

As early as 1998, the tissue distribution mRNA of the ERβ splice variants was published by Moore et al. (1998). They showed that ERβ 2 and 5 were widely expressed in most tissues and cell lines. ERβ4 was limited to the ovary and testis. There was no detectable ERβ3. More recently, a detailed reverse transcription PCR (RT-PCR) study (Ishii et al. 2010) revealed that there are many additional ERβ splice variants with the testis expressing most of them. ERβ1 was detectable with cycle threshold (Ct) values of 33 and ERβ2 with 34. ERβ1 and ERβ5 were expressed in the fetal brain with Ct values of 33 and 34. So far, the functions of ERβ splice variants in the human brain have not been investigated.

ERβ in cell lines

Very early in the study of ERβ, every available cell line was examined by PCR for the presence of ERβ but no high levels of ERβ were found. This is still true today with quantitative PCR (qPCR) showing Ct values of 29 and higher. Despite the low levels of mRNA, many labs report high levels of ERβ detected on Western blots. Although this may well be true, it is one of the cases where controls for specificity should always be included. A large discrepancy between the level of mRNA and protein would indicate a level of control of ERβ protein different from that of its mRNA.

ERβ and prostate cancer, androgen signaling, and the genes regulated

We were taught that there is an AR and an estrogen receptor and that they are very specific for their hormones. We were taught the breast is an estrogen-regulated organ and the prostate was androgen-regulated. We always knew that estrogens were synthesized from androgens but not so much else about the estrogenandrogen cross talk. We now know that androgens are important in the breast and estrogens regulate the prostate. However, this concept of an estrogen-regulated prostate has not yet caught the attention of most clinicians. Perhaps clinicians are familiar with the problems caused by administering high doses of estrogen to men with prostate cancer: high doses of estrogen had all the bad side-effects of estrogen on the cardiovascular system and pituitary. Ligands for ERβ do not have these adverse effects on the cardiovascular system and the pituitary as they do not bind to ERα. Thus, the antiproliferative and antiandrogenic effects of ERβ ligands may be used clinically to advantage to treat proliferative diseases of the prostate. At present prostate cancer research is still focused on better AR blockers.

ERβ and the CNS

In the rodent fetal brain, ERβ is widely expressed in neurons all over the brain but not in neurons in the ventricular zone (Wang et al. 2003, Song et al. 2019). ERβ is not involved in neuronal proliferation but regulates neuronal migration. As the brain matures postnatally, ERβ is lost from most large neurons except those in the dorsal raphe, some parts of the hypothalamus and amygdala. It remains highly expressed in interneurons, microglia, and oligodendrocytes throughout life (Milner et al. 2005, Fan et al. 2006, Sugiyama et al. 2009). Several aspects of ERβ signaling suggest that ERβ ligands should have beneficial effects in the CNS (Table 2). These include: (1) stimulation of GABAergic over glutaminergic signaling which suggests that they should behave as anticonvulsants (Velísková 2007, Tan et al. 2012); (2) maturation of oligodendrocytes which should facilitate myelination (Karim et al. 2019); (3) modulation of microglial activation which should reduce inflammation (Valdés-Sustaita et al. 2021), and (4) maintenance of serotonergic neurons which should make them antidepressants (Suzuki et al. 2013). In rodent models, ERβ ligands have beneficial effects in anxiety, depression, epilepsy, and multiple sclerosis.

Table 2

Summary of the effects of ERβ ligands on neurological diseases in rodents and cell lines.

DisordersModelsERβ ligandsEffectsReference
EpilepsyKainic acid induced OVX chronic epileptic miceWAY-200070Suppressed epileptic phenotypes and normalized expression ion glutamine synthase in CA1 region(Wang et al. 2021)
Alzheimer’s DiseaseThe human neuroblastoma SH-SY5Y cellDPNRestore Aβ1–42 induced cytotoxicity(Wei et al. 2019)
Primary cortical neuronsPuerarinSuppressed Aβ1-42-induced decrease in cortical neuron numbers via activation of ERβ(Li et al. 2017)
PC-12 cellsLuteolinProtects PC-12 cells against Aβ25-35 induced cell apoptosis via selectively acting on ERβ(Wang et al. 2020a)
Primary hippocampal neurons of newborn ratsGenisteinIncrease the expression of ChAT, and exert neuroprotective effects against amyloid peptide 25–35 by activating ERβ(Wang et al. 2020b)
Parkinson’s disease6-OHDA-induced PD rat modelAC-186Prevent motor, cognitive, and sensorimotor gating deficits and mitigate the loss of dopamine neurons in the substantia nigra(McFarland et al. 2013)
ROT-induced PD rat model3β-Adiol (ADIOL)Ameliorate neurodegeneration process and motor dysfunction(Salama et al. 2018).
Multiple sclerosisEAE mice modelDPNStimulate endogenous remyelination, and improve axon conduction(Khalaj et al. 2013).
EAE mice modelDPNActivate PI3K/Akt/mTOR signaling in oligodendrocytes and promote remyelination(Kumar et al. 2013)
EAE mice modelindazole-chloride (Ind-Cl)Increase oligodendrocyte progenitor cell (OPC) and mature oligodendrocyte numbers(Moore et al. 2014)
EAE mice modelDPNInhibit MHC II expression in microglia via inhibition of class II trans-activator (CIITA) expression(Liu et al. 2019)
EAE mice modelPHTPPSuppress pathogenic Th responses and induce iL-10-producing regulation(Aggelakopoulou et al. 2016)
EAE mice modelInd-Cl

DPN

WAY-202041
Increase in peripheral and brain CXCL1 levels that correlate with an increase in axon remyelination(Karim et al. 2018)
AnxietyOVX female ratDPN CoumestrolProduce clear antianxiety behavior in the open field, elevated plus maze, emergence, lightdarkness transition, defensive freezing, and Vogel punished drinking tasks.(Walf & Frye 2005)
Gonadectomized male and female ratDPNDecrease stress-induced HPA reactivity and anxiety-like behaviors via an OT pathway(Kudwa et al. 2014)
DepressionOVX female ratDPNShow more central entries in the open field, more open-arm duration in the elevated plus maze, and less immobility duration in the forced-swim test(Yang et al. 2014)
OVX female miceC-1Reduce obesity and depressive-like behavior(Sasayama et al. 2017)
OVX female mice and ERβknockout miceLY3201Maintain functional DR neurons to treat postmenopausal depression(Suzuki et al. 2013)
OVX female ratDPNReduce depressive behavior and increase serotonergic activity via enhancing TPH expression in the DR(Yang et al. 2019)
Autism spectrum disordersPrenatal progestin exposure-induced ASD rat modelResveratrol (RSV)Activate ERβ and ameliorate autism-like behavior(Xie et al. 2018)
GlioblastomaHuman glioma cell linesDPN

MF101

Liquiritigenin
Inhibit glioma cell proliferation and tumor growth(Sareddy et al. 2012)

Despite being very effective in rodent models of CNS diseases, ERβ agonists have not been effective in the human brain. We do not have enough information about ERβ and its splice variants in primates to be able to understand this enormous difference between mouse and man. However, this situation is reminiscent of the difference between mouse and man in response to administration of DHEA. This steroid has many beneficial effects in rodents but none in man. The reason for the difference is simply that DHEA is the most abundant circulating steroid in man but is present at very low levels in rodents and the reason for this is the absence of steroid 17α-hydroxylase in the rodent adrenal cortex (see Warner & Gustafsson 2015 for a review).

Natural and synthetic ERβ ligands

Natural ERβ ligands

Endoestrogens are steroids produced within the body. 17β-Estradiol (E2), is the most potent estrogen and binds with similar affinity to ERα and ERβ. The two most abundant metabolites of E2 are estrone and estriol. The roles of these two metabolites remain unclear. Estrone binds with a high affinity to ERα and ERβ, but does not stimulate transcription. This means that it could be an antagonist. ERβ binds estriol with higher affinity than does ERα, and could be a selective ERβ agonist under certain conditions. 5α-Androstane-3β, 17β-diol (3β-Adiol) binds to both ERα and ERβ. The cellular specificity of 3β-Adiol rests on the presence in a cell of the enzyme CYP7β1 which inactivates this steroid (Pettersson et al. 2008). One very interesting aspect of 3β-Adiol is that, because of the high levels of CYP7β1 in the pituitary, it does not act as an estrogen in the pituitary. What this means is that men can be given this steroid to stimulate ERβ action in the prostate without causing a chemical castration. The level of 3β-Adiol in the mouse prostate is about 100-fold higher than that of estradiol; this steroid is considered as the natural ligand of ERβ in the gland.

