Academic literature on the topic 'Estrogen receptor. eng'
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Journal articles on the topic "Estrogen receptor. eng"
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Albiñana, Virginia, Maria Bernabeu-Herrero, Roberto Zarrabeitia, Carmelo Bernabeu, and Luisa Botella. "Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells." Thrombosis and Haemostasis 103, no. 03 (2010): 441–51. http://dx.doi.org/10.1160/th09-07-0425.
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SummaryHereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor β pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploin-sufficiency of ENG and ALK1.
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Albiñana, Virginia, Angel M. Cuesta, Isabel de Rojas-P, Eunate Gallardo-Vara, Lucía Recio-Poveda, Carmelo Bernabéu, and Luisa María Botella. "Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding." Journal of Clinical Medicine 9, no. 6 (June 6, 2020): 1766. http://dx.doi.org/10.3390/jcm9061766.
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The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. Despite clear knowledge of the symptoms and genes of the disease, we still lack a definite cure for HHT, having just palliative measures and pharmacological trials. Among the former, two strategies are: intervention at “ground zero” to minimize by iron and blood transfusions in order to counteract anemia. Among the later, along the last 15 years, three different strategies have been tested: (1) To favor coagulation with antifibrinolytic agents (tranexamic acid); (2) to increase transcription of ENG and ALK1 with specific estrogen-receptor modulators (bazedoxifene or raloxifene), antioxidants (N-acetylcysteine, resveratrol), or immunosuppressants (tacrolimus); and (3) to impair the abnormal angiogenic process with antibodies (bevacizumab) or blocking drugs like etamsylate, and propranolol. This manuscript reviews the main strategies and sums up the clinical trials developed with drugs alleviating HHT.
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Abramenko, Nikita, Fréderic Vellieux, Petra Tesařová, Zdeněk Kejík, Robert Kaplánek, Lukáš Lacina, Barbora Dvořánková, et al. "Estrogen Receptor Modulators in Viral Infections Such as SARS−CoV−2: Therapeutic Consequences." International Journal of Molecular Sciences 22, no. 12 (June 18, 2021): 6551. http://dx.doi.org/10.3390/ijms22126551.
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COVID-19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient’s death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient’s organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal.
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Zarrabeitia, Roberto, Luisa Ojeda-Fernandez, Lucia Recio, Carmelo Bernabéu, José Parra, Virginia Albiñana, and Luisa Botella. "Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia." Thrombosis and Haemostasis 115, no. 06 (2016): 1167–77. http://dx.doi.org/10.1160/th15-03-0239.
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SummaryHereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients’ quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).
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Pentikäinen, Virve, Krista Erkkilä, Laura Suomalainen, Martti Parvinen, and Leo Dunkel. "Estradiol Acts as a Germ Cell Survival Factor in the Human Testis in Vitro*." Journal of Clinical Endocrinology & Metabolism 85, no. 5 (May 1, 2000): 2057–67. http://dx.doi.org/10.1210/jcem.85.5.6600.
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Abstract The necessity of estrogens for male fertility was recently discovered in studies on both estrogen receptor α knockout and aromatase (cyp 19 gene) knockout mice. However, direct testicular effects of estrogens in male reproduction have remained unclear. Here we studied the protein expression of ERα and the recently described estrogen receptor β in the human seminiferous epithelium and evaluated the role of 17β-estradiol, the main physiological estrogen, in male germ cell survival. Interestingly, both estrogen receptors α and β were found in early meiotic spermatocytes and elongating spermatids of the human testis. Furthermore, low concentrations of 17β-estradiol (10−9 and 10−10 mol/L) effectively inhibited male germ cell apoptosis, which was induced in vitro by incubating segments of human seminiferous tubules without survival factors (i.e. serum and hormones). Dihydrotestosterone, which, in addition to estradiol, is an end metabolite of testosterone, was also capable of inhibiting testicular apoptosis, but at a far higher concentration (10−7 mol/L) than estradiol. Thus, estradiol appears to be a potent germ cell survival factor in the human testis. The novel findings of the present study together with the previously reported indirect effects of estrogens on male germ cells indicate the importance of estrogens for the normal function of the testis.
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Dama, Aida, Chiara Baggio, Carlotta Boscaro, Mattia Albiero, and Andrea Cignarella. "Estrogen Receptor Functions and Pathways at the Vascular Immune Interface." International Journal of Molecular Sciences 22, no. 8 (April 20, 2021): 4254. http://dx.doi.org/10.3390/ijms22084254.
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Estrogen receptor (ER) activity mediates multiple physiological processes in the cardiovascular system. ERα and ERβ are ligand-activated transcription factors of the nuclear hormone receptor superfamily, while the G protein-coupled estrogen receptor (GPER) mediates estrogenic signals by modulating non-nuclear second messengers, including activation of the MAP kinase signaling cascade. Membrane localizations of ERs are generally associated with rapid, non-genomic effects while nuclear localizations are associated with nuclear activities/transcriptional modulation of target genes. Gender dependence of endothelial biology, either through the action of sex hormones or sex chromosome-related factors, is becoming increasingly evident. Accordingly, cardiometabolic risk increases as women transition to menopause. Estrogen pathways control angiogenesis progression through complex mechanisms. The classic ERs have been acknowledged to function in mediating estrogen effects on glucose metabolism, but 17β-estradiol also rapidly promotes endothelial glycolysis by increasing glucose transporter 1 (GLUT1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) levels through GPER-dependent mechanisms. Estrogens alter monocyte and macrophage phenotype(s), and induce effects on other estrogen-responsive cell lineages (e.g., secretion of cytokines/chemokines/growth factors) that impact macrophage function. The pharmacological modulation of ERs for therapeutic purposes, however, is particularly challenging due to the lack of ER subtype selectivity of currently used agents. Identifying the determinants of biological responses to estrogenic agents at the vascular immune interface and developing targeted pharmacological interventions may result in novel improved therapeutic solutions.
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Jordan, V. Craig. "The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer." Endocrine-Related Cancer 22, no. 1 (October 22, 2014): R1—R31. http://dx.doi.org/10.1530/erc-14-0448.
