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Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ERβ and significantly lower ERα levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ERα and ERβ in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies.

Breast cancer (BC) is a malignant tumor that develops in the mammary gland due to uncontrolled cell proliferation. Estrogen receptor (ER) signaling, mediated by 17β-estradiol (E2), plays a crucial role in regulating cell proliferation, differentiation, and survival. Specifically, the binding of E2 to the estrogen receptor alpha (ERα) increases cell proliferation. Conversely, selective estrogen receptor beta (ERβ) agonists inhibit cancer cell proliferation by suppressing the expression of oncogenes, making ERβ an important therapeutic target. Given the urgent need for targeted and effective therapies for BC, we implemented a strategy based on multicomplex pharmacophores modeling of ERβ (MPMERβ) and ERα (MPMERα), performing a virtual cross-screening of databases of clinically approved and experimental drugs to identify those with high affinity and stereoelectronic complementarity with the ERβ agonist pharmacophore hypothesis. The implementation of a chemoinformatic strategy enabled the identification of Sobetirome, Labetalol, and Procaterol as molecular hits on the ERβ pharmacophore map. Procaterol showed the most significant antiproliferative activity in vitro assays, with IC50 values of 21.26 and 36.10 µM in MCF-7 and MDA-MB-231, respectively. It is imperative to note that these findings require experimental validation of the ERβ activation pathways to strengthen the possible therapeutic repurposing of the drugs selected through our in silico approach. Finally, this strategy not only facilitates drug repurposing under in silico simulation but also provides valuable information for the rational design of new drugs against BC.

We recently demonstrated that short-term estradiol (E2) treatment improved insulin-mediated suppression of lipolysis in postmenopausal women, but to a greater extent in those who were late compared to early postmenopausal. In this follow-up study we tested whether subcutaneous adipose tissue (SAT) expression of estrogen receptors (ER) α and β differs between early and late postmenopausal women. We further tested whether the balance of ERα to ERβ in SAT determined the effect of E2 on SAT insulin sensitivity. The present study included 35 women who were ≤6 years past menopause (EPM; n = 16) or ≥10 years past menopause (LPM; n = 19). Fasted SAT samples were taken following 1-week transdermal E2 treatment or placebo (PL) in a random cross-over design. Samples were analyzed for nuclear/cytosolic protein content and mRNA expression using Western blot and qPCR, respectively. While ESR1 increased slightly (~1.4-fold) following E2 treatment in both groups, ERα and ERβ protein expression did not differ between groups at baseline or in response to E2. However, the balance of ERα/ERβ protein in the SAT nuclear fraction increased 10% in EPM compared to a 25% decrease in LPM women (group x treatment interaction, p<0.05). A greater proportion of ERα/ERβ protein in the nuclear fraction of SAT at baseline (placebo day) was associated with greater reduction in SAT insulin resistance (i.e., better suppression of lipolysis, EC50) in response to E2 (r = -0.431, p<0.05). In conclusion, there do not appear to be differences in the proportion of adipose tissue ERα/ERβ protein in late, compared to early, postmenopausal women. However, the balance of ERα/ERβ may be important for E2-mediated improvement in adipose tissue insulin sensitivity. Clinical Trials#: NCT01605071.

The discovery of oestrogen receptor β (ERβ/ ESR2 ) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ERα ( ESR1 ) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ERβ antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ERβ in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ERβ protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray. A large body of work into the role of oestrogen receptor b (ERb) in breast cancer is contradictory, hindering future progress. Here the authors conduct extensive validation of anti-ERb antibodies , and show that normal and cancerous breast tissue do not express ERb, consistent with RNA-seq data.