Phytoestrogens are polyphenolic non-steroidal compounds synthesized by plants. There are three major groups of phytoestrogens: coumestans, lignans, and isoflavones (Dixon 2004) Although phytoestrogens bind with a higher affinity to ERβ than ERα (Kuiper et al. 1998, Harris et al. 2005) they are not dispensed clinically, because at high doses they can activate ERα.

Synthetic ERβ ligands

SERMs (selective estrogen receptor modulators) as raloxifene, tamoxifen, toremifene, and idoxifene are in clinical use. They are non-steroidal molecules that bind with high affinity to both ERs. Many ERβ-selective agonists have been synthesized by chemists in academic and pharmaceutical labs. Darylpropionitrile (DPN) and Indazole chloride (Ind-Cl), were developed by the Katzenellenbogen group (Carroll et al. 2012). DPN is 72-fold and Ind-Cl 100-fold more selective for binding to ERβ than to ERα (Moore et al. 2014).

WAY-166818 (Merchenthaler et al. 2005) is a full agonist on ERβ, 55 times more selective for ERβ than ERα in the rat (Merchenthaler et al. 2005). WAY-200070, an aryl diphenolic azole, is 68-fold selective for ERβ, relative to ERα, as assessed by radioligand binding assays. Both WAY-166818 and WAY-200070 (Hughes et al. 2008) upregulate progesterone receptor mRNA expression in the preoptic area of the brain, but not the ventromedial nucleus.

LY500307 and LY3201 are synthetic, nonsteroidal ERβ-selective agonists. Although these two agonists were very effective in treating mouse models of neurological disease, in clinical trials LY500307 had no beneficial effects in benign prostate hyperplasia (Roehrborn et al. 2015) or in schizophrenia (see Phase 2 clinical trials: The Efficacy and Safety of a Selective Estrogen Receptor Beta agonist (LY500307). Negative Symptoms and Cognitive Impairment Associated with Schizophrenia).

Prinaberel (ERB-041) (Cvoro et al. 2008, Yao et al. 2014) has a 200-fold selectivity for ERβ than for ERα. In a phase 2 clinical trial for treatment of rheumatoid arthritis, ERB-041 showed a good safety profile and there was no unexpected toxicity, however, there was no antiinflammatory efficacy in RA patients. One other mystery about ERβ agonists is why they are effective in human cell lines but not in the clinical settings. It is possible that because of the high circulating levels of DHEA in humans, there is sufficient material for the synthesis of the ERβ ligands, androstenediol, and 3β-Adiol.

Conclusions

From experiments in rodent models, it appears that ERβ should be a promising target in the treatment of many diseases. What has been a very great disappointment to everyone involved in the ERβ field is although ERβ agonists are very effective in mice, they totally lack efficacy in treating human disease. We have concluded that this discrepancy between mice and man could be due to the presence in humans, and not in rodents, of several ERβ splice variants with multiple functions in different cells. The problem of studying ERβ splice variants in neurological diseases is particularly daunting because of the paucity of appropriate models for studying the human brain.

Another issue which should be addressed is whether phytoestrogens have beneficial effects in the human brain. If this were the case, because the high soya content of the Asian diet, there would be a difference between Asians and Westerners in the incidence of neurological diseases. However, this does not appear to be the case. There are differences in the metabolism of phytoestrogens between rodents and humans and also between people of different age, gender, and ethnicity. Since ERβ and perhaps its splice variants rely on tethering to transcription factors for their biological effects, much more information is needed, not only about the cellular location of ERβ in humans, but also the milieu of the cells in which it is expressed. Until this information is available, treating people with ERβ ligands will only be like shots in the dark.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by grants from the Swedish Research Council and from The Robert A Welch Foundation (grant number E-0004).

References

  • Aggelakopoulou M, Kourepini E, Paschalidis N & Panoutsakopoulou V 2016 ERβ in CD4+ T cells is crucial for ligand-mediated suppression of central nervous system autoimmunity. Journal of Immunology 196 49474956. (https://doi.org/10.4049/jimmunol.1600246)

    • Search Google Scholar
    • Export Citation
  • Bialesova L, Xu L, Gustafsson , Haldosen LA, Zhao C & Dahlman-Wright K 2017 Estrogen receptor beta2 induces proliferation and invasiveness of triple negative breast cancer cells: association with regulation of PHD3 and HIF-1alpha. Oncotarget 8 7662276633. (https://doi.org/10.18632/oncotarget.20635)

    • Search Google Scholar
    • Export Citation
  • Campbell-Thompson M, Lynch IJ & Bhardwaj B 2001 Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. Cancer Research 61 632640.

    • Search Google Scholar
    • Export Citation
  • Carroll VM, Jeyakumar M, Carlson KE & Katzenellenbogen JA 2012 Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor beta-selective ligands. Journal of Medicinal Chemistry 55 528537. (https://doi.org/10.1021/jm201436k)

    • Search Google Scholar
    • Export Citation
  • Cvoro A, Tatomer D, Tee MK, Zogovic T, Harris HA & Leitman DC 2008 Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. Journal of Immunology 180 630636. (https://doi.org/10.4049/jimmunol.180.1.630)

    • Search Google Scholar
    • Export Citation
  • Dey P, Velazquez-Villegas LA, Faria M, Turner A, Jonsson P, Webb P, Williams C, Gustafsson & Strom AM 2015 Estrogen receptor beta2 induces hypoxia signature of gene expression by stabilizing HIF-1alpha in prostate cancer. PLoS ONE 10 e0128239. (https://doi.org/10.1371/journal.pone.0128239)

    • Search Google Scholar
    • Export Citation
  • Dixon RA 2004 Phytoestrogens. Annual Review of Plant Biology 55 225261. (https://doi.org/10.1146/annurev.arplant.55.031903.141729)

  • Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P & Mark M 2000 Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 127 42774291. (https://doi.org/10.1242/dev.127.19.4277)

    • Search Google Scholar
    • Export Citation
  • Esslimani-Sahla M, Simony-Lafontaine J, Kramar A, Lavaill R, Mollevi C, Warner M, Gustafsson JA & Rochefort H 2004 Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer. Clinical Cancer Research 10 57695776. (https://doi.org/10.1158/1078-0432.CCR-04-0389)

    • Search Google Scholar
    • Export Citation
  • Fan X, Warner M & Gustafsson JA 2006 Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons. PNAS 103 1933819343. (https://doi.org/10.1073/pnas.0609663103)

    • Search Google Scholar
    • Export Citation
  • Fujimura T, Takahashi S, Urano T, Ogawa S, Ouchi Y, Kitamura T, Muramatsu M & Inoue S 2001 Differential expression of estrogen receptor beta (ERbeta) and its C-terminal truncated splice variant ERbetacx as prognostic predictors in human prostatic cancer. Biochemical and Biophysical Research Communications 289 692699. (https://doi.org/10.1006/bbrc.2001.6038)

    • Search Google Scholar
    • Export Citation
  • Hamilton-Burke W, Coleman L, Cummings M, Green CA, Holliday DL, Horgan K, Maraqa L, Peter MB, Pollock S & Shaaban AM et al.2010 Phosphorylation of estrogen receptor beta at serine 105 is associated with good prognosis in breast cancer. American Journal of Pathology 177 10791086. (https://doi.org/10.2353/ajpath.2010.090886)

    • Search Google Scholar
    • Export Citation
  • Harris HA 2007 Estrogen receptor-beta: recent lessons from in vivo studies. Molecular Endocrinology 21 113. (https://doi.org/10.1210/me.2005-0459)