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The successful use of high-dose synthetic estrogens to treat postmenopausal metastatic breast cancer is the first effective ‘chemical therapy’ proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) in postmenopausal hysterectomized women, which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen-induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long-term estrogen deprivation. However, estrogen-independent growth occurs through trial and error. At the cellular level, estrogen-induced apoptosis is dependent upon the presence of the estrogen receptor (ER), which can be blocked by nonsteroidal or steroidal antiestrogens. The shape of an estrogenic ligand programs the conformation of the ER complex, which, in turn, can modulate estrogen-induced apoptosis: class I planar estrogens (e.g., estradiol) trigger apoptosis after 24 h, whereas class II angular estrogens (e.g., bisphenol triphenylethylene) delay the process until after 72 h. This contrasts with paclitaxel, which causes G2 blockade with immediate apoptosis. The process is complete within 24 h. Estrogen-induced apoptosis is modulated by glucocorticoids and cSrc inhibitors, but the target mechanism for estrogen action is genomic and not through a nongenomic pathway. The process is stepwise through the creation of endoplasmic reticulum stress and inflammatory responses, which then initiate an unfolded protein response. This, in turn, initiates apoptosis through the intrinsic pathway (mitochondrial) with the subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a 5-year gap is necessary after menopause to permit the selection of estrogen-deprived breast cancer cell populations to cause them to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around menopause encourages growth of ER-positive tumor cells, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen-induced apoptosis can be orchestrated in the laboratory in estrogen-deprived breast cancers now supports the clinical findings regarding the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long-term antihormonal adjuvant therapy, and the results of treatment with ERT and ERT plus progestin in the Women's Health Initiative for women over the age of 60. Principles have emerged for understanding and applying physiological estrogen therapy appropriately by targeting the correct patient populations.
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Sonnenschein, C., A. M. Soto, M. F. Fernandez, N. Olea, M. F. Olea-Serrano, and M. D. Ruiz-Lopez. "Development of a marker of estrogenic exposure in human serum." Clinical Chemistry 41, no. 12 (December 1, 1995): 1888–95. http://dx.doi.org/10.1093/clinchem/41.12.1888.
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Abstract The deleterious, disruptive effects of estrogen mimics on the endocrine system were discovered after the compounds were released into the environment. Their chemical structure does not obviously resemble that of steroid hormones; hence, their estrogenic effects were totally unexpected. In addition to occupational exposures, environmental estrogens may have played a role in decreasing the quantity and quality of human semen during the last 50 years and in increasing the incidences of testicular cancer and cryptorchidism in men and breast cancer in women and men in industrialized countries. Testing the environmental estrogen hypothesis will require developing appropriate biomarkers of exposure and measuring these biomarkers at developmental points where exposure is critical. We report the ongoing development of a method to extract and separate xenoestrogens from ovarian estrogens with human serum as a source, followed by determination of xenoestrogen concentration by a bioassay. We also critically assess bioassays currently available to measure the cumulative effect of xenoestrogens, e.g., (a) the E-SCREEN assay, which measures the proliferative effect of estrogens on their target cells, and (b) the induction by estrogens of specific gene products, such as progesterone receptor and pS2.
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Martin, Olwenn, Tassos Shialis, John Lester, Mark Scrimshaw, Alan Boobis, and Nikolaos Voulvoulis. "Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis." Ciência & Saúde Coletiva 13, no. 5 (October 2008): 1601–18. http://dx.doi.org/10.1590/s1413-81232008000500024.
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Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The only quantitative summary estimate of the link between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago; other reviews of the link between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α-mediated mode of action was specifically explored. Eight studies were included, investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.
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Bernard, Daniel J., George E. Bentley, Jacques Balthazart, Fred W. Turek, and Gregory F. Ball. "Androgen Receptor, Estrogen Receptor α, and Estrogen Receptorβ Show Distinct Patterns of Expression in Forebrain Song Control Nuclei of European Starlings1." Endocrinology 140, no. 10 (October 1, 1999): 4633–43. http://dx.doi.org/10.1210/endo.140.10.7024.
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Abstract In songbirds, singing behavior is controlled by a discrete network of interconnected brain nuclei known collectively as the song control system. Both the development of this system and the expression of singing behavior in adulthood are strongly influenced by sex steroid hormones. Although both androgenic and estrogenic steroids have effects, androgen receptors (AR) are more abundantly and widely expressed in song nuclei than are estrogen receptors (ERα). The recent cloning of a second form of the estrogen receptor in mammals, ERβ, raises the possibility that a second receptor subtype is present in songbirds and that estrogenic effects in the song system may be mediated via ERβ. We therefore cloned the ERβ complementary DNA (cDNA) from a European starling preoptic area-hypothalamic cDNA library and used in situ hybridization histochemistry to examine its expression in forebrain song nuclei, relative to the expression of AR and ERα messenger RNA (mRNA), in the adjacent brain sections. The starling ERβ cDNA has an open reading frame of 1662-bp, predicted to encode a protein of 554 amino acids. This protein shares greater than 70% sequence identity with ERβ in other species. We report that starling ERβ is expressed in a variety of tissues, including brain, pituitary, skeletal muscle, liver, adrenal, kidney, intestine, and ovary. Similar to reports in other songbird species, we detected AR mRNA-containing cells in several song control nuclei, including the high vocal center (HVc), the medial and lateral portions of the magnocellular nucleus of the anterior neostriatum, and the robust nucleus of the archistriatum. We detected ERα expression in the medial portion of HVc (also called paraHVc) and along the medial border of the caudal neostriatum. ERβ was not expressed in HVc, in the medial and lateral portions of the magnocellular nucleus of the anterior neostriatum, in the robust nucleus of the archistriatum, or in area X. In contrast, ERβ mRNA-containing cells were detected in the caudomedial neostriatum and medial preoptic area in a pattern reminiscent of P450 aromatase expression in the same brain regions in other songbirds. These data suggest that estrogenic effects on the song system are not mediated via ERβ-producing cells within song nuclei. Nonetheless, the overlapping expression of ERβ- and aromatase-producing cells in the caudomedial neostriatum suggests that locally synthesized estrogens may act via ERβ, in addition to ERα, to mediate seasonal or developmental effects on nearby song nuclei (e.g. HVc).
Dissertations / Theses on the topic "Estrogen receptor. eng"
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Dune, Ana Cláudia. "Expressão de recptor de estrógeno, vimentina, TGF"beta", e marcador de macrófagos em tumor ósseo de células gigantes em gatos domésticos /." Jaboticabal : [s.n.], 2008. http://hdl.handle.net/11449/95976.
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Orientador: Mirela Tinucci CostaBanca: Gisele Fabrino Machado
Banca: Gervásio Henrique Bechara
Resumo: O tumor ósseo de células gigantes apresenta 3 diferentes tipos celulares, sendo duas estromais: fibroblastos neoplásicos e células mononucleares; e o terceiro tipo, células gigantes. Propôs-se que este tumor é de linhagem monócito-macrofágica e acredita-se que as células gigantes se formam por fusão de células mononucleares. Aparentemente os fibroblastos neoplásicos que expressam o fator transformador de crescimento TGF"beta"1 estão envolvidos no recrutamento das células gigantes para o tumor. Com o intuito de compreender melhor a histogênese, o envolvimento do estrógeno e a expressão de receptores TGF"beta"1, foi realizado este estudo em casos deste tumor em gatos domésticos. Para tanto foi utilizado o método imuno-enzimático Streptoavidina-biotina utilizando-se o anticorpo primário anti-vimentina, clone 3B4 (Dako A/s, Denmark); o anticorpo marcador de macrófago, MAC387 (Dako A/s, Denmark); o anticorpo para receptores de estrógeno, clone 15D (Dako A/s, Denmark) e o anticorpo marcador para TGF"Beta"1 (Santa Cruz Biotechnology). Os resultados foram analisados pela porcentagem e desvio padrão de células marcadas para cada anticorpo e permitiram concluir que: o TOCG de gatos domésticos, assim como em humanos, tem origem mesenquimal e expressa receptores de estrógeno e de TGF 1 e as células gigantes do tumor não reagem com o clone 387, marcador de células de linhagem mielomonocítica.
