Lymphovascular space invasion and estrogen receptor status in high-grade serous ovarian cancer - A multicenter study by the FRANCOGYN group.

BACKGROUND: The aim of this study was to evaluate the impact of Lymphovascular Space Invasion (LVSI) on Overall Survival (OS) and Recurrence-Free Survival (RFS) in patients managed for high-grade serous epithelial ovarian cancer (HGSOC). MATERIALS AND METHODS: Retrospective multicenter study by the FRANCOGYN research group between January 2001 and December 2018. All patients managed for HGSOC and for whom histological slides for the review of LVSI were available, were included. The characteristics of patients with LVSI (LVSI group) were compared to those without LVSI (No LVSI group). A Cox analysis for OS and RFS analysis was performed in all populations. RESULTS: Over the study period, 410 patients were included in the thirteen institutions. Among them, 289 patients had LVSI (33.9%). LVSI was an independent predictive factor for poorer Overall and Recurrence-Free Survival. LVSI affected OS (p<0.001) and RFS (p<0.001), Association of LVSI status and estrogen receptor status (ER) also affected OS and RFS (p = 0.04; p = 0.04 respectively). CONCLUSION: The presence of LVSI in HGSOC has an impact on OS and RFS and should be routinely included in the pathology examination along with ER status.

Hepatic expression profiles of three subtypes of vitellogenin and estrogen receptor during vitellogenesis in cultured female yellowtail.

Estradiol-17ß (E2) promotes the transcription of vitellogenin (Vtg) via nuclear estrogen receptor (ER). Three Vtg (VtgAa, VtgAb, and VtgC) and ER subtypes (ERα, ERß1, and ERß2) have been reported in perciform fish; however, the relationship between the transcriptional regulation of Vtg and ER subtypes remains unclear. Molecular characterization was performed and the expression profiles of vtg and er subtypes were investigated to elucidate mechanisms of synthesis of vtg subtypes in yellowtail, Seriola quinqueradiata. Primary structures and promoter regions were revealed in three subtypes of vtg and er, and all the vtg subtypes and erα were presumed to be estrogen-responsive genes. When all vtg subtypes were expressed significantly in the liver, hepatic expression levels of all the er subtypes also increased. Conversely, although plasma E2 concentrations did not change significantly, the concentrations were high at the same time. Hepatic expression levels of all the vtg subtypes were highly correlated with hepatic erα, rather than with hepatic erß subtypes and plasma E2. A high positive correlation was also observed between erß1 and ß2, which seemed to be highly expressed at the pre- and late-vitellogenic stages. The results of the present study suggest that the transcription of the three vtg subtypes are regulated by three ER subtypes jointly, and ERα is the key transcription factor regulating the three vtg subtypes in yellowtail.

Receptor-based Surrogate Subtypes and Discrepancies with Breast Cancer Intrinsic Subtypes: Implications for Image Biomarker Development.

Purpose To determine the concordance and accuracy of imaging surrogates of immunohistochemical (IHC) markers and the molecular classification of breast cancer. Materials and Methods A total of 3050 patients from 17 public breast cancer data sets containing IHC marker receptor status (estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 [HER2]) and their molecular classification (basal-like, HER2-enriched, luminal A or B) were analyzed. Diagnostic accuracy and concordance as measured with the κ statistic were calculated between the IHC and molecular classifications. Simulations were performed to assess the relationship between accuracy of imaging-based IHC markers to predict molecular classification. A simulation was performed to examine effects of misclassification of molecular type on patient survival. Results Accuracies of intrinsic subtypes based on IHC subtype were 71.7% (luminal A), 53.7% (luminal B), 64.8% (HER2-enriched), and 81.7% (basal-like). The κ agreement was fair (κ = 0.36) for luminal A and HER2-enriched subtypes, good (κ = 0.65) for the basal-like subtype, and poor (κ = 0.09) for the luminal B subtypes. Introduction of image misclassification by simulation lowered image-true subtype accuracies and κ values. Simulation analysis showed that misclassification caused survival differences between luminal A and basal-like subtypes to decrease. Conclusion There is poor concordance between triple-receptor status and intrinsic molecular subtype in breast cancer, arguing against their use in the design of prognostic genomic-based image biomarkers. © RSNA, 2018 Online supplemental material is available for this article.

Estrogen receptor subtypes dictate the proliferative nature of the mammary gland.

