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International Journal of Molecular... Dec 2021In addition to being a steroid hormone, 17β-estradiol (E) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans.... (Review)
Review
In addition to being a steroid hormone, 17β-estradiol (E) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron-derived E (NDE) is synthesized from androgen precursors via the action of the biosynthetic enzyme aromatase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE as a neuromodulator that regulates synaptic plasticity and memory. Evidence supporting an important neuromodulatory role of NDE in the brain has come from studies using aromatase inhibitors, aromatase overexpression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron-specific knockout mice. Collectively, these studies demonstrate a key role of NDE in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal-dependent recognition memory, spatial reference memory, and contextual fear memory. NDE is suggested to achieve these effects through estrogen receptor-mediated regulation of rapid kinase signaling and CREB-BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.
Topics: Animals; Aromatase; Estradiol; Female; Humans; Male; Neuronal Plasticity; Neurons; Signal Transduction; Spatial Memory; Synapses
PubMed: 34948039
DOI: 10.3390/ijms222413242 -
Endocrine Journal Jul 2008It is well-known that estrogens are closely involved in the growth of human breast carcinomas, and that the great majority of breast carcinoma express estrogen... (Review)
Review
It is well-known that estrogens are closely involved in the growth of human breast carcinomas, and that the great majority of breast carcinoma express estrogen receptors. Recent studies have demonstrated that estrogens are locally produced and act on the breast carcinoma tissue. Among these pathways, aromatase is a key enzyme for intratumoral production of estrogens in breast carcinomas, and aromatase inhibitors are currently used in the breast carcinoma in postmenopausal women as an estrogen deprivation therapy. This review summarizes the results of recent studies on the expression and regulation of aromatase in breast carcinoma tissues, and discusses the potential biological and/or clinical significance of aromatase. Aromatase is abundantly expressed in various cell types, such as carcinoma cells, intratumoral stromal cells, and adipocytes adjacent to the carcinoma, in breast carcinoma tissues. Further, a key regulator for aromatase expression differed according to cell type. In addition, aromatase suppressed in situ production of bioactive androgen, 5alpha-dihydrotestosterone (DHT), in breast carcinoma. Aromatase inhibitors may thus have additional antiproliferative effects through increasing local DHT concentration with estrogen deprivation.
Topics: Aromatase; Breast Neoplasms; Carcinoma; Estrogens; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gonadal Steroid Hormones; Humans; Models, Biological; Neoplasms, Hormone-Dependent; Osmolar Concentration; Tissue Distribution
PubMed: 18480557
DOI: 10.1507/endocrj.k07e-053 -
Seminars in Reproductive Medicine May 2009Aromatization of testosterone to estradiol by neural tissue has classically been associated with the regulation of sexual differentiation, gonadotropin secretion, and... (Review)
Review
Aromatization of testosterone to estradiol by neural tissue has classically been associated with the regulation of sexual differentiation, gonadotropin secretion, and copulatory behavior. However, new data indicate that the capacity for aromatization is not restricted to the endocrine brain and demonstrate roles for locally formed estrogens in neurogenesis and in responses of brain tissue to injury. This article summaries our current understanding of the distribution and regulation of aromatase in the brain and describes the classic and novel roles it plays. A better understanding of brain aromatization could shed new light on its physiologic and pathologic functions and someday lead to new, centrally acting drug therapies.
Topics: Animals; Aromatase; Brain; Estradiol; Female; Gene Expression Regulation, Enzymologic; Gonadotropins; Humans; Male; Nervous System Diseases; Phosphorylation; Protein Processing, Post-Translational; Sex Differentiation; Sexual Behavior, Animal; Sexual Development; Stroke; Testosterone
PubMed: 19401952
DOI: 10.1055/s-0029-1216274 -
Bone Sep 2008Findings from estrogen-resistant and aromatase-deficient men have provided important insights into the role of estrogen in the male skeleton during growth. Importantly,...
Findings from estrogen-resistant and aromatase-deficient men have provided important insights into the role of estrogen in the male skeleton during growth. Importantly, as reported elsewhere in this issue, these data also suggested dose-response relationships between estrogen and bone turnover. In addition, studies in these unusual patients have stimulated research on defining the role of estrogen in regulating bone metabolism in normal adult and aging men, providing further insights into estrogen regulation of bone metabolism not only in men, but also in women.