Abstract: Giant cell tumor of bone are composed of 3 different cell types: round mononuclear stromal cells, spindle-shaped mononuclear stromal cells, and giant cells. Some authors assert giant cell could arise by fusion of mononuclear cell mielomonocytic. Aparently neoplasic fibroblast that expression TGF is involved in the recruitment of giant cells from tumor. For better understand of histogenesis, the involved of receptors estrogen and of expression of TGF receptors, achieved this study in this cases tumor in domestics cats. By using the immune-enzymatic Streptoavidin- biotin using the primary antibody anti-vimentin, clone VIM 3B4 (Dako A/s, Denmark); antibody myeloid/histocyte clone MAC 387 (Dako A/s, Denmark); antibody estrogen receptor clone 1D5 (Dako A/s, Denmark) and the antibody TGFb1 (Santa Cruz Biotechnology). The results analyzed for percent and standara deviation of marks cells for each antibody and permissive to come to a conclusion: the GCT of bone in domestic cats, like humans, has mesenchymal origin and has expression of estrogen receptors and of TGF"beta", and giants cells this tumor not react with the clone 387, mark the cells myeloidmonocyte lineage.
Mestre
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Vladimir, Vidović. "Značaj određivanja androgenih receptora u odgovoru na hormonsku terapiju kod estrogen receptor pozitivnih pacijenata sa karcinomom dojke." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2020. https://www.cris.uns.ac.rs/record.jsf?recordId=114127&source=NDLTD&language=en.
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Glavni problem u lečenju karcinoma dojke je kako na osnovu kliničke klasifikacije i morfoloških osobina tumora predvideti njegovo dalje ponašanje. Vrlo često ni kombinacija standardnih prognostičkih faktora ne daje odgovor o potrebi davanja adjuvantne hemioterapije. U cilju sprovođenja adekvatne dalje terapije karcinoma dojke i otkrivanja agresivnih tipova tumora, a nakon hirurškog lečenja, postoji stalna potreba za pronalaženjem novih pokazatelja pomoću kojih bi se identifikovale bolesnice koje imaju povećan rizik od razvoja relapsa bolesti. Ciljevi ove studije su bili da se odredi učestalost ekspresije androgenih receptora (AR) u infiltrativnom duktalnom karcinomu dojke. Da se utvrdi povezanost ekspresije AR i kliničko-patoloških prognostičkih faktora u infiltrativnom duktalnom karcinomu dojke. Odnos ekspresije AR i ekspresije estrogen receptora (ER), progesteron receptora (PR) i humanog epidermalnog faktora rasta (HER-2). Da se proceni povezanosti pozitivne ekspresije AR, kao i odnosa AR/ER, sa odgovorom na primenjenu hormonsku terapiju kod ER pozitivnih bolesnica. Da se proceni povezanost ekspresije AR, kao i odnosa AR/ER, sa kliničkim tokom bolesti: pojavom recidiva, metastaza, kao i smrtnim ishodom u toku petogodišnjeg perioda praćenja pacijentkinja. Istraživanjem je obuhvaćeno oko 200 pacijentkinja obolelih od infiltrativnog duktalnog karcinoma dojke, koje su operisane na Institutu za onkologiju Vojvodine u periodu 2010-2012. godine. Pacijentkinje su odabrane metodom slučajnog izbora. Ne postoji statistički značajna razlika između kliničko patololoških faktora i ekspresije androgenih receptora. Kod pacijentkinja sa infiltrativnim duktalnih karcinomom dojke koje su ER-/AR+ nije pokazana statistički značajna razlika u HER2 proteinskoj ekspresiji. Učestalost receptora za progesteron, estrogen, HER2, Ki-67, tripl negativne ćelija ne karakterišu prisustvo androgenskih receptora Nije dokazana statistička značajnost za prvi i drugi stadijum bolesti duktalnog invazivnog karcinoma dojke kada se uzme u obzir kraće vreme preživljavanja kod pacijentkinja koje su primale hormonoterapiju. Statistički značajno kraće vreme preživljavanja pokazano je za treći stadijum bolesti kod pacijentkinja koje su AR i ER (≥ 2) u odnosu na pacijentkinje kod kojih je odnos AR/ER < 2, čime je za treći stadijum bolesti dokazana inicijalna hipoteza . Analize u prikazanom istraživanju nisu pokazale statističku značajnost kada se porede učestalost relapsa i smrtnog ishoda kada se posmatraju pacijentkinje sa AR pozitivnim i AR negativnim infiltrativnim duktalnim karcinomom dojke. Pokazana je statistički značajna razlika u učestalosti smrtnog ishoda između pacijenatkinja koje su lečene i inhibitorima aromataze i tamoksifenom. Zaključci ove studije bi mogli biti osnova za preporuku da se utvrđivanje ekspresije AR kod karcinoma dojke uvrsti u rutinsku praksu i sadržaj patohistološkog nalaza. Određivanje odnosa ekspresije AR i ER u grupi ER pozitivnih bolesnica moglo bi poslužiti kao vodič za primenu konvencionalne hormonske terapije ili, s druge strane, preporuka za terapiju antiandrogenima, sa ciljem da se izborom novih terapijskih modaliteta poboljša efikasnost lečenja bolesnica sa karcinomom dojke.The main problem in the treatment of breast cancer is how to predict its future behavior based on the clinical classification and morphological characteristics of the tumor. Very often even a combination of standard prognostic factors does not answer the need for adjuvant chemotherapy. In order to conduct adequate further breast cancer therapy and to detect aggressive tumor types, and following surgical treatment, there is a continuing need to find new indicators to identify patients at increased risk of relapse. The objectives of this study were to determine the frequency of androgen receptor (AR) expression in infiltrative ductal breast cancer. To determine the association between AR expression and clinical-pathological prognostic factors in infiltrative ductal breast cancer. Relationship between AR expression and expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER-2). To evaluate the association of positive AR expression, as well as the AR / ER ratio, with response to hormone therapy in ER positive patients. To evaluate the association of AR expression, as well as the relationship of AR / ER, with the clinical course of the disease: onset of relapse, metastasis, as well as fatal outcome during the 5-year follow-up period. The study included about 200 patients suffering from infiltrative ductal breast cancer, operated on at the Institute of Oncology of Vojvodina in the period 2010-2012. years. Patients were selected by random selection. The results there is no statistically significant difference between clinically pathologic factors and androgen receptor expression. No statistically significant difference in HER2 protein expression was shown in patients with infiltrative ductal breast cancer who are ER- / AR +. The frequency of progesterone receptors, estrogen, HER2, Ki-67, tripl negative cells do not characterize the presence of androgen receptors. No statistical significance was demonstrated for the first and second stages of ductal invasive breast cancer when considering shorter survival times in patients receiving hormone therapy. A statistically significant shorter survival time was shown for the third stage of disease in patients with AR and ER (≥ 2) compared to patients with an AR / ER ratio of <2, thus proving an initial hypothesis for the third stage of disease. The analyzes in the study presented showed no statistical significance when comparing the incidence of relapse and death when looking at patients with AR positive and AR negative infiltrative ductal breast cancer. There was a statistically significant difference in the incidence of death between patients treated with both aromatase inhibitors and tamoxifen. Conclusions of this study could be the basis for recommending that the determination of AR expression in breast cancer be incorporated into the routine practice and content of pathohistological findings. Determining the ratio of AR and ER expression in a group of ER-positive patients could serve as a guide for the administration of conventional hormone therapy or, on the other hand, a recommendation for anti-androgen therapy, with the aim of improving the effectiveness of breast cancer treatment in the choice of new therapeutic modalities.