    • Search Google Scholar
    • Export Citation
  • Harris HA, Katzenellenbogen JA & Katzenellenbogen BS 2002 Characterization of the biological roles of the estrogen receptors, ERalpha and ERbeta, in estrogen target tissues in vivo through the use of an ERalpha-selective ligand. Endocrinology 143 41724177. (https://doi.org/10.1210/en.2002-220403)

    • Search Google Scholar
    • Export Citation
  • Harris DM, Besselink E, Henning SM, Go VL & Heber D 2005 Phytoestrogens induce differential estrogen receptor alpha- or beta-mediated responses in transfected breast cancer cells. Experimental Biology and Medicine 230 558568. (https://doi.org/10.1177/153537020523000807)

    • Search Google Scholar
    • Export Citation
  • Hughes ZA, Liu F, Platt BJ, Dwyer JM, Pulicicchio CM, Zhang G, Schechter LE, Rosenzweig-Lipson S & Day M 2008 WAY-200070, a selective agonist of estrogen receptor beta as a potential novel anxiolytic/antidepressant agent. Neuropharmacology 54 11361142. (https://doi.org/10.1016/j.neuropharm.2008.03.004)

    • Search Google Scholar
    • Export Citation
  • Inoue S, Ogawa S, Horie K, Hoshino S, Goto W, Hosoi T, Tsutsumi O, Muramatsu M & Ouchi Y 2000 An estrogen receptor beta isoform that lacks exon 5 has dominant negative activity on both ERalpha and ERbeta. Biochemical and Biophysical Research Communications 279 814819. (https://doi.org/10.1006/bbrc.2000.4010)

    • Search Google Scholar
    • Export Citation
  • Isaacs JT, Mcdermott IR & Coffey DS 1979 Characterization of two new enzymatic activities of the rat ventral prostate: 5 alpha-androstane-3 beta, 17 beta-diol 6 alpha-hydroxylase and 5 alpha-androstane-3 beta, 17 beta-diol 7 alpha-hydroxylase. Steroids 33 675692. (https://doi.org/10.1016/0039-128x(7990116-8)

    • Search Google Scholar
    • Export Citation
  • Ishii H, Kobayashi M & Sakuma Y 2010 Alternative promoter usage and alternative splicing of the rat estrogen receptor alpha gene generate numerous mRNA variants with distinct 5’-ends. Journal of Steroid Biochemistry and Molecular Biology 118 5969. (https://doi.org/10.1016/j.jsbmb.2009.10.001)

    • Search Google Scholar
    • Export Citation
  • Karim H, Kim SH, Lapato AS, Yasui N, Katzenellenbogen JA & Tiwari-Woodruff SK 2018 Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination. PNAS 115 62916296. (https://doi.org/10.1073/pnas.1721732115)

    • Search Google Scholar
    • Export Citation
  • Karim H, Kim SH, Lauderdale K, Lapato AS, Atkinson K, Yasui N, Yamate-Morgan H, Sekyi M, Katzenellenbogen JA & Tiwari-Woodruff SK 2019 Analogues of ERβ ligand chloroindazole exert immunomodulatory and remyelinating effects in a mouse model of multiple sclerosis. Scientific Reports 9 503. (https://doi.org/10.1038/s41598-018-37420-x)

    • Search Google Scholar
    • Export Citation
  • Khalaj AJ, Yoon J, Nakai J, Winchester Z, Moore SM, Yoo T, Martinez-Torres L, Kumar S, Itoh N & Tiwari-Woodruff SK 2013 Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand. PNAS 110 1912519130. (https://doi.org/10.1073/pnas.1311763110)

    • Search Google Scholar
    • Export Citation
  • Konduri S & Schwarz RE 2007 Estrogen receptor beta/alpha ratio predicts response of pancreatic cancer cells to estrogens and phytoestrogens. Journal of Surgical Research 140 5566. (https://doi.org/10.1016/j.jss.2006.10.015)

    • Search Google Scholar
    • Export Citation
  • Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA & Smithies O 1998 Generation and reproductive phenotypes of mice lacking estrogen receptor beta. PNAS 95 1567715682. (https://doi.org/10.1073/pnas.95.26.15677)

    • Search Google Scholar
    • Export Citation
  • Kudwa AE, Mcgivern RF & Handa RJ 2014 Estrogen receptor β and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats. Physiology and Behavior 129 287296. (https://doi.org/10.1016/j.physbeh.2014.03.004)

    • Search Google Scholar
    • Export Citation
  • Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S & Gustafsson JA 1996 Cloning of a novel receptor expressed in rat prostate and ovary. PNAS 93 59255930. (https://doi.org/10.1073/pnas.93.12.5925)

    • Search Google Scholar
    • Export Citation
  • Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, Van Der Saag PT, Van Der Burg B & Gustafsson JA 1998 Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139 42524263. (https://doi.org/10.1210/endo.139.10.6216)

    • Search Google Scholar
    • Export Citation
  • Kumar S, Patel R, Moore S, Crawford DK, Suwanna N, Mangiardi M & Tiwari-Woodruff SK 2013 Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiology of Disease 56 131144. (https://doi.org/10.1016/j.nbd.2013.04.005)

    • Search Google Scholar
    • Export Citation
  • Leung YK, Lam HM, Wu S, Song D, Levin L, Cheng L, Wu CL & Ho SM 2010 Estrogen receptor beta2 and beta5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion. Endocrine-Related Cancer 17 675689. (https://doi.org/10.1677/ERC-09-0294)

    • Search Google Scholar
    • Export Citation
  • Li L, Xue Z, Chen L, Chen X, Wang H & Wang X 2017 Puerarin suppression of Aβ-induced primary cortical neuron death is largely dependent on ERβ. Brain Research 1657 8794. (https://doi.org/10.1016/j.brainres.2016.11.023)

    • Search Google Scholar
    • Export Citation
  • Liu J, Sareddy GR, Zhou M, Viswanadhapalli S, Li X, Lai Z, Tekmal RR, Brenner A & Vadlamudi RK 2018 Differential effects of estrogen receptor beta isoforms on glioblastoma progression. Cancer Research 78 31763189. (https://doi.org/10.1158/0008-5472.CAN-17-3470)

    • Search Google Scholar
    • Export Citation
  • Liu X, Deng J, Li R, Tan C, Li H, Yang Z, Chen L, Chen Y & Tan X 2019 ERβ-selective agonist alleviates inflammation in a multiple sclerosis model via regulation of MHC II in microglia. American Journal of Translational Research 11 44114424.

    • Search Google Scholar
    • Export Citation
  • Mak P, Chang C, Pursell B & Mercurio AM 2013 Estrogen receptor beta sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription. PNAS 110 47084713. (https://doi.org/10.1073/pnas.1221654110)

    • Search Google Scholar
    • Export Citation
  • Makinen S, Makela S, Weihua Z, Warner M, Rosenlund B, Salmi S, Hovatta O & Gustafsson JA 2001 Localization of oestrogen receptors alpha and beta in human testis. Molecular Human Reproduction 7 497503. (https://doi.org/10.1093/molehr/7.6.497)

    • Search Google Scholar
    • Export Citation
  • McFarland K, Price DL, Davis CN, Ma JN, Bonhaus DW, Burstein ES & Olsson R 2013 AC-186, a selective nonsteroidal estrogen receptor β agonist, shows gender specific neuroprotection in a Parkinson’s disease rat model. ACS Chemical Neuroscience 4 12491255. (https://doi.org/10.1021/cn400132u)

    • Search Google Scholar
    • Export Citation
  • Merchenthaler I, Hoffman GE & Lane MV 2005 Estrogen and estrogen receptor-{beta} (ER{beta})-selective ligands induce galanin expression within gonadotropin hormone-releasing hormone-immunoreactive neurons in the female rat brain. Endocrinology 146 27602765. (https://doi.org/10.1210/en.2004-1562)

    • Search Google Scholar
    • Export Citation
  • Milner TA, Ayoola K, Drake CT, Herrick SP, Tabori NE, Mcewen BS, Warrier S & Alves SE 2005 Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation. Journal of Comparative Neurology 491 8195. (https://doi.org/10.1002/cne.20724)

    • Search Google Scholar
    • Export Citation
  • Moore JT, Mckee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL, Kliewer SA, Lehmann JM & Willson TM 1998 Cloning and characterization of human estrogen receptor beta isoforms. Biochemical and Biophysical Research Communications 247 7578. (https://doi.org/10.1006/bbrc.1998.8738)

    • Search Google Scholar
    • Export Citation
  • Moore SM, Khalaj AJ, Kumar S, Winchester Z, Yoon J, Yoo T, Martinez-Torres L, Yasui N, Katzenellenbogen JA & Tiwari-Woodruff SK 2014 Multiple functional therapeutic effects of the estrogen receptor beta agonist indazole-Cl in a mouse model of multiple sclerosis. PNAS 111 1806118066. (https://doi.org/10.1073/pnas.1411294111)

    • Search Google Scholar
    • Export Citation
  • Muthusamy S, Andersson S, Kim HJ, Butler R, Waage L, Bergerheim U & Gustafsson JA 2011 Estrogen receptor beta and 17beta-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer. PNAS 108 2009020094.