Estrogen induces proliferation of breast epithelial cells and is responsible for breast development at puberty. This tightly regulated control is lost in estrogen-receptor-positive (ER+) breast cancers, which comprise over 70% of all breast cancers. Currently, breast cancer diagnosis and treatment considers only the α isoform of ER; however, there is a second ER, ERß. Whilst ERα mediates estrogen-driven proliferation of the normal breast in puberty and breast cancers, ERß has been shown to exert an anti-proliferative effect on the normal breast. It is not known how the expression of each ER (alone or in combination) correlates with the ability of estrogen to induce proliferation in the breast. We assessed the levels of each ER in normal mouse mammary glands subdivided into proliferative and non-proliferative regions. ERα was most abundant in the proliferative regions of younger mice, with ERß expressed most abundantly in old mice. We correlated this expression profile with function by showing that the ability of estrogen to induce proliferation was reduced in older mice. To show that the ER profile associated with breast cancer risk, we assessed ER expression in parous mice which are known to have a reduced risk of developing ERα breast cancer. ERα expression was significantly decreased yet co-localization analysis revealed ERß expression increased with parity. Parous mice had less unopposed nuclear ERα expression and increased levels of ERß. These changes suggest that the nuclear expression of ERs dictates the proliferative nature of the breast and may explain the decreased breast cancer risk with parity.

Nuclear receptor research in zebrafish.

Nuclear receptors (NRs) form a superfamily of transcription factors that can be activated by ligands and are involved in a wide range of physiological processes. NRs are well conserved between vertebrate species. The zebrafish, an increasingly popular animal model system, contains a total of 73 NR genes, and orthologues of almost all human NRs are present. In this review article, an overview is presented of NR research in which the zebrafish has been used as a model. Research is described on the three most studied zebrafish NRs: the estrogen receptors (ERs), retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs). The studies on these receptors illustrate the versatility of the zebrafish as a model for ecotoxicological, developmental and biomedical research. Although the use of the zebrafish in NR research is still relatively limited, it is expected that in the next decade the full potential of this animal model will be exploited.

Potential mechanisms underlying estrogen-induced expression of the molluscan estrogen receptor (ER) gene.

In vertebrates, estrogens and estrogen mimicking chemicals modulate gene expression mainly through a genomic pathway mediated by the estrogen receptors (ERs). Although the existence of an ER orthologue in the mollusc genome has been known for some time, its role in estrogen signalling has yet to be deciphered. This is largely due to its constitutive (ligand-independent) activation and a limited mechanistic understanding of its regulation. To fill this knowledge gap, we cloned and characterised an ER cDNA (sgER) and the 5'-flanking region of the gene from the Sydney rock oyster Saccostrea glomerata. The sgER cDNA is predicted to encode a 477-amino acid protein that contains a DNA-binding domain (DBD) and a ligand-binding domain (LBD) typically conserved among both vertebrate and invertebrate ERs. A comparison of the sgER LBD sequence with those of other ligand-dependent ERs revealed that the sgER LBD is variable at several conserved residues known to be critical for ligand binding and receptor activation. Ligand binding assays using fluorescent-labelled E2 and purified sgER protein confirmed that sgER is devoid of estrogen binding. In silico analysis of the sgER 5'-flanking sequence indicated the presence of three putative estrogen responsive element (ERE) half-sites and several putative sites for ER-interacting transcription factors, suggesting that the sgER promoter may be autoregulated by its own gene product. sgER mRNA is ubiquitously expressed in adult oyster tissues, with the highest expression found in the ovary. Ovarian expression of sgER mRNA was significantly upregulated following in vitro and in vivo exposure to 17ß-estradiol (E2). Notably, the activation of sgER expression by E2 in vitro was abolished by the specific ER antagonist ICI 182, 780. To determine whether sgER expression is epigenetically regulated, the in vivo DNA methylation status of the putative proximal promoter in ovarian tissues was assessed using bisulfite genomic sequencing. The results showed that the promoter is predominantly hypomethylated (with 0-3.3% methylcytosines) regardless of sgER mRNA levels. Overall, our investigations suggest that the estrogen responsiveness of sgER is regulated by a novel ligand-dependent receptor, presumably via a non-genomic pathway(s) of estrogen signalling.

Efficient prediction of progesterone receptor interactome using a support vector machine model.