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Aleksandra, Fejsa Levakov. "Ekspresija estrogenog receptora β u prekanceroznim lezijama i adenokarcinomu prostate." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2016. http://www.cris.uns.ac.rs/record.jsf?recordId=99993&source=NDLTD&language=en.
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Adenokarcinom prostate (PCa) je najčešći karcinom u muškaraca. Intraepitelne prostatične neoplazme visokog gradusa (HGPIN) su lezije koje prethode nastanku invazivnog karcinoma i podrazumevaju kompletno odsustvo bazalnih ćelija i invaziju strome malignim acinusima. Estrogeni receptor β (ERβ) se nalazi u jedrima bazalnih i sekretornih ćelija acinusa i delimično u stromalnim ćelijama. Cilj istraživanja je da prikaže i lokalizuje ERβ u različitim morfološkim lezijama prostate: hiperplaziji (BHP), PINu i u PCa sa različitim Gleason scorom. Pretpostavlja se da prekancerozne lezije u svojim različitim fazama evolucije ne koreliraju u potpunosti sa ekspresijom ERβ. LGPIN pokazuje ekspresiju, dok u HGPINu nema ekspresije. Takođe je pretpostavka da ekspresija ERβ postoji u većine srednje diferentovanih PCa, te da se ekspresija posmatranog receptora gubi sa porastom Gleason scora. Ispitivano je pet grupa bolesnika: kontrolna grupa sa BHP i četiri eksperimentalne grupe (PIN i 3 različite grupe PCa). Studija je sprovedena na muškarcima različite starosti u periodu 2010–2012. Nijedan pacijent nije prethodno primio hormonsku terapiju. Sekstant biopsije prostate su bojene na ERβ (Novocastra). Lokalizacija i intenzitet ERβ ekspresije prikazani su kroz skor: 0 = nula; 1 = <1%; 2 = 1–10%; 3 = 11–33%; 4 = 34–66%; 5 = > 66%. Pozitivni fibroblasti i endotelne ćelije su korišćene za poređenje. Smanjena ekspresija ERβ primećena je kod malignih i premalignih lezija prostate naspram BHP. Ekspresija ERβ u epitelnim ćelijama acinusa bila je najslabija u dobro diferentovanim PCa. Kod BHP i dobro diferentovanih PCa bila je veća ekspresija ERβ u bazalnim ćelijama nego u sekretornim. Loše diferentovani PCa prikazali su smanjenje ekspresije ERβ u bazalnim ćelijama. Ukupna ćelijska ekspresija ERβ predstavlja složen i ponekad moguće paradoksalan nalaz, na osnovu čega primarni PCa zadržava ekspresiju ovog receptora, ali ipak značajno nižu u poređenju sa benignim epitelom i premalignim lezijama. Ovaj nalaz podupire stanovište o antiproliferativnoj ulozi ERβ u tkivu prostate.Adenocarcinoma of the prostate (PCa) is the most common cancer in men. High-grade prostatic intraepithelial neoplasia (HGPIN) are lesions that precede to invasive carcinomas and include complete absence of basal cells and stromal invasion by malignant acini. Estrogen receptor ß(ERß) is located in the nuclei of basal and secretory cells and partly in stromal ones.The aim of the research is to describe and localize ERß in different morphological lesions: prostate hyperplasia (BPH), PIN and PCa with different Gleason score. It is assumed that pre-cancerous lesions in different stages of their evolution not correlate completely with the expression ERß. LGPIN shows expression, while there is no expression in HGPIN. It is also an assumption that the expression ERß exists in most medium differentiated PCa, and that the expression of this receptor loses with increasing of Gleason score. Five groups of patient were investigated: control group with BPH and four experimental groups (PIN and 3 different groups of PCa). The study was conducted on men of different ages in the period 2010-2012. None of the patients received prior hormonal therapy. Sextant prostate biopsy were stained on ERß (Novocastra). ERß expression is shown through the score: 0 = zero; 1 = <1%; 2 = 1-10%; 3 = 11-33%; 4 = 34-66%; 5 => 66%. Positive fibroblasts and endothelial cells were used for comparison. Reduced expression was observed in malignant and premalignant lesions of the prostate versus BPH. ERß expression in the epithelial cells of acini was the weakest in well-differentiated PCa. In BPH and well differentiated PCa was greater expression in the basal cells than in secretory ones. Poorly differentiated PCa showed a decreased ERß expression in basal cells. Total cellular expression of ERß is a complex and sometimes paradoxical finding on the basis of which the primary PCa retains expression of this receptor, but significantly lower compared to benign epithelium and premalignant lesions. This finding supports the antiproliferative role of ERß in prostate tissue.
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Smith, Matthew John. "Exploring the effects of estrogen receptor beta polymorphisms on wound repair." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/exploring-the-effects-of-estrogen-receptor-beta-polymorphisms-on-wound-repair(af2ae557-16ef-43a2-b5a7-db541b7c5d65).html.
Full textAbstract:
Estrogen is an important regulator and promoter of epithelial wound healing. This is facilitated by increased keratinocyte and fibroblast migration and proliferation, as well as promotion of angiogenesis, matrix deposition and inflammatory response dampening. The potential to target this pathway for therapeutics is highlighted by observations that post-menopausal women on hormone replacement therapy have a significantly lower incidence of venous ulcers. Previous work from this laboratory identified four SNPs (single nucleotide polymorphisms) in the 5’UTR of estrogen receptor beta (ERβ) gene that are associated with venous ulcer predisposition. Disease association is further supported by the identification of ERβ as the main conduit of the beneficial effects of estrogen signalling on wound healing. SNP’s of the 5’UTR can affect transcriptional expression through the modification of transcription factor binding sites, epigenetic modifications and translational efficiency via mRNA localisation and secondary structure alterations. To investigate the possible biological function of these SNPs, we have developed disease relevant cell based assays where primary keratinocyte and fibroblast cells were selected harbouring disease-associated SNPs. We demonstrate that the presence of venous ulcer-associated ERβ SNPs reduced the expression of ERβ in skin cells and reduced their migration and proliferative capabilities. Evidence gathered here suggests that ERβ expression is curtailed by a change in transcription factor binding, likely facilitated by the change in nucleotide sequence brought about by the rs2987983 SNP. Further, we demonstrate that SNP-induced changes in fibroblast expression of growth factors and inflammatory mediators can hinder keratinocyte migration and induce a pro-inflammatory phenotype in human monocytes. Lastly, RNAseq analysis of keratinocytes reveals a SNP-dependant gene expression profile that is detrimental to wound healing. This work provides the first evidence of a direct functional link between venous ulcer-associated ERβ SNPs and dysfunctional wound healing. Investigating ERβ SNPs has provided insight into novel mechanisms of estrogen signalling that can be applied for therapeutic development to treat venous ulcers.