Topics: Adult; Aromatase; Bone Remodeling; Bone and Bones; Cohort Studies; Dose-Response Relationship, Drug; Estrogens; Female; Humans; Male; Models, Biological; Osteogenesis; Phenotype; Sex Factors
PubMed: 18567553
DOI: 10.1016/j.bone.2008.05.005 -
Experimental & Molecular Medicine Jan 2023Production of estradiol (E2) by the placenta during human pregnancy ensures successful maintenance of placental development and fetal growth by stimulating trophoblast...
Production of estradiol (E2) by the placenta during human pregnancy ensures successful maintenance of placental development and fetal growth by stimulating trophoblast proliferation and the differentiation of cytotrophoblasts into syncytiotrophoblasts. Decreased levels of E2 are closely associated with obstetrical diseases such as preeclampsia (PE) in the clinic. However, the mechanisms underlying the inhibition of placental E2 biosynthesis remain poorly understood. Here, we report that regulator of G-protein signaling 2 (RGS2) affects E2 levels by regulating aromatase, a rate-limiting enzyme for E2 biosynthesis, by using human trophoblast-derived JEG-3 cells and human placental villus tissues. RGS2 enhanced the protein degradation of the transcription factor heart and neural crest derivatives expressed 1 (HAND1) by suppressing ubiquitin-specific protease 14 (USP14)-mediated deubiquitination of HAND1, resulting in the restoration of HAND1-induced trans-inactivation of the aromatase gene and subsequent increases in E2 levels. However, aromatase bound to RGS2 and repressed RGS2 GTPase activating protein (GAP) activity. Moreover, we observed a positive correlation between RGS2 and aromatase expression in clinical normal and preeclamptic placental tissues. Our results uncover a hitherto uncharacterized role of the RGS2-aromatase axis in the regulation of E2 production by human placental trophoblasts, which may pinpoint the molecular pathogenesis and highlight potential biomarkers for related obstetrical diseases.
Topics: Humans; Pregnancy; Female; Trophoblasts; Placenta; Estradiol; Aromatase; Cell Line, Tumor; Pre-Eclampsia; RGS Proteins; Ubiquitin Thiolesterase
PubMed: 36653442
DOI: 10.1038/s12276-023-00927-z -
Anticancer Research Apr 2009There is a large and compelling body of epidemiological and experimental evidence that oestrogens are the fuel behind the aetiology of breast cancer. The carcinogenic... (Review)
Review
There is a large and compelling body of epidemiological and experimental evidence that oestrogens are the fuel behind the aetiology of breast cancer. The carcinogenic effects of oestrogen are postulated to be mediated by: the stimulation of cellular proliferation through their receptor-mediated hormonal activity. Other mechanisms include; direct genotoxic effects by increasing mutation rates through a cytochrome P450-mediated metabolic activation and induction of aneuploidy. The local biosynthesis of oestrogens, especially in postmenopausal women as a result of the interactions of various enzymes, is believed to play a very important role in the pathogenesis and development of hormone dependent breast carcinoma. The over-expression of such enzymes seems to be associated with the development of a more aggressive disease process, a poorer outcome and increased local and distant recurrences.
Topics: 17-Hydroxysteroid Dehydrogenases; Animals; Aromatase; Breast Neoplasms; Enzyme Inhibitors; Estrogens; Humans; Hydro-Lyases; Steryl-Sulfatase
PubMed: 19414351
DOI: No ID Found -
The Journal of Steroid Biochemistry and... 2007Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. In contrast to... (Review)
Review
Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. In contrast to tamoxifen, an antagonist of the estrogen receptor (ER), AIs have shown to be better tolerated along with decreased recurrence rates of the disease. Currently, three third-generation AIs are being used: exemestane, letrozole, and anastrozole. Our laboratory is attempting to understand several aspects of AI functionality. In this paper, we first review recent findings from our structure-function studies of aromatase as well as the molecular characterization of the interaction between AIs and aromatase. Based on these studies, we propose new evidence for the interaction of letrozole and exemestane with aromatase. In addition, we will discuss recent results generated from our AI-resistant cell lines. Our laboratory has generated MCF-7aro cells that are resistant to letrozole, anastrozole, exemestane, and tamoxifen. Basic functional characterization of aromatase and ERalpha in these resistant cell lines has been done and microarray analysis has been employed in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. The results generated so far suggest the presence of at least four types of resistant cell lines. Overall, the information presented in this paper supplements our understanding of AI function, and such information can be valuable for the development of treatment strategies against AI resistant breast cancers.