    • Search Google Scholar
    • Export Citation
  • Nelson AW, Groen AJ, Miller JL, Warren AY, Holmes KA, Tarulli GA, Tilley WD, Katzenellenbogen BS, Hawse JR & Gnanapragasam VJ et al.2016 Corrigendum to ‘Comprehensive assessment of estrogen receptor beta antibodies in cancer cell line models and tissue reveals critical limitations in reagent specificity’ [Mol. Cell Endocrinol. 440 (2016) 138-150]. Molecular and Cellular Endocrinology 44 3 1 75.

    • Search Google Scholar
    • Export Citation
  • Pettersson H, Holmberg L, Axelson M & Norlin M 2008 CYP7B1-mediated metabolism of dehydroepiandrosterone and 5alpha-androstane-3beta,17beta-diol-potential role(s) for estrogen signaling. FEBS Journal 275 17781789. (https://doi.org/10.1111/j.1742-4658.2008.06336.x)

    • Search Google Scholar
    • Export Citation
  • Roehrborn CG, Spann ME, Myers SL, Serviss CR, Hu L & Jin Y 2015 Estrogen receptor beta agonist LY500307 fails to improve symptoms in men with enlarged prostate secondary to benign prostatic hypertrophy. Prostate Cancer and Prostatic Diseases 18 4348. (https://doi.org/10.1038/pcan.2014.43)

    • Search Google Scholar
    • Export Citation
  • Salama RM, Tadros MG, Schaalan MF, Bahaa N, Abdel-Tawab AM & Khalifa AE 2018 Potential neuroprotective effect of androst-5-ene-3β, 17β-diol (ADIOL) on the striatum, and substantia nigra in Parkinson’s disease rat model. Journal of Cellular Physiology 233 59816000. (https://doi.org/10.1002/jcp.26412)

    • Search Google Scholar
    • Export Citation
  • Sareddy GR, Nair BC, Gonugunta VK, Zhang QG, Brenner A, Brann DW, Tekmal RR & Vadlamudi RK 2012 Therapeutic significance of estrogen receptor β agonists in gliomas. Molecular Cancer Therapeutics 11 11741182. (https://doi.org/10.1158/1535-7163.MCT-11-0960)

    • Search Google Scholar
    • Export Citation
  • Sasayama D, Sugiyama N, Yonekubo S, Pawlak A, Murasawa H, Nakamura M, Hayashi M, Ogawa T, Moro M & Washizuka S et al.2017 Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice. Scientific Reports 7 4663. (https://doi.org/10.1038/s41598-017-04946-5)

    • Search Google Scholar
    • Export Citation
  • Sneddon SF, Walther N & Saunders PT 2005 Expression of androgen and estrogen receptors in Sertoli cells: studies using the mouse SK11 cell line. Endocrinology 146 53045312. (https://doi.org/10.1210/en.2005-0914)

    • Search Google Scholar
    • Export Citation
  • Song XY, Wu WF, Gabbi C, Dai YB, So M, Chaurasiya SP, Wang L, Warner M & Gustafsson 2019 Retinal and optic nerve degeneration in liver X receptor beta knockout mice. PNAS 116 1650716512. (https://doi.org/10.1073/pnas.1904719116)

    • Search Google Scholar
    • Export Citation
  • Stapleton G, Steel M, Richardson M, Mason JO, Rose KA, Morris RG & Lathe R 1995 A novel cytochrome P450 expressed primarily in brain. Journal of Biological Chemistry 270 2973929745. (https://doi.org/10.1074/jbc.270.50.29739)

    • Search Google Scholar
    • Export Citation
  • Sugiyama N, Andersson S, Lathe R, Fan X, Alonso-Magdalena P, Schwend T, Nalvarte I, Warner M & Gustafsson JA 2009 Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain. Molecular Psychiatry 14 22323 2, 117. (https://doi.org/10.1038/mp.2008.118)

    • Search Google Scholar
    • Export Citation
  • Sundin M, Warner M, Haaparanta T & Gustafsson JA 1987 Isolation and catalytic activity of cytochrome P-450 from ventral prostate of control rats. Journal of Biological Chemistry 262 1229312297. (https://doi.org/10.1016/S0021-9258(1845350-1)

    • Search Google Scholar
    • Export Citation
  • Suzuki H, Barros RP, Sugiyama N, Krishnan V, Yaden BC, Kim HJ, Warner M & Gustafsson 2013 Involvement of estrogen receptor beta in maintenance of serotonergic neurons of the dorsal raphe. Molecular Psychiatry 18 674680. (https://doi.org/10.1038/mp.2012.62)

    • Search Google Scholar
    • Export Citation
  • Tan XJ, Dai YB, Wu WF, Kim HJ, Barros RP, Richardson TI, Yaden BC, Warner M, Mckinzie DL & Krishnan V et al.2012 Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor beta ligand. PNAS 109 17081712. (https://doi.org/10.1073/pnas.1121162109)

    • Search Google Scholar
    • Export Citation
  • Thieulant ML, Samperez S & Jouan P 1981 Evidence for 5 alpha-androstane-3 beta, 17 beta-diol binding to the estrogen receptor in the cytosol from male rat pituitary. Endocrinology 108 15521560. (https://doi.org/10.1210/endo-108-4-1552)

    • Search Google Scholar
    • Export Citation
  • Valdés-Sustaita B, Estrada-Camarena E, González-Trujano ME & López-Rubalcava C 2021 Estrogen receptors-β and serotonin mediate the antidepressant-like effect of an aqueous extract of pomegranate in ovariectomized rats. Neurochemistry International 142 104904. (https://doi.org/10.1016/j.neuint.2020.104904)

    • Search Google Scholar
    • Export Citation
  • Velísková J 2007 Estrogens and epilepsy: why are we so excited? Neuroscientist 13 7788. (https://doi.org/10.1177/1073858406295827)

  • Vinayagam R, Sibson DR, Holcombe C, Aachi V & Davies MP 2007 Association of oestrogen receptor beta 2 (ER beta 2/ER beta cx) with outcome of adjuvant endocrine treatment for primary breast cancer – a retrospective study. BMC Cancer 7 131. (https://doi.org/10.1186/1471-2407-7-131)

    • Search Google Scholar
    • Export Citation
  • Walf AA & Frye CA 2005 ERbeta-selective estrogen receptor modulators produce antianxiety behavior when administered systemically to ovariectomized rats. Neuropsychopharmacology 30 15981609. (https://doi.org/10.1038/sj.npp.1300713)

    • Search Google Scholar
    • Export Citation
  • Wang L, Andersson S, Warner M & Gustafsson JA 2003 Estrogen receptor (ER)beta knockout mice reveal a role for ERbeta in migration of cortical neurons in the developing brain. PNAS 100 703708. (https://doi.org/10.1073/pnas.242735799)

    • Search Google Scholar
    • Export Citation
  • Wang H-R, Pei S-Y, Fan D-X, Liu Y-H, Pan X-F, Song F-X, Deng S-H, Qiu H-B & Zhang N 2020a Luteolin protects pheochromocytoma (PC-12) cells against A-induced cell apoptosis through the ER/ERK/MAPK signalling pathway. Evidence-Based Complementary and Alternative Medicine 2020 2861978.