Protein-protein interaction (PPI) is essential for almost all cellular processes and identification of PPI is a crucial task for biomedical researchers. So far, most computational studies of PPI are intended for pair-wise prediction. Theoretically, predicting protein partners for a single protein is likely a simpler problem. Given enough data for a particular protein, the results can be more accurate than general PPI predictors. In the present study, we assessed the potential of using the support vector machine (SVM) model with selected features centered on a particular protein for PPI prediction. As a proof-of-concept study, we applied this method to identify the interactome of progesterone receptor (PR), a protein which is essential for coordinating female reproduction in mammals by mediating the actions of ovarian progesterone. We achieved an accuracy of 91.9%, sensitivity of 92.8% and specificity of 91.2%. Our method is generally applicable to any other proteins and therefore may be of help in guiding biomedical experiments.

Versatility or promiscuity: the estrogen receptors, control of ligand selectivity and an update on subtype selective ligands.

The estrogen receptors (ERs) are a group of versatile receptors. They regulate an enormity of processes starting in early life and continuing through sexual reproduction, development, and end of life. This review provides a background and structural perspective for the ERs as part of the nuclear receptor superfamily and discusses the ER versatility and promiscuity. The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs. Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes. Even when interacting with endogenous hormones, ER actions can have adverse effects in disease progression. Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed. The intent of this review is to complement the large body of literature with emphasis on most recent developments in selective ER ligands.

Estrogen receptor function and regulation in fish and other vertebrates.

Estrogens, steroid hormones critically involved in reproductive processes of vertebrates, signal primarily through their intracellular estrogen receptors (ERs). The ERs belong to a superfamily of nuclear receptors that act as ligand inducible transcription factors. Herein, we review what is known about ER structure, subtypes, mechanism(s) of action and auto-regulation by estrogens. Focus is placed on the ER in fish but comparisons are made to mammals and other vertebrates. Finally, we provide context and a proposed model integrating our knowledge on autoregulation of the receptor and its functions in the liver. Future areas of study are suggested, along with cautions when designing experiments, especially for the detection of endocrine disruptors.

Retinoid X receptor (RXR), estrogen receptor (ER) and other nuclear receptors in tissues of the mussel Mytilus galloprovincialis: cloning and transcription pattern.

Bivalve molluscs accumulate chemical compounds from the environment that could cause alterations in lipid homeostasis and endocrine system. In vertebrates such cell processes are modulated by transcription factors belonging to the superfamily of nuclear receptors (NRs). The goal of this study was to clone fragments of mussel Mytilus galloprovincialis NR genes that could mediate cell responses such as peroxisome proliferation and endocrine disruption. PCR-based screening of mussel digestive gland cDNA using degenerate primers provided cDNA fragments or whole ORFs of retinoid X receptor (RXR), estrogen receptor (ER) and 5 proteins belonging to the NR1 subfamily highly similar to the arthropod ecdysone inducible protein E75. NR1G, whose whole ORF was cloned, is related to the nematode and trematode G group of NR1 receptors; NR1DEF is related to the D, E and F groups, and NR1Dv1, NR1Dv2 and NR1DΔ belong to the D group. mRNA transcripts for all these receptors were detected in gill, mantle and digestive gland. In all cases, except ER, transcript levels were lower in June than in January. NR1Dv1 and NR1DΔ did not show identical transcription levels, although both were at their lowest in digestive gland in June. On the contrary, NR1Dv2 and NR1DΔ transcription profiles were similar. Further studies are needed to determine the function(s) of mussel RXR, ER and novel NR1 subfamily receptors and their possible role in the regulation of physiological cell responses and/or adaptive response to xenobiotic exposures.

Localization and divergent profiles of estrogen receptors and aromatase in the vocal and auditory networks of a fish with alternative mating tactics.

Estrogens play a salient role in the development and maintenance of both male and female nervous systems and behaviors. The plainfin midshipman (Porichthys notatus), a teleost fish, has two male reproductive morphs that follow alternative mating tactics and diverge in multiple somatic, hormonal, and neural traits, including the central control of morph-specific vocal behaviors. After we identified duplicate estrogen receptors (ERß1 and ERß2) in midshipman, we developed antibodies to localize protein expression in the central vocal-acoustic networks and saccule, the auditory division of the inner ear. As in other teleost species, ERß1 and ERß2 were robustly expressed in the telencephalon and hypothalamus in vocal-acoustic and other brain regions shown previously to exhibit strong expression of ERα and aromatase (estrogen synthetase, CYP19) in midshipman. Like aromatase, ERß1 label colocalized with glial fibrillary acidic protein (GFAP) in telencephalic radial glial cells. Quantitative polymerase chain reaction revealed similar patterns of transcript abundance across reproductive morphs for ERß1, ERß2, ERα, and aromatase in the forebrain and saccule. In contrast, transcript abundance for ERs and aromatase varied significantly between morphs in and around the sexually polymorphic vocal motor nucleus (VMN). Together, the results suggest that VMN is the major estrogen target within the estrogen-sensitive hindbrain vocal network that directly determines the duration, frequency, and amplitude of morph-specific vocalizations. Comparable regional differences in steroid receptor abundances likely regulate morph-specific behaviors in males and females of other species exhibiting alternative reproductive tactics.