Topics: Aromatase; Aromatase Inhibitors; Drug Resistance; Humans; Models, Biological; Tamoxifen
PubMed: 17611102
DOI: 10.1016/j.jsbmb.2007.05.020 -
Molecular and Cellular Endocrinology Jul 2011Aromatase, estrone sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 are involved in the key steps of 17β-estradiol biosynthesis. Structure-function studies of... (Review)
Review
Aromatase, estrone sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 are involved in the key steps of 17β-estradiol biosynthesis. Structure-function studies of aromatase, estrone sulfatase and 17β-hydroxysteroid dehydrogenase type 1 are important to evaluate the molecular basis of the interaction between these enzymes and their inhibitors. Selective and potent inhibitors of the three enzymes have been developed as antiproliferative agents in hormone-dependent breast carcinoma. New treatment strategies for hormone-dependent breast cancer are discussed.
Topics: 17-Hydroxysteroid Dehydrogenases; Animals; Aromatase; Drug Design; Enzyme Inhibitors; Humans; Structure-Activity Relationship; Sulfatases
PubMed: 20888390
DOI: 10.1016/j.mce.2010.09.012 -
Journal of Neuroendocrinology Apr 2022We previously reported that aromatase protein levels do not parallel aromatase enzyme activity. This suggests that oestrogenic signalling may be modulated via...
We previously reported that aromatase protein levels do not parallel aromatase enzyme activity. This suggests that oestrogenic signalling may be modulated via post-translational modification of aromatase protein. The tyrosine and serine phosphorylation state of aromatase are known to influence its activity. To investigate the possible relevance of aromatase phosphorylation to the incongruity observed between aromatase protein and its activity, we explored interactions between aromatase and the tyrosine kinase c-Src and the serine protein phosphatases 2A and 5 (PP2A and PP5), as well as the relationship between levels of tyrosine-phosphorylated aromatase and the extrapolated aromatase activity. We found that (a) hypothalamic aromatase was significantly more heavily tyrosine-phosphorylated than spinal aromatase; (b) aromatase was oligomerized with c-Src and PP2A/PP5, potentially activating aromatase via tyrosine-phosphorylation and serine-dephosphorylation; (c) the associations of c-Src and PP2A/PP5 with hypothalamic aromatase were substantially greater than with spinal aromatase; and (d) aromatase, oestrogen receptor α, PP2A, and c-Src were present in a common membrane oligomer. The existence of c-Src and PP2A in an oligomer that also contains aromatase and membrane oestrogen receptor α (and presumably other signalling molecules) indicates the presence in the CNS of a potentially self-regulating oestrogenic signalling unit. The degree to which such a complex operates autonomously and the regulatory factors thereof are likely to have substantial physiological implications and clinical relevance.
Topics: Animals; Aromatase; Central Nervous System; Estrogen Receptor alpha; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein-Tyrosine Kinases; Rats; Serine; Tyrosine
PubMed: 35043508
DOI: 10.1111/jne.13089 -
International Journal of Molecular... Jan 2021Aromatase is the cytochrome P450 enzyme converting androgens into estrogen in the last phase of steroidogenesis. As estrogens are crucial in reproductive biology,...
Aromatase is the cytochrome P450 enzyme converting androgens into estrogen in the last phase of steroidogenesis. As estrogens are crucial in reproductive biology, aromatase is found in vertebrates and the invertebrates of the genus , where it carries out the aromatization reaction of the A-ring of androgens that produces estrogens. Here, we investigate the molecular evolution of this unique and highly substrate-selective enzyme by means of structural, sequence alignment, and homology modeling, shedding light on its key role in species conservation. The alignments led to the identification of a core structure that, together with key and unique amino acids located in the active site and the substrate recognition sites, has been well conserved during evolution. Structural analysis shows what their roles are and the reason why they have been preserved. Moreover, the residues involved in the interaction with the redox partner and some phosphorylation sites appeared late during evolution. These data reveal how highly substrate-selective cytochrome P450 has evolved, indicating that the driving forces for evolution have been the optimization of the interaction with the redox partner and the introduction of phosphorylation sites that give the possibility of modulating its activity in a rapid way.
Topics: Amino Acid Sequence; Animals; Aromatase; Catalytic Domain; Estrogens; Evolution, Molecular; Humans; Models, Molecular; Sequence Alignment; Structure-Activity Relationship; Vertebrates
PubMed: 33435208
DOI: 10.3390/ijms22020631