Background Breast cancer, a leading cause of female mortality, is closely linked to mutations in estrogen receptor beta (ESR2), particularly in the ligand‐binding domain, which contributed to altered signaling pathways and uncontrolled cell growth. Objectives/Aims This study investigates the molecular and structural aspects of ESR2 mutant proteins to identify shared pharmacophoric regions of ESR2 mutant proteins and potential therapeutic targets aligned within the pharmacophore model. Methods This study was initiated by establishing a common pharmacophore model among three mutant ESR2 proteins (PDB ID: 2FSZ, 7XVZ, and 7XWR). The generated shared feature pharmacophore (SFP) includes four primary binding interactions: Hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic interactions (HPho), and Aromatic interactions (Ar), along with halogen bond donors (XBD) and totalling 11 features (HBD: 2, HBA: 3, HPho: 3, Ar: 2, XBD: 1). By employing an in‐house Python script, these 11 features distributed into 336 combinations, which were used as query to isolate a drug library of 41,248 compounds and subjected to virtual screening through the generated SFP. Results The virtual screening demonstrated 33 hits showing potential pharmacophoric fit scores and low RMSD value. The top four compounds: ZINC94272748, ZINC79046938, ZINC05925939, and ZINC59928516 showed a fit score of more than 86% and satisfied the Lipinski rule of five. These four compounds and a control underwent molecular (XP Glide mode) docking analysis against wild‐type ESR2 protein (PDB ID: 1QKM), resulting in binding affinity of −8.26, −5.73, −10.80, and −8.42 kcal/mol, respectively, along with the control −7.2 kcal/mol. Furthermore, the stability of the selected candidates was determined through molecular dynamics (MD) simulations of 200 ns and MM‐GBSA analysis. Conclusion Based on MD simulations and MM‐GBSA analysis, our study identified ZINC05925939 as a promising ESR2 inhibitor among the top four hits. However, it is essential to conduct further wet lab evaluation to assess its efficacy.

High-mobility group box 2 (HMGB2) is a chromatin-associated protein that is an important regulator of gene transcription, recombination, and repair processes. The functional importance of HMGB2 has been reported in various organs, including the testis, heart, and cartilage. However, its role in the ovary is largely unknown. In this study, ovary tissues from wild-type (WT) and HMGB2-knock-out (KO) mice were examined by histopathological staining and immunohistochemistry. The ovary size and weight were significantly lower in HMGB2-KO mice than in age-matched WT littermates. Histopathological analysis revealed ovarian atrophy and progressive fibrosis in 10-month-old HMGB2-KO mouse ovaries. Compared to age-matched WT mice, the numbers of oocytes and developing follicles were significantly decreased at 2 months of age and were completely depleted at 10 months of age in HMGB2-KO mice. Immunohistochemistry revealed the expression of HMGB2 in the granulosa cells of developing follicles, oocytes, some corpora lutea, and stromal cells. Importantly, HMGB2-positive cells were co-localized with estrogen receptor beta (ERβ), but not ERα. Estrogen response element-binding activity was demonstrated by southwestern histochemistry, and it was decreased in HMGB2-KO mouse ovaries. Cell proliferation activity was also decreased in HMGB2-KO mouse ovaries in parallel with the decreased folliculogenesis. These results indicated that the depletion of HMGB2 induced ovarian atrophy that was characterized by a decreased ovarian size and weight, progressive fibrosis, as well as decreased oocytes and folliculogenesis. In conclusion, we demonstrated the crucial role of HMGB2 in mouse ovarian folliculogenesis through ERβ expression.

Triple Negative Breast Cancer (TNBC) has the worst prognosis among all breast cancers, and survival in patients with recurrence is rarely beyond 12 months due to acquired resistance to chemotherapy, which is the standard of care for these patients. Our hypothesis is that Estrogen Receptor β1 (ERβ1) increases response to chemotherapy but is opposed by ERβ4, which it preferentially dimerizes with. The role of ERβ1 and ERβ4 in influencing chemotherapy sensitivity has never been studied before. CRISPR/CAS9 was used to truncate ERβ1 Ligand Binding Domain (LBD) and knock down the exon unique to ERβ4. We show that the truncated ERβ1 LBD in a variety of mutant p53 TNBC cell lines, where ERβ1 ligand dependent function was inactivated, had increased resistance to Paclitaxel, whereas the ERβ4 knockdown cell line was sensitized to Paclitaxel. We further show that ERβ1 LBD truncation, as well as treatment with ERβ1 antagonist 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a] pyrimidine (PHTPP), leads to increase in the drug efflux transporters. Hypoxia Inducible Factors (HIFs) activate factors involved in pluripotency and regulate the stem cell phenotype, both in normal and cancer cells. Here we show that the ERβ1 and ERβ4 regulate these stem cell markers like SOX2, OCT4, and Nanog in an opposing manner; and we further show that this regulation is mediated by HIFs. We show the increase of cancer cell stemness due to ERβ1 LBD truncation is attenuated when HIF1/2α is knocked down by siRNA. Finally, we show an increase in the breast cancer stem cell population due to ERβ1 antagonist using both ALDEFLUORTM and SOX2/OCT4 response element (SORE6) reporters in SUM159 and MDA-MB-231 cell lines. Since most TNBC cancers are ERβ4 positive, while only a small proportion of TNBC patients are ERβ1 positive, we believe that simultaneous activation of ERβ1 with agonists and inactivation of ERβ4, in combination with paclitaxel, can be more efficacious and yield better outcome for chemotherapy resistant TNBC patients.