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Alexander, Amy. "GPR30 : a role for a novel estrogen-sensing receptor in hippocampal function?" Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/a51c1614-e36e-40b6-aad3-7efacdce0f48.
Full textAbstract:
17ß-estradiol (E2), the most potent form of the steroid hormone class, the estrogens, is a known regulator of hippocampal function and is capable of being synthesised within hippocampal neurons. E2 can modulate glutamatergic synaptic transmission and hippocampal synaptic plasticity, as well as enhance hippocampal dependent learning in rodent models. However, not all effects of estradiol are mediated by the two canonical estrogen receptors, ERa and ERß. Recently, a novel estrogen-sensing G protein coupled receptor (GPR30) was identified, and hippocampal expression of GPR30 indicates a potential role for this receptor in modulating hippocampal function. Thus, the primary aims of this thesis were to clarify the effects of E2 on glutamatergic synaptic transmission and establish whether activation of GPR30 is involved. Using evoked population EPSP recordings within the dendritic field of hippocampal region CA1, we show that acute application of a physiologically relevant concentration of E2 modulates excitatory synaptic transmission in a bi-directional manner; the most consistent effect however was the induction of a novel form of LTD. Moreover, we show that the GPR30 agonist (G1) mimics the bi-directional effects of E2 on excitatory synaptic transmission. Subsequent characterisation of the E2 and G1 induced LTD revealed that both forms of agonist-induced plasticity are expressed post-synaptically, correlating with findings in hippocampal cultures in which treatment with these agonists resulted in a reduction in the relative density of GluA1-containing AMPA receptors expressed at synapses. In addition, further investigation into the pharmacology of the G1-induced LTD revealed that this effect was not prevented by selective antagonists for GPR30, ERa or ERß, however could be attenuated by a selective estrogen receptor downregulator and putative ligand for GPR30, ICI 182 780. Furthermore, we establish that in hippocampal neurons, the G1-induced reduction in surface AMPA receptor expression is mediated via the ERK 1/2 signalling pathway. In summary, the data presented here suggests that at CA3 to CA1 synapses, E2 and the GPR30 agonist can induce a novel form of LTD in adult hippocampal tissue. Considering the multifaceted role of estrogens in human physiology, pharmaceuticals which modulate this system in a site specific manner (either by influencing estrogen synthesis or targeting estrogen receptors) could be of benefit in hippocampal dependent learning and memory processes in health and disease.
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Tanja, Lakić. "Klinička vrednost određivanja Ki-67 proliferativnog indeksa u karcinomima dojke sa pozitivnim hormonskim receptorima." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2018. https://www.cris.uns.ac.rs/record.jsf?recordId=107631&source=NDLTD&language=en.
Full textAbstract:
Uvod: Karcinom dojke je heterogena bolest koju karakterišu različita morfologija, imunohisto-hemijski profil, klinički tok i terapijski odgovor. Ki-67 proliferativni indeks je jedan od markera sa prognostičkim i prediktivnim značajem, čije metodološko određivanje i analiza još uvek nisu standardizovani. Cilj: Utvrditi graničnu (“cut-off”) prognostičku vrednost Ki-67 indeksa, kao i povezanost vrednosti Ki-67 u ranom luminalnom karcinomu dojke sa prognostičkim i prediktivnim parametrima karcinoma dojke, kao što su životna dob bolesnica, veličina tumora, histološki gradus (HG) i nivo tumorske ekspresije receptora estrogena (ER) i progesterona (PR). Takođe, cilj istraživanja je i utvrđivanje značajnosti razlike u vrednosti Ki-67 proliferativnog indeksa u odnosu na pojavu lokalnog recidiva, udaljenih metastaza i dužinu preživljavanja u toku petogodišnjeg perioda praćenja pacijentkinja. Metode: Retrospektivno je analizirano 120 patohistoloških izveštaja bolesnica kojima je u periodu od 01.01.2009. godine do 31.12.2011. godine na Institutu za onkologiju Vojvodine imunohistohemijskom analizom dokazan luminalni karcinom dojke (pozitivan ER i PR, negativan HER2), bez metastaza u aksilarnim limfnim čvorovima. Rezultati: Metodama deskriptivne statistike prosečna starost pacijentkinja je iznosila 57,42±10,17 godina; prosečna veličina tumora 17,98±6,97mm; recidiv je registrovan kod 8 (6,7%) pacijentkinja uz prosečan vremenski period do pojave recidiva od 49±20,23 meseci. Vrednost “cut off” indeksa Ki-67 od prognostičkog značaja za vremenski period bez recidiva je iznosio 20,75%. Nije dokazana signifikantna veza između vrednosti Ki-67 i godina starosti pacijentkinja (p=0,401, odnosno p=0,293), kao i jačine ekspresije ER (p=1,00, p=0,957) i PR (p=0,273, p=0,189). Ustanovljena je signifikantna povezanost Ki-67 postoji sa veličinom (p=0,035, p=0,20) i HG tumora (p=0,041, p=0,20). Prosečan period praćenja bolesnica iznosio je 72,92±8,38 meseci; nije registrovana pojava udaljenih metastaza, kao ni smrtni ishod. U odnosu na pojavu lokalnog recidiva, Kaplan-Majerovom analizom i Koksovom regresionom analizom proliferativni indeks Ki-67 se pokazao kao signifikantan prediktor za procenu ponovnog javljanja bolesti, lokalnog recidiva (Log rank (df = 1) = 2,73; p=0,045). Takođe je ustanovljeno da je statistički značajan prediktor za procenu recidiva bolesti i starosna dob bolesnica (Log rank (df = 1) = 6,885; p=0,009). Intenzitet pozitivnosti ER i PR, veličina tumora i histološki gradus se nisu pokazali kao prediktori za pojavu recidiva luminalnih karcinoma dojke (p > 0,05). Zaključak: Zbog heterogene prirode oboljenja, korišćenjem standardnih histopatoloških faktora i biomarkera teško je predvideti tok i ishod karcinoma dojke. Ki-67 je proliferativni marker, čija visoka vrednost korelira sa faktorima loše prognoze.Introduction: Breast cancer is a heterogeneous disease characterized by different morphology, immunohistochemical profile, clinical course and response to applied therapy. Ki-67 proliferative index is one of the prognostic and predictive factors, whose methodological determination and analysis are still unstandardized. Objective: Determination of cut-off value for Ki-67 index, its corelation in luminal breast carcinoma with patient's age, tumor size, histological grade (HG) and expression of estrogen (ER) and progesterone (PR). Also, the aim of the study was to determine the significance of the difference in the value of the Ki-67 proliferative index in relation to the occurrence of local relapse, distant metastases and survival rates during the five-year follow-up period of the patient. Methods: Retrospectively, we analysed 120 pathohistological reports of patients who were treated in the period from 01.01.2009 until 31.12.2011 at the Oncology Institute of Vojvodina, and to whom immunohistochemically was proven luminal breast cancer (positive ER and PR, negative HER2), without axillary lymph node metastases. Results: The average patient’s age was 57.42±10.17 years; average tumor size 17.98±6.97mm; recurrence was registered in 8 (6.7%) patients with average recurrence time of 49±20.23 months. "Cut off" Ki-67 value of prognostic significance for