    • Search Google Scholar
    • Export Citation
  • Wang YX, Xia ZH, Jiang X, Li LX, Wang HG, An D & Liu YQ 2020b Genistein inhibits amyloid peptide 25–35-induced neuronal death by modulating estrogen receptors, choline acetyltransferase and glutamate receptors. Archives of Biochemistry and Biophysics 693 108561. (https://doi.org/10.1016/j.abb.2020.108561)

    • Search Google Scholar
    • Export Citation
  • Wang Z, Xie R, Yang X, Yin H, Li X, Liu T, Ma Y, Gao J, Zang Z & Ruan R et al.2021 Female mice lacking ERβ display excitatory/inhibitory synaptic imbalance to drive the pathogenesis of temporal lobe epilepsy. Theranostics 11 60746089. (https://doi.org/10.7150/thno.56331)

    • Search Google Scholar
    • Export Citation
  • Warner M & Gustafsson JA 2015 DHEA – a precursor of ERbeta ligands. Journal of Steroid Biochemistry and Molecular Biology 145 245247. (https://doi.org/10.1016/j.jsbmb.2014.08.003)

    • Search Google Scholar
    • Export Citation
  • Warner M, Wu WF, Montanholi L, Nalvarte I, Antonson P & Gustafsson JA 2020 Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene. PNAS 117 49024909. (https://doi.org/10.1073/pnas.1920478117)

    • Search Google Scholar
    • Export Citation
  • Wei Y, Zhou J, Wu J & Huang J 2019 ERβ promotes Aβ degradation via the modulation of autophagy. Cell Death and Disease 10 565. (https://doi.org/10.1038/s41419-019-1786-8)

    • Search Google Scholar
    • Export Citation
  • Weihua Z, Lathe R, Warner M & Gustafsson JA 2002 An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth. PNAS 99 1358913594. (https://doi.org/10.1073/pnas.162477299)

    • Search Google Scholar
    • Export Citation
  • Wolfe A & Wu S 2012 Estrogen receptor-beta in the gonadotropin-releasing hormone neuron. Seminars in Reproductive Medicine 30 2331. (https://doi.org/10.1055/s-0031-1299594)

    • Search Google Scholar
    • Export Citation
  • Wu WF, Tan XJ, Dai YB, Krishnan V, Warner M & Gustafsson 2013 Targeting estrogen receptor beta in microglia and T cells to treat experimental autoimmune encephalomyelitis. PNAS 110 35433548. (https://doi.org/10.1073/pnas.1300313110)

    • Search Google Scholar
    • Export Citation
  • Wu WF, Maneix L, Insunza J, Nalvarte I, Antonson P, Kere J, Yu NY, Tohonen V, Katayama S & Einarsdottir E et al.2017 Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate. PNAS 114 E3816E3822. (https://doi.org/10.1073/pnas.1702211114)

    • Search Google Scholar
    • Export Citation
  • Xie W, Ge X, Li L, Yao A, Wang X, Li M, Gong X, Chu Z, Lu Z & Huang X et al.2018 Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Molecular Autism 9 43. (https://doi.org/10.1186/s13229-018-0225-5)

    • Search Google Scholar
    • Export Citation
  • Yakimchuk K, Norin S, Kimby E, Hagglund H, Warner M & Gustafsson 2012 Up-regulated estrogen receptor beta2 in chronic lymphocytic leukemia. Leukemia and Lymphoma 53 139144. (https://doi.org/10.3109/10428194.2011.605187)

    • Search Google Scholar
    • Export Citation
  • Yan S, Dey P, Ziegler Y, Jiao X, Kim SH, Katzenellenbogen JA & Katzenellenbogen BS 2021 Contrasting activities of estrogen receptor beta isoforms in triple negative breast cancer. Breast Cancer Research and Treatment 185 281292. (https://doi.org/10.1007/s10549-020-05948-0)

    • Search Google Scholar
    • Export Citation
  • Yang F, Tao J, Xu L, Zhao N, Chen J, Chen W, Zhu Y & Qiu J 2014 Estradiol decreases rat depressive behavior by estrogen receptor beta but not alpha: no correlation with plasma corticosterone. NeuroReport 25 100104. (https://doi.org/10.1097/WNR.0000000000000052)

    • Search Google Scholar
    • Export Citation
  • Yang F, Cheung A, Tao J, Zhao N, Wan W & Sheng J 2019 Physiological dosages of estradiol and diarylpropionitrile decrease depressive behavior and increase tryptophan hydroxylase expression in the dorsal raphe nucleus of rats subjected to the forced swim test. NeuroReport 30 6670. (https://doi.org/10.1097/WNR.0000000000001158)

    • Search Google Scholar
    • Export Citation
  • Yao PL, Gonzalez FJ & Peters JM 2014 Targeting estrogen receptor-beta for the prevention of nonmelanoma skin cancer. Cancer Prevention Research 7 182185. (https://doi.org/10.1158/1940-6207.CAPR-13-0409)

    • Search Google Scholar
    • Export Citation
  • Younes M & Honma N 2011 Estrogen receptor beta. Archives of Pathology and Laboratory Medicine 135 6366. (https://doi.org/10.5858/2010-0448-RAR.1)

    • Search Google Scholar
    • Export Citation
  • Zhao C, Gao H, Liu Y, Papoutsi Z, Jaffrey S, Gustafsson JA & Dahlman-Wright K 2010 Genome-wide mapping of estrogen receptor-beta-binding regions reveals extensive cross-talk with transcription factor activator protein-1. Cancer Research 70 51745183. (https://doi.org/10.1158/0008-5472.CAN-09-4407)

    • Search Google Scholar
    • Export Citation
  • Zhou Q, Nie R, Prins GS, Saunders PT, Katzenellenbogen BS & Hess RA 2002 Localization of androgen and estrogen receptors in adult male mouse reproductive tract. Journal of Andrology 23 870881.

    • Search Google Scholar
    • Export Citation

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1327 1327 610
PDF Downloads 176 176 101
  • Aggelakopoulou M, Kourepini E, Paschalidis N & Panoutsakopoulou V 2016 ERβ in CD4+ T cells is crucial for ligand-mediated suppression of central nervous system autoimmunity. Journal of Immunology 196 49474956. (https://doi.org/10.4049/jimmunol.1600246)

    • Search Google Scholar
    • Export Citation
  • Bialesova L, Xu L, Gustafsson , Haldosen LA, Zhao C & Dahlman-Wright K 2017 Estrogen receptor beta2 induces proliferation and invasiveness of triple negative breast cancer cells: association with regulation of PHD3 and HIF-1alpha. Oncotarget 8 7662276633. (https://doi.org/10.18632/oncotarget.20635)

    • Search Google Scholar
    • Export Citation
  • Campbell-Thompson M, Lynch IJ & Bhardwaj B 2001 Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. Cancer Research 61 632640.

