Definition of the Molecular and Cellular Mechanisms Underlying the Tissue-selective Agonist/Antagonist Activities of Selective Estrogen Receptor Modulators

The steroid hormone, estradiol (E 2 ), has numerous targets in the central nervous system, including the hippocampus, which plays a key role in cognition and affective behavior. This review focuses on our evidence from studies in rodents that E 2 has diverse mechanisms in the hippocampus for its functional effects E 2 has rapid, membrane-mediated effects in the hippocampus to enhance cognitive performance. Administration of E 2 to the hippocampus of rats for 10 minutes following training enhances performance in a hippocampus-mediated task. Increased cell firing in the hippocampus occurs within this short time frame. Furthermore, administration of free E 2 or an E 2 conjugate, E 2 :bovine serum albumin (BSA), to the hippocampus produces similar performance-enhancing effects in this task, suggesting that E 2 has membrane actions in the hippocampus for these effects. Further evidence that E 2 has rapid, membrane-mediated effects is that co-administration of E 2 and inhibitors of mitogen activated protein kinase (MAPK), rather than intracellular E 2 receptors (ERs) or protein synthesis, attenuate the enhancing effects of E 2 in this task. Despite these data that demonstrate E 2 can have rapid and/or membrane-mediated effects in the hippocampus, there is clear evidence to suggest that intracellular ERs, particularly the β (rather than α) isoform of ERs, may be important targets for E 2 's functional effects for hippocampal processes. Administration of ligands that are specific for ERβ, but not ERα, have enhancing effects on hippocampal processes similar to that of E 2 (which has similar affinity for ERα and ERβ). These effects are attenuated when ERβ expression is knocked down in transgenic models or with central administration of antisense oligonucleotides. Thus, there may be a convergence of E 2 's actions through rapid, membranemediated effects and intracellular ERs and in the hippocampus for these functional effects.

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“…[94]. Whether ERs act as homodimers versus heterodimers for these effects requires further investigation.…”

Section: The Role Of Erα (And Erβ) For Functional Effects Of Estogensmentioning

confidence: 99%

Rapid and estrogen receptor beta mediated actions in the hippocampus mediate some functional effects of estrogen

Walf

Frye

2008

Steroids

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“…Estrogens and ERs are vital for ovarian development and function (Knapczyk et al 2008, Wąsowicz et al 2011. By forming a complex with the receptor, ZEN initiates conformational changes that cause estrogen-responsive elements (EREs) to bind to DNA, which induces/inhibits the transcription of estrogen-sensitive genes (Mayr et al 1992, McDonnell et al 2002. This balance is determined mostly by the type of ERs in the involved tissue, and the relative levels of ligands and receptors (McDonnell et al 2002, Shang and Brown 2002, Singh et al 2007.…”

Section: Introductionmentioning

confidence: 99%

The effect of low-dose experimental zearalenone intoxication on the immunoexpression of estrogen receptors in the ovaries of pre-pubertal bitches

Gajęcka¹

2012

Polish Journal of Veterinary Sciences

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Zearalenone is an estrogenic mycotoxin that often contaminates plant material used in the production of feeds for companion animals. Small daily doses of ingested zearalenone -a competitive substrate modulating the activity of enzymes participating in estrogen biosynthesis at the pre-receptor level -can induce subclinical symptoms of hyperestrogenism in bitches. The objective of this study was to determine the effects of low zearalenone doses on the presence of estrogen receptors in the ovaries of pre-pubertal Beagle bitches. The bitches were divided into three groups of 10 animals each: experimental group I -50 μg zearalenone/kg body weight administered once daily per os; experimental group II -75 μg zearalenone/kg body weight administered once daily per os; control group -placebo containing no ZEN administered per os. The animals were ovariorectomized at the end of the experiment, at 112 days of age. Estrogen receptors were detected in ovarian specimens by immunohistochemical methods. The results revealed an absence of estrogen receptors alpha in all groups. In both experimental groups a decrease in the positive response of estrogen receptors beta in specified structures of ovaries was observed. Very low α-zearalenol levels probably attested to the slowing down (hypostimulation) of the biotransformation process. Overall, zearalenone intoxication led to hyperestrogenism during a specific developmental stage of pre-pubertal bitches. As regards hormesis, the threshold dose of zearalenone (adaptive capability) was exceeded in the ovaries of experimental group II animals. The results obtained in both experimental groups suggest that long-term exposure to low-dose zearalenone intoxication decreased the degree of estrogen receptors beta staining in particular structures of ovaries in the experimental bitches, which initiated epigenetic modification mechanisms that inhibited ovarian development.

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“…Moreover, studies conducted with synthetic antiestrogens, such as tamoxifen, have shown that the agonist/antagonist profile of a ligand varies with the tissue and the target gene considered. This led to the term of selective estrogen receptor modulators (SERMs) to define this class of drug [13][14][15]. ER activity can also be modulated through indirect activation of the ER by growth factors or cytokines independently of the binding of natural or synthetic hormones [16,17].…”

Section: Introductionmentioning

confidence: 99%

Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion

Platet

Cathiard

Gleizes

et al. 2004

Critical Reviews in Oncology/Hematology

318

236

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Estrogens play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially breast epithelial cells, through interaction with two nuclear estrogen receptors (ER and ERIn this review, we present a brief overview of the actions of estrogens in the different steps of breast carcinogenesis, including cancer progression to metastasis, and of their clinical consequences in the prevention, prognosis and treatment of the disease. The requirement of estrogen receptors, mainly of the alpha subtype, in normal mammary gland differentiation and growth has been evidenced by estrogen receptor deficiency in animals. The promotion of breast cancer carcinogenesis by prolonged exposure to estrogens is well-documented and this has logically led to the use of antiestrogens as potentially chemopreventive agents. In breast cancer progression, however, the exact roles of estrogen receptors have been less well established but they may possibly be dual. Estrogens are mitogenic in ER-positive cells and antiestrogens are an efficient adjuvant therapy for these tumors. On the other hand, the fact that estrogens and their receptors protect against cancer cell invasiveness through distinct mechanisms in experimental models may explain why the presence of ER is associated with well-differentiated and less invasive tumors.2

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Definition of the Molecular and Cellular Mechanisms Underlying the Tissue-selective Agonist/Antagonist Activities of Selective Estrogen Receptor Modulators

Cited by 113 publications

References 74 publications

Rapid and estrogen receptor beta mediated actions in the hippocampus mediate some functional effects of estrogen

Rapid and estrogen receptor beta mediated actions in the hippocampus mediate some functional effects of estrogen

The effect of low-dose experimental zearalenone intoxication on the immunoexpression of estrogen receptors in the ovaries of pre-pubertal bitches

Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion

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