period without recurrence was 20.75%. Test didn’t show significant relationship between Ki-67 and patient’s age (p=0.401 and p=0.293), as well as the strength of expression ER (p=1.00, p=0.957) and PR (p=0.273, p=0.189). Significant correlation was present for Ki-67 with size (p=0.035, p=0.20) and tumor’s HG (p=0.041, p=0.20). The average follow-up period for patients was 72.92±8.38 months; there was no registered occurrence of distant metastases or fatal outcome. In relation to the occurrence of local relapse, Kaplan-Meier analysis and Cox regression analysis, the proliferative index Ki-67 proved to be a significant predictor for the assessment of recurrence of the disease, local relapse (Log rank (df = 1) = 2.73; p = 0.045). Also, it was founded that a statistically significant predictor for assessing the recurrence of the disease is the age of the patients (Log rank (df = 1) = 6.885; p = 0.009). The intensity of ER and PR expression, tumor size and histological grade have not been shown to be predictors of the recurrence of luminal breast carcinoma (p> 0.05). Conclusion: Breast carcinoma is heterogeneous disease, so it is difficult to predict its course and outcome using standard histopathological factors and biomarkers. Ki-67 is proliferative marker whose high value correlates with factors of bad prognosis.
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Dzida, Tomasz. "Predicting context specific enhancer-promoter interactions from ChIP-Seq time course data." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/predicting-context-specific-enhancerpromoter-interactions-from-chipseq-time-course-data(281a8cee-87f9-49e7-8106-a9d76603a806).html.
Full textAbstract:
We develop machine learning approaches to predict context specific enhancer-promoter interactions using evidence from changes in genomic protein occupancy over time. Occupancy of estrogen receptor alpha (ER-alpha), RNA polymerase (Pol II) and histone marks H2AZ and H3K4me3 were measured over time using ChIP-Seq experiments in MCF7 cells stimulated with estrogen. Two Bayesian classifiers were developed, unsupervised and supervised. The supervised approach uses the correlation of temporal binding patterns at enhancers and promoters and genomic proximity as features and predicts interactions. The method was trained using experimentally determined interactions from the same system and achieves much higher precision than predictions based on the genomic proximity of nearest ER-alpha binding. We use the method to identify a confident set of ER-alpha target genes and their regulatory enhancers genome-wide. Validation with publicly available GRO-Seq data shows our predicted targets are much more likely to show early nascent transcription than predictions based on genomic ER-alpha binding proximity alone. Accuracy of the predictions from the supervised model was compared against the second more complex unsupervised generative approach which uses proximity-based prior and temporal binding patterns at enhancers and promoters to infer protein-mediated regulatory complexes involving individual genes and their networks of multiple distant regulatory enhancers.
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"A functional study of the orphan nuclear receptor estrogen-related receptor alpha in advanced growth of prostate cancer: 孤兒受體ERRα在前列腺癌中惡性增殖的功能研究." 2014. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1291462.
Full textAbstract:
Background and aims of the study. Prostate cancer (PCa) is one of the most common hormone-dependent cancers in men in Western and also Asian countries. The standard treatment options for localized PCa include surgery and androgen-deprivation therapy (ADT). However, most patients upon ADT therapy invariably relapse and progress to a more aggressive and metastatic stage termed as castration-resistant PCa (CRPC). Accumulating studies indicate that androgen receptor (AR) transcriptional activity is dysregulated during the advanced progression of CRPC. One important mechanism responsible for the growth of CRPC includes increased intra-tumoral androgen synthesis in PCa. Recently, a novel androgen-responsive fusion gene TMPRSS2:ERG formed by fusion between the transmembrane protein TMPRSS2 and transcription factor ERG, has been identified in approximately 50% PCa samples, which results in the aberrant expression of ERG function as oncogenic factor in PCa. Currently, TMPRSS2:ERG is regarded as a significant potential diagnostic and prognostic biomarker for PCa. Estrogen-related receptor alpha-ERRα, the first identified ligand-independent orphan nuclear receptor, is characterized to be up-regulated in advanced cancers, suggesting that ERRα might play important regulatory roles in the malignant progression of PCa. Previous studies showed that ERRα can functionally cross-talk with AR signaling via co-targeting to AR targets and regulate the expression of some steroidogenic enzymes in breast cancer. Based on this background, it is hypothesized that ERRα could functionally regulate the TMPRSS2:ERG fusion gene and play a regulatory role in the development and progression of CRPC through activation of the intracellular androgen synthesis pathway.Results. 1) The results obtained in this study showed that suppression of ERRα by its specific inverse agonist XCT790 or shRNA-knockdown could induce down-regulation of TMPRSS2:ERG and also its target genes in AR-positive VCaP PCa cells. 2) Ectopic expression of ERRα and/or its coactivator PGC-1α could increase the expression of TMPRSS2:ERG in AR-negative NCI-H660 PCa cells. 3) Two ERRα-DNA binding elements were identified by ChIP assay and sequence analysis in the promoter of TMPRSS2:ERG and both of these two elements could be transactivated by ERRα and PGC-1α. 4) Ectopic expression of TMPRSS2:ERG under the regulation of ERRα enhanced the prostatic cell invasion capacity as shown in the TMPRSS2:ERG infectants of BPH-1 and PC-3 prostatic cells. 5) ERG expressed by the TMPRSS2:ERG fusion could directly transactivate the ERRα gene in prostatic cells. 6) A positive correlation on the expressions between TMPRSS2:ERG and ERRα was demonstrated in a xenograft model of CRPC (VCaP-CRPC). 7) The expression of TMPRSS2:ERG and ERRα showed significant up-regulation and the transactivation activity of ERRα was also enhanced in castration-resistant VCaP-CRPC cells. 8) Ectopic expression of ERRα could promote resistant growth capacity to androgen-deprivation condition in LNCaP PCa cells, whereas shRNA-mediated silence of ERRα could weaken this resistant capacity. Furthermore, ectopic expression of ERRα in LNCaP-ERRα infectants could promote their in vivo growth resistance to castration in SCID mice. 9) Expression of several androgenic enzyme genes, including CYP11A1, CYP17A1 and ARK1C3, were detected to be up-regulated in castration-resistant VCaP-CRPC cells. Moreover, ectopic expression of ERRα could induce the increased expression of these enzyme genes in LNCaP-ERRα infectants, whereas knockdown of ERRα by shRNA could decrease their expression. 10) ERRα could directly transactivate the gene promoters of CYP11A1, CYP17A1 and ARK1C3 which contain ERRE elements prediction by sequence analysis. These results suggested that ERRα could play a role in de novo or intra prostatic androgen synthesis in the PCa cells.