    • Search Google Scholar
    • Export Citation
  • Carroll VM, Jeyakumar M, Carlson KE & Katzenellenbogen JA 2012 Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor beta-selective ligands. Journal of Medicinal Chemistry 55 528537. (https://doi.org/10.1021/jm201436k)

    • Search Google Scholar
    • Export Citation
  • Cvoro A, Tatomer D, Tee MK, Zogovic T, Harris HA & Leitman DC 2008 Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. Journal of Immunology 180 630636. (https://doi.org/10.4049/jimmunol.180.1.630)

    • Search Google Scholar
    • Export Citation
  • Dey P, Velazquez-Villegas LA, Faria M, Turner A, Jonsson P, Webb P, Williams C, Gustafsson & Strom AM 2015 Estrogen receptor beta2 induces hypoxia signature of gene expression by stabilizing HIF-1alpha in prostate cancer. PLoS ONE 10 e0128239. (https://doi.org/10.1371/journal.pone.0128239)

    • Search Google Scholar
    • Export Citation
  • Dixon RA 2004 Phytoestrogens. Annual Review of Plant Biology 55 225261. (https://doi.org/10.1146/annurev.arplant.55.031903.141729)

  • Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P & Mark M 2000 Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 127 42774291. (https://doi.org/10.1242/dev.127.19.4277)

    • Search Google Scholar
    • Export Citation
  • Esslimani-Sahla M, Simony-Lafontaine J, Kramar A, Lavaill R, Mollevi C, Warner M, Gustafsson JA & Rochefort H 2004 Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer. Clinical Cancer Research 10 57695776. (https://doi.org/10.1158/1078-0432.CCR-04-0389)

    • Search Google Scholar
    • Export Citation
  • Fan X, Warner M & Gustafsson JA 2006 Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons. PNAS 103 1933819343. (https://doi.org/10.1073/pnas.0609663103)

    • Search Google Scholar
    • Export Citation
  • Fujimura T, Takahashi S, Urano T, Ogawa S, Ouchi Y, Kitamura T, Muramatsu M & Inoue S 2001 Differential expression of estrogen receptor beta (ERbeta) and its C-terminal truncated splice variant ERbetacx as prognostic predictors in human prostatic cancer. Biochemical and Biophysical Research Communications 289 692699. (https://doi.org/10.1006/bbrc.2001.6038)

    • Search Google Scholar
    • Export Citation
  • Hamilton-Burke W, Coleman L, Cummings M, Green CA, Holliday DL, Horgan K, Maraqa L, Peter MB, Pollock S & Shaaban AM et al.2010 Phosphorylation of estrogen receptor beta at serine 105 is associated with good prognosis in breast cancer. American Journal of Pathology 177 10791086. (https://doi.org/10.2353/ajpath.2010.090886)

    • Search Google Scholar
    • Export Citation
  • Harris HA 2007 Estrogen receptor-beta: recent lessons from in vivo studies. Molecular Endocrinology 21 113. (https://doi.org/10.1210/me.2005-0459)

    • Search Google Scholar
    • Export Citation
  • Harris HA, Katzenellenbogen JA & Katzenellenbogen BS 2002 Characterization of the biological roles of the estrogen receptors, ERalpha and ERbeta, in estrogen target tissues in vivo through the use of an ERalpha-selective ligand. Endocrinology 143 41724177. (https://doi.org/10.1210/en.2002-220403)

    • Search Google Scholar
    • Export Citation
  • Harris DM, Besselink E, Henning SM, Go VL & Heber D 2005 Phytoestrogens induce differential estrogen receptor alpha- or beta-mediated responses in transfected breast cancer cells. Experimental Biology and Medicine 230 558568. (https://doi.org/10.1177/153537020523000807)

    • Search Google Scholar
    • Export Citation
  • Hughes ZA, Liu F, Platt BJ, Dwyer JM, Pulicicchio CM, Zhang G, Schechter LE, Rosenzweig-Lipson S & Day M 2008 WAY-200070, a selective agonist of estrogen receptor beta as a potential novel anxiolytic/antidepressant agent. Neuropharmacology 54 11361142. (https://doi.org/10.1016/j.neuropharm.2008.03.004)

    • Search Google Scholar
    • Export Citation
  • Inoue S, Ogawa S, Horie K, Hoshino S, Goto W, Hosoi T, Tsutsumi O, Muramatsu M & Ouchi Y 2000 An estrogen receptor beta isoform that lacks exon 5 has dominant negative activity on both ERalpha and ERbeta. Biochemical and Biophysical Research Communications 279 814819. (https://doi.org/10.1006/bbrc.2000.4010)

    • Search Google Scholar
    • Export Citation
  • Isaacs JT, Mcdermott IR & Coffey DS 1979 Characterization of two new enzymatic activities of the rat ventral prostate: 5 alpha-androstane-3 beta, 17 beta-diol 6 alpha-hydroxylase and 5 alpha-androstane-3 beta, 17 beta-diol 7 alpha-hydroxylase. Steroids 33 675692. (https://doi.org/10.1016/0039-128x(7990116-8)

    • Search Google Scholar
    • Export Citation
  • Ishii H, Kobayashi M & Sakuma Y 2010 Alternative promoter usage and alternative splicing of the rat estrogen receptor alpha gene generate numerous mRNA variants with distinct 5’-ends. Journal of Steroid Biochemistry and Molecular Biology 118 5969. (https://doi.org/10.1016/j.jsbmb.2009.10.001)

    • Search Google Scholar
    • Export Citation
  • Karim H, Kim SH, Lapato AS, Yasui N, Katzenellenbogen JA & Tiwari-Woodruff SK 2018 Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination. PNAS 115 62916296. (https://doi.org/10.1073/pnas.1721732115)

    • Search Google Scholar
    • Export Citation
  • Karim H, Kim SH, Lauderdale K, Lapato AS, Atkinson K, Yasui N, Yamate-Morgan H, Sekyi M, Katzenellenbogen JA & Tiwari-Woodruff SK 2019 Analogues of ERβ ligand chloroindazole exert immunomodulatory and remyelinating effects in a mouse model of multiple sclerosis. Scientific Reports 9 503. (https://doi.org/10.1038/s41598-018-37420-x)

    • Search Google Scholar
    • Export Citation
  • Khalaj AJ, Yoon J, Nakai J, Winchester Z, Moore SM, Yoo T, Martinez-Torres L, Kumar S, Itoh N & Tiwari-Woodruff SK 2013 Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand. PNAS 110 1912519130. (https://doi.org/10.1073/pnas.1311763110)

    • Search Google Scholar
    • Export Citation
  • Konduri S & Schwarz RE 2007 Estrogen receptor beta/alpha ratio predicts response of pancreatic cancer cells to estrogens and phytoestrogens. Journal of Surgical Research 140 5566. (https://doi.org/10.1016/j.jss.2006.10.015)

    • Search Google Scholar
    • Export Citation
  • Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA & Smithies O 1998 Generation and reproductive phenotypes of mice lacking estrogen receptor beta. PNAS 95 1567715682. (https://doi.org/10.1073/pnas.95.26.15677)

    • Search Google Scholar
    • Export Citation
  • Kudwa AE, Mcgivern RF & Handa RJ 2014 Estrogen receptor β and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats. Physiology and Behavior 129 287296. (https://doi.org/10.1016/j.physbeh.2014.03.004)

    • Search Google Scholar
    • Export Citation
  • Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S & Gustafsson JA 1996 Cloning of a novel receptor expressed in rat prostate and ovary. PNAS 93 59255930. (https://doi.org/10.1073/pnas.93.12.5925)

    • Search Google Scholar
    • Export Citation
  • Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, Van Der Saag PT, Van Der Burg B & Gustafsson JA 1998 Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139 42524263. (https://doi.org/10.1210/endo.139.10.6216)

    • Search Google Scholar
    • Export Citation
  • Kumar S, Patel R, Moore S, Crawford DK, Suwanna N, Mangiardi M & Tiwari-Woodruff SK 2013 Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiology of Disease 56 131144. (https://doi.org/10.1016/j.nbd.2013.04.005)

    • Search Google Scholar
    • Export Citation
  • Leung YK, Lam HM, Wu S, Song D, Levin L, Cheng L, Wu CL & Ho SM 2010 Estrogen receptor beta2 and beta5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion. Endocrine-Related Cancer 17 675689. (https://doi.org/10.1677/ERC-09-0294)

    • Search Google Scholar
    • Export Citation
  • Li L, Xue Z, Chen L, Chen X, Wang H & Wang X 2017 Puerarin suppression of Aβ-induced primary cortical neuron death is largely dependent on ERβ. Brain Research 1657 8794. (https://doi.org/10.1016/j.brainres.2016.11.023)

    • Search Google Scholar
    • Export Citation
  • Liu J, Sareddy GR, Zhou M, Viswanadhapalli S, Li X, Lai Z, Tekmal RR, Brenner A & Vadlamudi RK 2018 Differential effects of estrogen receptor beta isoforms on glioblastoma progression. Cancer Research 78 31763189. (https://doi.org/10.1158/0008-5472.CAN-17-3470)

    • Search Google Scholar
    • Export Citation
  • Liu X, Deng J, Li R, Tan C, Li H, Yang Z, Chen L, Chen Y & Tan X 2019 ERβ-selective agonist alleviates inflammation in a multiple sclerosis model via regulation of MHC II in microglia. American Journal of Translational Research 11 44114424.