A review of the biological and clinical characteristics of luminal-like oestrogen receptor-positive breast cancer.

Global gene expression profiling (GEP) studies of breast cancer have identified distinct biological classes with different clinical and therapeutic implications. Oestrogen receptor (ER) has been found to be a central marker of the molecular signature. GEP studies have consistently recognized a molecularly distinct class of tumours that is characterized by high-level expression of ER and other biomarkers recognized to be characteristic of normal luminal cells of the breast. This class is the largest of the GEP-defined molecular subclasses, comprising 60-70% of breast cancer cases. Moreover, it has been proposed that this group of tumours is composed of at least two subclasses distinguished by differing GEP profiles. At present, there is no consensus on the definition of the luminal subclasses and, in clinical practice, luminal-like tumours and ER-positive tumours are frequently considered to be the same. A better understanding of the biological features of luminal tumours could lead to their improved characterization and consistent identification. In this review, we explore the concept and definitions of the luminal-like class of breast carcinoma and their contribution to our understanding of their molecular features, clinical significance and therapeutic implications.

Beyond triple-negative breast cancer: the need to define new subtypes.

Advances in the systemic treatment of early breast cancer have led to significant improvements in survival for patients with hormone receptor- and/or HER2-positive disease. In recent years, interest has focused on tumors that lack expression of the estrogen receptor, progesterone receptor and HER2, the so-called triple-negative subgroup. As a group, triple-negative cancers have a relatively aggressive clinical course, with early development of visceral metastases and a poor long-term prognosis. These tumors, however, encompass a wide range of subtypes with varying prognosis, including a number of special types with a good prognosis (e.g., adenoid cystic carcinomas and secretory carcinoma). There is considerable overlap between triple-negative and basal-like tumors; however, microarray studies have demonstrated that the overlap between basal-like and triple-negative cancers is not complete. The similarities between sporadic triple-negative cancers and tumors arising in BRCA1 mutation carriers and the fact that the majority of BRCA1 tumors display a triple-negative phenotype have led to studies demonstrating a potential loss of BRCA1 function in triple-negative cancers and offered potential therapeutic avenues for patients with these cancers. However, it should be noted that triple-negative breast cancers comprise a heterogeneous group of tumors. Understanding the molecular underpinning of distinct subgroups of these cancers is crucial for the identification of novel therapeutic targets and individualization of treatment for patients with triple-negative disease.

Cloning and functional characterization of Chondrichthyes, cloudy catshark, Scyliorhinus torazame and whale shark, Rhincodon typus estrogen receptors.

Sex-steroid hormones are essential for normal reproductive activity in both sexes in all vertebrates. Estrogens are required for ovarian differentiation during a critical developmental stage and promote the growth and differentiation of the female reproductive system following puberty. Recent studies have shown that environmental estrogens influence the developing reproductive system as well as gametogenesis, especially in males. To understand the molecular mechanisms of estrogen actions and to evaluate estrogen receptor-ligand interactions in Elasmobranchii, we cloned a single estrogen receptor (ESR) from two shark species, the cloudy catshark (Scyliorhinus torazame) and whale shark (Rhincodon typus) and used an ERE-luciferase reporter assay system to characterize the interaction of these receptors with steroidal and other environmental estrogens. In the transient transfection ERE-luciferase reporter assay system, both shark ESR proteins displayed estrogen-dependent activation of transcription, and shark ESRs were more sensitive to 17beta-estradiol compared with other natural and synthetic estrogens. Further, the environmental chemicals, bisphenol A, nonylphenol, octylphenol and DDT could activate both shark ESRs. The assay system provides a tool for future studies examining the receptor-ligand interactions and estrogen disrupting mechanisms in Elasmobranchii.

Allred scoring for ER reporting and it's impact in clearly distinguishing ER negative from ER positive breast cancers.