Conclusions. The results obtained in this study suggested that ERRα and TMPRSS2:ERG could form a positive reciprocal loop in PCa cells, and ERRα could also promote the resistant growth capacity of PCa cells resistant to the androgen-deprivation condition in vitro and also castration-resistant growth in vivo via a mechanism of up-regulation of androgenic enzyme genes. The results also suggested that ERRα might play a significant regulatory role in the development and progression of PCa, particularly the advanced CRPC, and also ERRα could be a potential therapeutic target for the treatment of PCa, particularly the advanced PCa-CRPC.
研究背景與研究目的：前列腺癌作為激素依賴的一種癌症，經常出現在西方和亞洲國家的男性人群中。對於局限性前列腺癌多採用外科手術和去勢的治療。但是大多數病人經過去勢治療后會再次復發並且形成更加惡心幾轉移的前列腺癌，稱之為去勢難治性前列腺癌（CRPC）。越來越多的研究表明在去勢難治性前列腺癌發病過程中，雄激素受體轉錄活性異性增強。其中一個重要機理解釋為前列腺癌細胞自身合成的雄激素增多。進來，在大約50%的前列腺癌病人中新檢測到一個受雄激素受（AR）體調控的融合基因TMPRSS2:ERG，它是由稱為TMPRSS2的一個跨膜蛋白和一個稱為ERG的轉錄因子融合而成，它的出現導致了在前列腺癌中異常的稱為致癌因子的ERG蛋白的高表達。目前，TMPRSS2:ERG已經被作為一個重要的潛在的診斷和預測的標誌物應用在前列腺癌中。作為第一個鑒定的配體不依賴的孤兒受體-ERRα，被證明在晚期的癌症中有很高的表達，預示著ERRα可能在惡性的癌症中起到一個非常重要的調控作用。之前的研究表明通過共同調控AR的下游基因，ERRα同AR信號通路之間有功能性的交叉調控；除此之外，在乳腺癌中，ERRα還可以調控一些類固醇類化合物的合成相關的一些酶的合成。依據上述，我們推定ERRα可能功能性地調控TMPRSS2:ERG融合基因的表達並且通過調控細胞內的雄激素的合成進而在去勢難治性前列腺癌的發生和發展中起到一個非常重要的作用。
結果：本論文研究結果總結如下：1）在有AR表達的前列腺癌細胞-VCaP細胞中，通過ERRα特異性的抑制劑XCT790處理或者shRNA介入的干擾ERRα的mRNA的方法來抑制ERRα，下調了TMPRSS2:ERG和它的一些下游調控基因的表達。2）在沒有AR表達的前列腺癌細胞-NCI-H660細胞中，上調ERRα或者它的特異性的共激活因子PGC-1α表達可以提升TMPRSS2:ERG的表達。3）通過ChIP實驗，在TMPRSS2:ERG的啟動子上面，兩個ERRα的DNA結合位點被鑒定出來。並且這兩個位點可以被ERRα和PGC-1α轉錄激活。4）在兩個前列腺細胞BPH-1和PC-3細胞中，在ERRα的調控下高表達TMPRSS2:ERG融合基因可以增強細胞的侵襲能力。5）融合基因TMPRSS2:ERG導致的ERG蛋白的表達可以直接轉錄激活ERRα的表達。6）我們通過VCaP細胞的異種移植建立VCaP-CRPC的體內模型來模擬CRPC過程，在整個過程中，我們發現TMPRSS2:ERG和ERRα有一致性的表達相關性。除此之外，我們根據上述動物模型通建立了VCaP-CRPC細胞系，並且發現在VCaP-CRPC細胞細胞中，TMPRSS2:ERG和ERRα都有被上調並且ERRα的轉錄活性同樣也提升。7）在LNCaP細胞中高表達ERRα可以提升細胞在去除雄激素的環境中生長的能力。但是當在LNCaP細胞中用shRNA干擾掉ERRα可以明顯減弱這種生長的能力。用LNCaP-ERRα穩轉ERRα的細胞異種移植建立SCID老鼠體內腫瘤模型，我們發現和LNCaP-pBABE對照組相比，LNCaP-ERRα細胞生長的更快更大。並且在對老鼠進行睪丸切除術后，LNCaP-ERRα組細胞更快適應這種環境并繼續生長，相比之下，LNCaP-pBABE對照組則持續萎縮減小。8）在上述的VCaP-CRPC細胞中，我們發現一些和雄激素合成相關的關鍵的酶包括CYP11A1，CYP17A1和ARK1C3的表達量有顯著地提升。而且在LNCaP-ERRα細胞中同樣檢測到這些酶的表達量的提升。然而當在LNCaP細胞中用shRNA干擾掉ERRα可以明顯減降低上述酶的表達。9）我們在CYP11A1，CYP17A1和ARK1C3基因的啟動子區域發現有ERRα結合位點，並且發現這些位點可以被ERRα轉錄激活。
結論：本論文的研究結果提示在前列腺癌細胞中，ERRα和TMPRSS2:ERG可以形成一個相互正向調控的循環。除此之外，上調ERRα可以促進細胞在去除雄激素的環境中生長的能力，並且在動物體內可以提升細胞在睪丸去除的環境中的適應和生長能力。這種體內和體外的能力的提升是通過一種潛在的上調前列腺癌細胞的雄激素合成相關的關鍵的酶的表達，進而提升雄激素的含量而得以實現的。上述的結果預示著ERRα可能在前列腺癌發生機發展的過程中起到非常重要的調控作用，尤其在晚期的CRPC中。同時，ERRα也可能作為一個潛在的重要的前列腺癌尤其是晚期的CRPC的治療靶點，尤其是一些潛在ERRα的特異性抑制劑，比如XCT790，可能作為將來用以作為治療前列腺癌的特異性靶點藥物。
Xu, Zhenyu.
Thesis Ph.D. Chinese University of Hong Kong 2014.
Includes bibliographical references (leaves 126-143).
Abstracts also in Chinese.
Title from PDF title page (viewed on 05, October, 2016).
Xu, Zhenyu.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
9
"Expression of G protein-coupled estrogen receptor (GPER) and its effects on P2Y receptor-mediated Ca²⁺ signalling and cytokine secretion in human bronchial epithelia." 2014. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1290692.
