The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Cynthia Ma - One of the best experts on this subject based on the ideXlab platform.
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Revisiting the Estrogen Receptor pathway and its role in endocrine therapy for postmenopausal women with Estrogen Receptor-positive metastatic breast cancer
Breast Cancer Research and Treatment, 2015Co-Authors: Gayathri Nagaraj, Cynthia MaAbstract:Endocrine therapy (ET) is the most commonly administered first-line systemic therapy for Estrogen Receptor-positive (ER+) metastatic breast cancer (MBC). Manipulation of hormone levels was one of the earliest ET approaches. However, treatment modalities have since evolved with the growing understanding of Estrogen biosynthesis and ER biology. The current armamentarium of ET includes selective Estrogen Receptor modulation, aromatase inhibition, and selective Estrogen Receptor downregulation. However, intrinsic or acquired resistance to ET is frequently observed. Significant strides have been made in recent years in our understanding of the mechanisms of resistance to ET, and several targeted approaches including inhibitors against the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway and cyclin-dependent kinase 4/6 (CDK4/6) have shown great promise. The mTOR inhibitor, everolimus, is already in clinical use for the treatment of resistant ER+MBC. However, multiple levels of evidence indicate that ER signaling remains as an important therapeutic target even in the resistance setting, providing the rationale for sequencing multiple lines and combinations of ET. In addition, recurrent mutations in Estrogen Receptor 1 ( ESR1 ), the gene that encodes the ER, have been identified in the genomic studies of metastatic ER+ breast cancer. ESR1 mutations are an important mechanism for acquired resistance, and effective ER targeting in this setting is particularly important.
Stefan Nilsson - One of the best experts on this subject based on the ideXlab platform.
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differential response of Estrogen Receptor alpha and Estrogen Receptor beta to partial Estrogen agonists antagonists
Molecular Pharmacology, 1998Co-Authors: Tomas Barkhem, Janake Gustafsson, Bo Carlsson, Yvonne Nilsson, Eva Enmark, Stefan NilssonAbstract:The existence of two rather than one Estrogen Receptor, today characterized as Estrogen Receptor α (ERα) and Estrogen Receptor β (ERβ), indicates that the mechanism of action of 17β-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERβ is high compared with those amino acid residues in ERα LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both Receptor subtypes. We report that 17α-ethynyl,17β-estradiol, for example, has an ERα-selective agonist potency and that 16β,17α-epiestriol has an ERβ-selective agonist potency. We also report that genistein has an ERβ-selective affinity and potency but an ERα-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERα-selective partial agonist/antagonist function but a pure antagonist effect through ERβ. In addition, raloxifene displayed an ERα-selective antagonist potency, in agreement with its ERα-selective affinity. However, although ICI 164,384 showed an ERβ-selective affinity, it had a similar potency to antagonize the effect of 17β-estradiol in the ERα- and ERβ-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERβ is probably more different from that of ERα than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop Receptor-specific ligands that may form the basis of novel pharmaceuticals with betterin vivo efficacy and side effect profile than current available drugs.
Gayathri Nagaraj - One of the best experts on this subject based on the ideXlab platform.
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Revisiting the Estrogen Receptor pathway and its role in endocrine therapy for postmenopausal women with Estrogen Receptor-positive metastatic breast cancer
Breast Cancer Research and Treatment, 2015Co-Authors: Gayathri Nagaraj, Cynthia MaAbstract:Endocrine therapy (ET) is the most commonly administered first-line systemic therapy for Estrogen Receptor-positive (ER+) metastatic breast cancer (MBC). Manipulation of hormone levels was one of the earliest ET approaches. However, treatment modalities have since evolved with the growing understanding of Estrogen biosynthesis and ER biology. The current armamentarium of ET includes selective Estrogen Receptor modulation, aromatase inhibition, and selective Estrogen Receptor downregulation. However, intrinsic or acquired resistance to ET is frequently observed. Significant strides have been made in recent years in our understanding of the mechanisms of resistance to ET, and several targeted approaches including inhibitors against the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway and cyclin-dependent kinase 4/6 (CDK4/6) have shown great promise. The mTOR inhibitor, everolimus, is already in clinical use for the treatment of resistant ER+MBC. However, multiple levels of evidence indicate that ER signaling remains as an important therapeutic target even in the resistance setting, providing the rationale for sequencing multiple lines and combinations of ET. In addition, recurrent mutations in Estrogen Receptor 1 ( ESR1 ), the gene that encodes the ER, have been identified in the genomic studies of metastatic ER+ breast cancer. ESR1 mutations are an important mechanism for acquired resistance, and effective ER targeting in this setting is particularly important.