    • Search Google Scholar
    • Export Citation
  • Mak P, Chang C, Pursell B & Mercurio AM 2013 Estrogen receptor beta sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription. PNAS 110 47084713. (https://doi.org/10.1073/pnas.1221654110)

    • Search Google Scholar
    • Export Citation
  • Makinen S, Makela S, Weihua Z, Warner M, Rosenlund B, Salmi S, Hovatta O & Gustafsson JA 2001 Localization of oestrogen receptors alpha and beta in human testis. Molecular Human Reproduction 7 497503. (https://doi.org/10.1093/molehr/7.6.497)

    • Search Google Scholar
    • Export Citation
  • McFarland K, Price DL, Davis CN, Ma JN, Bonhaus DW, Burstein ES & Olsson R 2013 AC-186, a selective nonsteroidal estrogen receptor β agonist, shows gender specific neuroprotection in a Parkinson’s disease rat model. ACS Chemical Neuroscience 4 12491255. (https://doi.org/10.1021/cn400132u)

    • Search Google Scholar
    • Export Citation
  • Merchenthaler I, Hoffman GE & Lane MV 2005 Estrogen and estrogen receptor-{beta} (ER{beta})-selective ligands induce galanin expression within gonadotropin hormone-releasing hormone-immunoreactive neurons in the female rat brain. Endocrinology 146 27602765. (https://doi.org/10.1210/en.2004-1562)

    • Search Google Scholar
    • Export Citation
  • Milner TA, Ayoola K, Drake CT, Herrick SP, Tabori NE, Mcewen BS, Warrier S & Alves SE 2005 Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation. Journal of Comparative Neurology 491 8195. (https://doi.org/10.1002/cne.20724)

    • Search Google Scholar
    • Export Citation
  • Moore JT, Mckee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL, Kliewer SA, Lehmann JM & Willson TM 1998 Cloning and characterization of human estrogen receptor beta isoforms. Biochemical and Biophysical Research Communications 247 7578. (https://doi.org/10.1006/bbrc.1998.8738)

    • Search Google Scholar
    • Export Citation
  • Moore SM, Khalaj AJ, Kumar S, Winchester Z, Yoon J, Yoo T, Martinez-Torres L, Yasui N, Katzenellenbogen JA & Tiwari-Woodruff SK 2014 Multiple functional therapeutic effects of the estrogen receptor beta agonist indazole-Cl in a mouse model of multiple sclerosis. PNAS 111 1806118066. (https://doi.org/10.1073/pnas.1411294111)

    • Search Google Scholar
    • Export Citation
  • Muthusamy S, Andersson S, Kim HJ, Butler R, Waage L, Bergerheim U & Gustafsson JA 2011 Estrogen receptor beta and 17beta-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer. PNAS 108 2009020094.

    • Search Google Scholar
    • Export Citation
  • Nelson AW, Groen AJ, Miller JL, Warren AY, Holmes KA, Tarulli GA, Tilley WD, Katzenellenbogen BS, Hawse JR & Gnanapragasam VJ et al.2016 Corrigendum to ‘Comprehensive assessment of estrogen receptor beta antibodies in cancer cell line models and tissue reveals critical limitations in reagent specificity’ [Mol. Cell Endocrinol. 440 (2016) 138-150]. Molecular and Cellular Endocrinology 44 3 1 75.

    • Search Google Scholar
    • Export Citation
  • Pettersson H, Holmberg L, Axelson M & Norlin M 2008 CYP7B1-mediated metabolism of dehydroepiandrosterone and 5alpha-androstane-3beta,17beta-diol-potential role(s) for estrogen signaling. FEBS Journal 275 17781789. (https://doi.org/10.1111/j.1742-4658.2008.06336.x)

    • Search Google Scholar
    • Export Citation
  • Roehrborn CG, Spann ME, Myers SL, Serviss CR, Hu L & Jin Y 2015 Estrogen receptor beta agonist LY500307 fails to improve symptoms in men with enlarged prostate secondary to benign prostatic hypertrophy. Prostate Cancer and Prostatic Diseases 18 4348. (https://doi.org/10.1038/pcan.2014.43)

    • Search Google Scholar
    • Export Citation
  • Salama RM, Tadros MG, Schaalan MF, Bahaa N, Abdel-Tawab AM & Khalifa AE 2018 Potential neuroprotective effect of androst-5-ene-3β, 17β-diol (ADIOL) on the striatum, and substantia nigra in Parkinson’s disease rat model. Journal of Cellular Physiology 233 59816000. (https://doi.org/10.1002/jcp.26412)

    • Search Google Scholar
    • Export Citation
  • Sareddy GR, Nair BC, Gonugunta VK, Zhang QG, Brenner A, Brann DW, Tekmal RR & Vadlamudi RK 2012 Therapeutic significance of estrogen receptor β agonists in gliomas. Molecular Cancer Therapeutics 11 11741182. (https://doi.org/10.1158/1535-7163.MCT-11-0960)

    • Search Google Scholar
    • Export Citation
  • Sasayama D, Sugiyama N, Yonekubo S, Pawlak A, Murasawa H, Nakamura M, Hayashi M, Ogawa T, Moro M & Washizuka S et al.2017 Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice. Scientific Reports 7 4663. (https://doi.org/10.1038/s41598-017-04946-5)

    • Search Google Scholar
    • Export Citation
  • Sneddon SF, Walther N & Saunders PT 2005 Expression of androgen and estrogen receptors in Sertoli cells: studies using the mouse SK11 cell line. Endocrinology 146 53045312. (https://doi.org/10.1210/en.2005-0914)

    • Search Google Scholar
    • Export Citation
  • Song XY, Wu WF, Gabbi C, Dai YB, So M, Chaurasiya SP, Wang L, Warner M & Gustafsson 2019 Retinal and optic nerve degeneration in liver X receptor beta knockout mice. PNAS 116 1650716512. (https://doi.org/10.1073/pnas.1904719116)

    • Search Google Scholar
    • Export Citation
  • Stapleton G, Steel M, Richardson M, Mason JO, Rose KA, Morris RG & Lathe R 1995 A novel cytochrome P450 expressed primarily in brain. Journal of Biological Chemistry 270 2973929745. (https://doi.org/10.1074/jbc.270.50.29739)

    • Search Google Scholar
    • Export Citation
  • Sugiyama N, Andersson S, Lathe R, Fan X, Alonso-Magdalena P, Schwend T, Nalvarte I, Warner M & Gustafsson JA 2009 Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain. Molecular Psychiatry 14 22323 2, 117. (https://doi.org/10.1038/mp.2008.118)

    • Search Google Scholar
    • Export Citation
  • Sundin M, Warner M, Haaparanta T & Gustafsson JA 1987 Isolation and catalytic activity of cytochrome P-450 from ventral prostate of control rats. Journal of Biological Chemistry 262 1229312297. (https://doi.org/10.1016/S0021-9258(1845350-1)

    • Search Google Scholar
    • Export Citation
  • Suzuki H, Barros RP, Sugiyama N, Krishnan V, Yaden BC, Kim HJ, Warner M & Gustafsson 2013 Involvement of estrogen receptor beta in maintenance of serotonergic neurons of the dorsal raphe. Molecular Psychiatry 18 674680. (https://doi.org/10.1038/mp.2012.62)

    • Search Google Scholar
    • Export Citation
  • Tan XJ, Dai YB, Wu WF, Kim HJ, Barros RP, Richardson TI, Yaden BC, Warner M, Mckinzie DL & Krishnan V et al.2012 Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor beta ligand. PNAS 109 17081712. (https://doi.org/10.1073/pnas.1121162109)