OBJECTIVE: To determine the scoring of Estrogen Receptor (ER) status in carcinoma breast by Allred method that is essentially bimodal and to compare the results with a conventional scoring system. MATERIALS AND METHODS: A retrospective, comparative study carried out at Aga Khan University Hospital Section of Histopathology over a period of 18 months, i.e., Jan 2005 to June 2006. Anti ER antibody (clone D07) was used for all IHC stains using envision detection system. ER stains of 860 consecutive breast cancer cases were reviewed and rescored by both conventional and Allred method of ER scoring. RESULTS: Comparison of results showed that there was a substantial decrease in weak positive cases from 18% to 5% by rescoring using Allred scoring system compared to conventional scoring. The data was analyzed using chi square test. CONCLUSION: The sensitivity and specificity of Allred method were calculated; Sensitivity of Allred method was 99.4% & Specificity of Allred method was 99.5% whereas sensitivity and specificity of conventional method was 88.0% and 84% respectively

Molecular cloning and characterization of ligand- and species-specificity of amphibian estrogen receptors.

Estrogens are essential for normal reproductive activity in both males and females as well as for ovarian differentiation during a critical developmental stage in most vertebrates. To understand the molecular mechanisms of estrogen action and to evaluate estrogen receptor ligand interactions in amphibians, we isolated cDNAs encoding the estrogen receptors (ERalpha and ERbeta) from the Japanese firebelly newt (Cynops pyrrhogaster), Tokyo salamander (Hynobius tokyoensis), axolotl (Ambystoma mexicanum), and Raucous toad (Bufo rangeri). Full-length amphibian ER cDNAs were obtained using 5' and 3' rapid amplification of cDNA ends. The predicted amino acid sequences of these amphibian ERs showed a high degree of amino acid sequence identity (over 70%) to each other. We analyzed the relationships of these amphibian ER sequences to other vertebrate ER sequences by constructing a phylogenetic tree. We verified that these were bona fide estrogen receptors using receptor dependent reporter gene assays. We analyzed the effects of natural estrogens, ethinylestradiol, and DDT and its metabolites on the transactivation of the four amphibian species listed above, and Xenopus tropicalis ERs and found that there were species-specific differences in the sensitivity of these ERs to hormones and environmental chemicals. These findings will expand our knowledge of endocrine-disrupting events in amphibians.

Selective estrogen receptor modulators decrease the production of interleukin-6 and interferon-gamma-inducible protein-10 by astrocytes exposed to inflammatory challenge in vitro.

Expression of proinflammatory molecules by glial cells is involved in the pathophysiological changes associated with chronic neurological diseases. Under pathological conditions, astrocytes release a number of proinflammatory molecules, such as interleukin-6 (IL-6) and interferon-gamma-inducible protein-10 (IP-10). The ovarian hormone estradiol exerts protective effects in the central nervous system that, at least in part, may be mediated by a reduction of local inflammation. This study was designed to assess whether estradiol affects the production of IL-6 and IP-10 by primary cultures of newborn mice astrocytes exposed to lipopolysaccharide (LPS), a bacterial endotoxin known to cause neuroinflammation. In addition, the possible anti-inflammatory effect of several selective estrogen receptor modulators (SERMs) was also assessed. LPS induced an increase in the expression of IL-6 and IP-10 mRNA levels in astrocytes and an increase in IL-6 and IP-10 protein levels in the culture medium. These effects of LPS were impaired by estradiol and by the four SERMs tested in our study: tamoxifen, raloxifene, ospemifene, and bazedoxifene. All SERMs tested showed a similar effect on IL-6 and IP-10 mRNA levels, but raloxifene and ospemifene were more effective than tamoxifen and bazedoxifene in reducing protein levels in LPS-treated cultures. Finally, we report that news SERMs, ospemifene and bazedoxifene, exert anti-inflammatory actions by a mechanism involving classical estrogen receptors and by the inhibition of LPS-induced NFkappaB p65 transactivation. The results suggest that estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of proinflammatory molecules by astrocytes.

Distinct expression of three estrogen receptors in response to bisphenol A and nonylphenol in male Nile tilapias (Oreochromis niloticus).