To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same breasts have been compared.We are interested in the roles of estrogen receptor β (ERβ) and the cytochrome P450 family (CYPs) as drivers of TNBC. We examined by RNA sequencing the mTNBC and nadj parts of five women. We found more than a fivefold elevation in mTNBC of genes already known to be expressed in TNBC: BIRC5/survivin, Wnt-10A and -7B, matrix metalloproteinases (MMPs), chemokines, anterior gradient proteins, and lysophosphatidic acid receptor and the known basal characteristics of TNBC, sox10, ROPN1B, and Col9a3. There were two unexpected findings: 1) a strong induction of CYPs involved in activation of fatty acids (CYP4), and in inactivation of calcitriol (CYP24A1) and retinoic acid (CYP26A1); and 2) a marked down-regulation of FOS, FRA1, and JUN, known tethering partners of ERβ. ERβ is expressed in 20 to 30% of TNBCs and is being evaluated as a target for treating TNBC. We used ERβ⁺ TNBC patient-derived xenografts in mice and found that the ERβ agonist LY500703 had no effect on growth or proliferation. Expression of CYPs was confirmed by immunohistochemistry in formalin-fixed and paraffin-embedded (FFPE) TNBC. In TNBC cell lines, the CYP4Z1-catalyzed fatty acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) increased proliferation, while calcitriol decreased proliferation but only after inhibition of CYP24A1. We conclude that CYP-mediated pathways can be drivers of TNBC but that ERβ is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ERβ functionless on genes involved in proliferation and inflammation.

Breast and prostate cancers are among the most common of all cancers. They are referred to as hormone‐dependent cancers, because estrogen and androgen are involved in their development and growth. The effects of these hormones are mediated by their respective receptors, estrogen receptor (ER) α and androgen receptor. Around 18 years ago, a second ER, ERβ, which has a very similar structure to ERα, was discovered. Its function has been investigated using a variety of methods and biological systems, leading to our present understanding that ERβ can interact with or inhibit ERα and androgen receptor function directly and/or indirectly, suppress cell growth, and influence responsiveness to endocrine therapy. In order to apply the “inhibition of cell growth” function to cancer treatment, several specific ERβ agonists have been synthesized and are being tested for effectiveness in cancer treatment. We need to keep our eyes on ERβ. Estrogen receptor β (ERβ) has been discovered in 1996 and its function was investigated with various way. ERβ can interact with or inhibit ERα and AR function directly and/or indirectly, suppress cell growth, and influence responsiveness to endocrine therapy. This manuscript summarize our knowledge about the significance of ERβ in breast and prostate cancer.

Labisia pumila var. alata (LP) is an herbaceous shrub commonly used by women to promote health and vitality, alleviate postmenopausal symptoms, and enhance libido. Research indicates that LP possesses significant oestrogenic and antiproliferative properties towards breast cancer; however, the specific mechanisms involved remain unclear. We investigate the oestrogenic effects of LP in inducing apoptosis in human breast adenocarcinoma (MCF-7) cells and the mechanisms underlying this process. Docking analysis reveals that the phytoestrogens in LP can bind to oestrogen receptors (ER), specifically ERα and ERβ. MTT assays demonstrate that LP has a dose- and time-dependent antiproliferative effect on MCF-7 cells. Furthermore, the antiproliferative activity of LP on MCF-7 cells is inhibited by Fulvestrant, indicating that its effects are mediated through oestrogen receptors. Flow cytometry analysis shows that the antiproliferative effect of LP results from the induction of apoptosis in MCF-7 cells. The activation of caspase 3, along with caspase 8 and caspase 9, suggests that LP triggers apoptosis through both intrinsic and extrinsic pathways. The findings regarding the aqueous extract of LP and its impact on the proliferative activity of MCF-7 cells may have significant therapeutic and preventive implications for future drug development, particularly in the context of breast cancer.