    • Search Google Scholar
    • Export Citation
  • Thieulant ML, Samperez S & Jouan P 1981 Evidence for 5 alpha-androstane-3 beta, 17 beta-diol binding to the estrogen receptor in the cytosol from male rat pituitary. Endocrinology 108 15521560. (https://doi.org/10.1210/endo-108-4-1552)

    • Search Google Scholar
    • Export Citation
  • Valdés-Sustaita B, Estrada-Camarena E, González-Trujano ME & López-Rubalcava C 2021 Estrogen receptors-β and serotonin mediate the antidepressant-like effect of an aqueous extract of pomegranate in ovariectomized rats. Neurochemistry International 142 104904. (https://doi.org/10.1016/j.neuint.2020.104904)

    • Search Google Scholar
    • Export Citation
  • Velísková J 2007 Estrogens and epilepsy: why are we so excited? Neuroscientist 13 7788. (https://doi.org/10.1177/1073858406295827)

  • Vinayagam R, Sibson DR, Holcombe C, Aachi V & Davies MP 2007 Association of oestrogen receptor beta 2 (ER beta 2/ER beta cx) with outcome of adjuvant endocrine treatment for primary breast cancer – a retrospective study. BMC Cancer 7 131. (https://doi.org/10.1186/1471-2407-7-131)

    • Search Google Scholar
    • Export Citation
  • Walf AA & Frye CA 2005 ERbeta-selective estrogen receptor modulators produce antianxiety behavior when administered systemically to ovariectomized rats. Neuropsychopharmacology 30 15981609. (https://doi.org/10.1038/sj.npp.1300713)

    • Search Google Scholar
    • Export Citation
  • Wang L, Andersson S, Warner M & Gustafsson JA 2003 Estrogen receptor (ER)beta knockout mice reveal a role for ERbeta in migration of cortical neurons in the developing brain. PNAS 100 703708. (https://doi.org/10.1073/pnas.242735799)

    • Search Google Scholar
    • Export Citation
  • Wang H-R, Pei S-Y, Fan D-X, Liu Y-H, Pan X-F, Song F-X, Deng S-H, Qiu H-B & Zhang N 2020a Luteolin protects pheochromocytoma (PC-12) cells against A-induced cell apoptosis through the ER/ERK/MAPK signalling pathway. Evidence-Based Complementary and Alternative Medicine 2020 2861978.

    • Search Google Scholar
    • Export Citation
  • Wang YX, Xia ZH, Jiang X, Li LX, Wang HG, An D & Liu YQ 2020b Genistein inhibits amyloid peptide 25–35-induced neuronal death by modulating estrogen receptors, choline acetyltransferase and glutamate receptors. Archives of Biochemistry and Biophysics 693 108561. (https://doi.org/10.1016/j.abb.2020.108561)

    • Search Google Scholar
    • Export Citation
  • Wang Z, Xie R, Yang X, Yin H, Li X, Liu T, Ma Y, Gao J, Zang Z & Ruan R et al.2021 Female mice lacking ERβ display excitatory/inhibitory synaptic imbalance to drive the pathogenesis of temporal lobe epilepsy. Theranostics 11 60746089. (https://doi.org/10.7150/thno.56331)

    • Search Google Scholar
    • Export Citation
  • Warner M & Gustafsson JA 2015 DHEA – a precursor of ERbeta ligands. Journal of Steroid Biochemistry and Molecular Biology 145 245247. (https://doi.org/10.1016/j.jsbmb.2014.08.003)

    • Search Google Scholar
    • Export Citation
  • Warner M, Wu WF, Montanholi L, Nalvarte I, Antonson P & Gustafsson JA 2020 Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene. PNAS 117 49024909. (https://doi.org/10.1073/pnas.1920478117)

    • Search Google Scholar
    • Export Citation
  • Wei Y, Zhou J, Wu J & Huang J 2019 ERβ promotes Aβ degradation via the modulation of autophagy. Cell Death and Disease 10 565. (https://doi.org/10.1038/s41419-019-1786-8)

    • Search Google Scholar
    • Export Citation
  • Weihua Z, Lathe R, Warner M & Gustafsson JA 2002 An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth. PNAS 99 1358913594. (https://doi.org/10.1073/pnas.162477299)

    • Search Google Scholar
    • Export Citation
  • Wolfe A & Wu S 2012 Estrogen receptor-beta in the gonadotropin-releasing hormone neuron. Seminars in Reproductive Medicine 30 2331. (https://doi.org/10.1055/s-0031-1299594)

    • Search Google Scholar
    • Export Citation
  • Wu WF, Tan XJ, Dai YB, Krishnan V, Warner M & Gustafsson 2013 Targeting estrogen receptor beta in microglia and T cells to treat experimental autoimmune encephalomyelitis. PNAS 110 35433548. (https://doi.org/10.1073/pnas.1300313110)

    • Search Google Scholar
    • Export Citation
  • Wu WF, Maneix L, Insunza J, Nalvarte I, Antonson P, Kere J, Yu NY, Tohonen V, Katayama S & Einarsdottir E et al.2017 Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate. PNAS 114 E3816E3822. (https://doi.org/10.1073/pnas.1702211114)

    • Search Google Scholar
    • Export Citation
  • Xie W, Ge X, Li L, Yao A, Wang X, Li M, Gong X, Chu Z, Lu Z & Huang X et al.2018 Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Molecular Autism 9 43. (https://doi.org/10.1186/s13229-018-0225-5)

    • Search Google Scholar
    • Export Citation
  • Yakimchuk K, Norin S, Kimby E, Hagglund H, Warner M & Gustafsson 2012 Up-regulated estrogen receptor beta2 in chronic lymphocytic leukemia. Leukemia and Lymphoma 53 139144. (https://doi.org/10.3109/10428194.2011.605187)

    • Search Google Scholar
    • Export Citation
  • Yan S, Dey P, Ziegler Y, Jiao X, Kim SH, Katzenellenbogen JA & Katzenellenbogen BS 2021 Contrasting activities of estrogen receptor beta isoforms in triple negative breast cancer. Breast Cancer Research and Treatment 185 281292. (https://doi.org/10.1007/s10549-020-05948-0)

    • Search Google Scholar
    • Export Citation
  • Yang F, Tao J, Xu L, Zhao N, Chen J, Chen W, Zhu Y & Qiu J 2014 Estradiol decreases rat depressive behavior by estrogen receptor beta but not alpha: no correlation with plasma corticosterone. NeuroReport 25 100104. (https://doi.org/10.1097/WNR.0000000000000052)

    • Search Google Scholar
    • Export Citation
  • Yang F, Cheung A, Tao J, Zhao N, Wan W & Sheng J 2019 Physiological dosages of estradiol and diarylpropionitrile decrease depressive behavior and increase tryptophan hydroxylase expression in the dorsal raphe nucleus of rats subjected to the forced swim test. NeuroReport 30 6670. (https://doi.org/10.1097/WNR.0000000000001158)

    • Search Google Scholar
    • Export Citation
  • Yao PL, Gonzalez FJ & Peters JM 2014 Targeting estrogen receptor-beta for the prevention of nonmelanoma skin cancer. Cancer Prevention Research 7 182185. (https://doi.org/10.1158/1940-6207.CAPR-13-0409)

    • Search Google Scholar
    • Export Citation
  • Younes M & Honma N 2011 Estrogen receptor beta. Archives of Pathology and Laboratory Medicine 135 6366. (https://doi.org/10.5858/2010-0448-RAR.1)

    • Search Google Scholar
    • Export Citation
  • Zhao C, Gao H, Liu Y, Papoutsi Z, Jaffrey S, Gustafsson JA & Dahlman-Wright K 2010 Genome-wide mapping of estrogen receptor-beta-binding regions reveals extensive cross-talk with transcription factor activator protein-1. Cancer Research 70 51745183. (https://doi.org/10.1158/0008-5472.CAN-09-4407)

    • Search Google Scholar
    • Export Citation
  • Zhou Q, Nie R, Prins GS, Saunders PT, Katzenellenbogen BS & Hess RA 2002 Localization of androgen and estrogen receptors in adult male mouse reproductive tract. Journal of Andrology 23 870881.

    • Search Google Scholar
    • Export Citation