John A Katzenellenbogen - One of the best experts on this subject based on the ideXlab platform.
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Estrogen Receptor transcription and transactivation Estrogen Receptor alpha and Estrogen Receptor beta: regulation by selective Estrogen Receptor modulators and importance in breast cancer
Breast Cancer Research, 2000Co-Authors: Benita S Katzenellenbogen, John A KatzenellenbogenAbstract:Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the Estrogen Receptor (ER), now referred to as selective Estrogen Receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various Estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of Estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two Estrogen Receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents.
Luis Miguel Garcia-segura - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotective actions of selective Estrogen Receptor modulators.
Psychoneuroendocrinology, 2020Co-Authors: Lydia L Doncarlos, Iñigo Azcoitia, Luis Miguel Garcia-seguraAbstract:Decreasing levels of sex hormones with aging may have a negative impact on brain function, since this decrease is associated with the progression of neurodegenerative disorders, increased depressive symptoms and other psychological disturbances. Extensive evidence from animal studies indicates that sex steroids, in particular estradiol, are neuroprotective. However, the potential benefits of estradiol therapy for the brain are counterbalanced by negative, life-threatening risks in the periphery. A potential therapeutic alternative to promote neuroprotection is the use of selective Estrogen Receptor modulators (SERMs), which may be designed to act with tissue selectivity as Estrogen Receptor agonists in the brain and not in other organs. Currently available SERMs act not only with tissue selectivity, but also with cellular selectivity within the brain and differentially modulate the activation of microglia, astroglia and neurons. Finally, SERMs may promote the interaction of Estrogen Receptors with the neuroprotective signaling of growth factors, such as the phosphatidylinositol 3-kinase/glycogen synthase kinase 3 pathway.
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Localization of Estrogen Receptor β-immunoreactivity in astrocytes of the adult rat brain
GLIA, 1999Co-Authors: Iñigo Azcoitia, Amanda Sierra, Luis Miguel Garcia-seguraAbstract:Estrogen Receptors are direct regulators of transcription that function by binding to specific DNA sequences in promoters of target genes. The two cloned forms of Estrogen Receptors, alpha and beta, are expressed in the central nervous system by different neuronal populations. Astrocytes in vitro are also reported to express Estrogen Receptor alpha; however, this expression has not been confirmed in the rat brain in vivo. The apparent absence of Estrogen Receptors in glia in vivo contrasts with the well-known effects of this hormone on astrocytes of different brain areas, including the hippocampal formation. In this study, the expression of Estrogen Receptors in the hippocampal formation of adult male rats has been assessed by confocal microscopy. Estrogen Receptor alpha-immunoreactivity was localized in neuronal nuclei in the pyramidal cell layer of CA1-CA3 fields. Estrogen Receptor beta-immunoreactivity was observed in the perikarya, apical dendrites, and cell nuclei of pyramidal neurons in CA1 and CA2. Furthermore, Estrogen Receptor beta-immunoreactive glia were observed in CA1, CA2, CA3, and in the hilus of the dentate gyrus of male and female rats. Estrogen Receptor beta-immunoreactivity was localized in glial processes and perikarya and, in some cases, in glial cell nuclei. Double immunocytochemical labeling of Estrogen Receptor beta and the specific astroglial marker glial fibrillary acidic protein revealed that Estrogen Receptor beta-immunoreactive glial cells were astrocytes. Estrogen Receptor alpha was not co-localized with glial fibrillary acidic protein. The presence of Estrogen Receptor beta in astrocytes of adult male and female rats demonstrates a possible mechanism by which Estrogen can directly modulate gene expression in these cells.