Environmental estrogens, such as bisphenol A (BisA) and nonylphenol (NP), have been shown to affect the estrogen receptor (ER) expression and induce male reproductive abnormalities. To elucidate molecular mechanisms of action of xenoestrogenic chemicals on the expression of estrogen receptors in the testes of Nile tilapia (Oreochromis niloticus), three full-length cDNAs respectively encoding ntERalpha, ntERbeta1 and ntERbeta2 were cloned from testes. The amino acid sequences of ntERalpha, ntERbeta1 and ntERbeta2 showed a high degree of similarity to the relevant fish species. Tissue-specific expression study showed that three receptors were highly expressed in pituitary, liver, testis, kidney and intestine tissues. The ntERalpha, ntERbeta1 and ntERbeta2 mRNA expressions were significantly higher at the sexual early recrudescing stage than at other recrudesced stages. After being exposed to xenoestrogens from weeks 2 to 4, the ntERalpha mRNA levels were increased significantly in testes after NP treatment at all sampling times or after 4 weeks of exposure to BPA. The ntERbeta1 mRNA levels remained unchanged, while a significant decrease of the ntERbeta2 mRNA level was observed in testes after exposure to NP and BPA. The present study demonstrates that the regulation of all three ntER subtypes in testes may act via different molecular mechanisms of exposure to NP and BPA.

Estrogen receptors and function in the male reproductive system: [review] / Receptores e função do estrógeno no sistema reprodutor masculino: [revisão]

A substantial advance in our understanding on the estrogen signaling occurred in the last decade. Estrogens interact with two receptors, ESR1 and ESR2, also known as ERα and ERβ, respectively. ESR1 and ESR2 belong to the nuclear receptor family of transcription factors. In addition to the well established transcriptional effects, estrogens can mediate rapid signaling, triggered within seconds or minutes. These rapid effects can be mediated by ESRs or the G protein-coupled estrogen receptor GPER, also known as GPR30. The effects of estrogen on cell proliferation, differentiation and apoptosis are often mediated by growth factors. The understanding of the cross-talk between androgen, estrogen and growth factors signaling pathways is therefore essential to understand the physiopathological mechanisms of estrogen action. In this review we focused on recent discoveries about the nature of the estrogen receptors, and on the signaling and function of estrogen in the male reproductive system.

Durante a última década, ocorreu um avanço substancial no conhecimento da sinalização do estrógeno. Estrógenos interagem com dois receptores, ESR1 e ESR2, também conhecidos como ERα e ERβ, respectivamente. ESR1 e ESR2 pertencem à família de receptores nucleares, que funcionam como fatores de transcrição. Além dos bem estabelecidos efeitos transcricionais, os estrógenos medeiam a sinalização rápida, desencadeada dentro de segundos ou minutos. Esses efeitos rápidos podem ser mediados por ESRs ou pelo receptor de estrógeno acoplado à proteína G, GPER, também conhecido como GPR30. Os efeitos de estrógenos sobre a proliferação celular, diferenciação e apoptose são, muitas vezes, mediados por fatores de crescimento. Portanto, a compreensão da interação entre as vias de sinalização de andrógeno, estrógeno e fatores de crescimento é essencial para entender os mecanismos fisiopatológicos envolvidos na ação estrogênica. Nesta revisão, foram abordadas descobertas recentes sobre a estrutura dos receptores, a sinalização e a função do estrógeno no sistema reprodutor masculino.

Differential estrogen receptor subtype modulators: assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles.

Several new cycloalkyl-fused diaryl pyrazoles were synthesized and their binding affinity for the estrogen receptor (ER) subtypes, ERalpha and ERbeta, and subtype-specific agonist/antagonist properties were determined. Cyclopentane- and cyclohexane-fused pyrazoles with p-hydroxyphenyl rings at positions 1 and 3 displayed modest ERbeta-binding selectivity and variable agonism through ERalpha, while behaving as full estrogen antagonists through ERbeta in estrogen-responsive element (ERE)-dependent gene expression assays. By contrast, the 2,3-diphenolic derivatives were non-selective and considerably less effective ERbeta antagonists compared to 1,3-diphenolic ones. The cyclohexane-fused 1,3-diphenolic pyrazole 8, in particular, behaved as full ERalpha agonist/ERbeta antagonist in these assays. Molecular modelling revealed the structural determinants possibly accounting for the differential regulation of transcription through the two ERs exhibited by 8. The data also shows that the ER subtype-binding selectivity and agonist/antagonist efficacy of the 1,3-diphenolic pyrazoles is influenced by the cycloalkyl ring fused to the pyrazole core. Using 8 we show that, though the mutant androgen receptor (AR) of LNCaP cells is required for estrogen as well as androgen stimulation of cell growth, estrogen responsiveness of the cells depends on ERbeta and AR but not on ERalpha.