Full textAbstract:
The airway epithelium plays a central role in respiratory physiology through its transport and immunological functions. Our previous study suggested that P2Y receptors are expressed in airway epithelia and play a significant role in regulating transepithelial ion transport. P2Y receptors belong to the family of purinergic receptors, which can be stimulated by nucleotides such as UTP and UDP. P2Y receptors are G protein-coupled receptors and classically signal through G[subscript q], resulting in an increase in intracellular Ca²⁺ concentration ([Ca²⁺]ᵢ) and thereby in the activation of Ca²⁺-dependent ion channels and downstream signalling pathway(s). Furthermore, P2Y receptors are involved in asthmatic inflammation.Estrogen (or E₂) is an important hormone in human physiology. In addition to the classical nuclear hormone receptors ERα and ERβ, a novel estrogen receptor, G protein-coupled estrogen receptor (GPER), was recently identified and found to be involved in both rapid signalling and transcriptional regulations. The action of GPER is unclear, but it has been implicated in mediating anti-inflammatory responses.
In our experiments, both human bronchial epithelial cell line, 16HBE14o-, and primary normal human bronchial epithelial cells expressed GPER at mRNA and protein levels, as demonstrated by RT-PCR and western blotting, respectively. ERα and ERβ expression were also detected at mRNA and protein level. Expression of GPER receptors was localized in the human bronchial epithelial cells by immunofluorescence staining and western blotting of fractionated cell lysates.
[Ca²⁺]ᵢ induced by nucleotides were monitored by calcium imaging technique using MetaFluor fluorescence ratio imaging system. Stimulation of epithelial cells with E₂ or with the specific agonist of GPER, G1, rapidly attenuated a UDP-, UTP- or ATPyS- evoked increase in [Ca²⁺]ᵢ in both 16HBE14o- cell line and primary cells. This inhibitory effect of E₂ and G1 were concentration dependent, while this effect was reversed by GPER specific antagonist, G15. To examine the effect of E₂ and G1 on UDP-activated intracellular Ca²⁺ release and influx, the epithelia were exposed to nominally Ca²⁺ -free solution in the presence or absence of G1 or E₂, and then stimulated with UDP. Subsequently, Ca²⁺ was added to the perfusate. Both E₂ and G1 could inhibit UDP-induced Ca²⁺ release. However, only E₂ but not G1 could inhibit UDP-induced Ca²⁺ influx.
E₂ or G1 inhibited the secretion of two pro-inflammatory cytokines, interleukin (IL)-6 or IL-8, in cells stimulated by different nucleotides or the cationic protein, poly-L-arginie, as quantified by ELISA. CFP-Epac-YPF, an Epac-based polypeptide FRET reporter was used to monitor the real-time cAMP changes in 16HBE14o- cells. Both G1 and E₂ induced an increase in cAMP production. The transepithelial chloride (Cl⁻) secretion was measured using short circuit current technique in cells grown on permeable support. Cl⁻ secretion induced by apical UDP was partially inhibited by G1 in a concentration dependent manner.
Our results provide the first evidence that human bronchial epithelia express GPER, which interact with the P2Y receptor-mediated calcium signalling pathway and cytokine secretion. Moreover, the anti-inflammatory role of GPER may be due to its opposing effect on the pro-inflammatory pathway activated by the P2Y receptors in inflamed airway epithelia.
气道上皮具有调节运输以及参与免疫反应等功能，在呼吸生理学研究中有着十分关键的意义。我们曾经的研究发现P2Y受体在气道上皮中表达并调节上皮细胞离子运输过程。P2Y受体属于嘌呤受体，可被三磷酸尿苷（UTP），二磷酸尿苷（UDP）等核苷酸激活。同时，P2Y受体也是一类G蛋白偶联受体，可通过活化G[subscript q]蛋白调控细胞内钙离子浓度而激活钙依赖性离子通道及其他下游信号通路。此外P2Y受体还参与哮喘炎症的调控。
雌激素（或雌二醇，E₂）是人体一类十分重要的激素。除传统的核受体ERα与ERβ外，一类新型雌激素受体GPER已被发现和鉴定。GPER属于G蛋白偶联受体，可同时参与转录调控和非基因依赖的快速信号调节。尽管具体机理尚不明确，但研究发现GPER可介导抗炎症反应。
实验结果显示，在支气管上皮细胞株16HBE14o-和原代人支气管上皮细胞中GPER都被检测到基因和蛋白水平的表达。GPER在人支气管上皮细胞中的定位也通过免疫荧光染色（immunofluorescence）和亚细胞组分蛋白质印迹（western blot of fractionated cells）得到鉴定。
本研究中，荧光显微技术（fluorescence microscopy）被用于测定核苷酸介导的细胞内钙离子浓度（[Ca²⁺]ᵢ）。在16HBE14o- 和原代培养人支气管上皮细胞中，E₂和GPER特异性激动剂G1都可抑制核苷酸介导的 [Ca²⁺]ᵢ增加，且这种抑制作用呈浓度依赖。GPER特异性拮抗剂G15可抵消G1的抑制作用。进一步研究表明，E₂和G1都可抑制UTP诱导的胞内钙库释放，然而只有E₂抑制UTP诱导的胞外钙离子内流。
除钙离子调节外，E₂和G1还可抑制支气管上皮细胞中核苷酸或聚精氨酸（poly-L-arginine）刺激介导的两种促炎症细胞因子，白介素6（IL-6）和白介素8（IL-8）的分泌。酶联免疫法（ELISA）被用于细胞因子的定量。同时，CFP-Epac-YPF作为一类多肽荧光共振能量转移（FRET）探针被转染入16HBE14o- ，探测细胞内腺苷-3',5'-环化一磷酸（cAMP）的实时变化。结果显示在人支气管上皮细胞中E₂和G1都可引导cAMP生成。此外，我们使用短路电流（short-circuit current, Isc）技术测定单层上皮细胞的氯离子（Cl⁻）分泌，并发现人支气管上皮顶膜面UDP诱导的Cl⁻ 分泌可被G1部分抑制，且抑制效果呈浓度依赖。
本研究首次证明GPER表达于人支气管上皮, 且激活GPER对P2Y受体介导的钙离子信号通路以及细胞因子生成起到抑制作用。这些结果表明在气道炎症反应中，GPER可通过反向调节P2Y受体激活的促炎症作用，达到抗炎症的效果。
Hao, Yuan.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2014.
Includes bibliographical references (leaves 187-211).
Abstracts also in Chinese.
Title from PDF title page (viewed on 03, November, 2016).
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
10
"The role of estrogen receptors in mechanical signal transduction during osteoporotic fracture healing augmented by mechanical stimulation." 2014. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1292088.
Full textAbstract:
Chow, Kwoon Ho Simon.Thesis Ph.D. Chinese University of Hong Kong 2014.
Includes bibliographical references (leaves 108-115).
Abstracts also in Chinese.
Title from PDF title page (viewed on 21, December, 2016).
Books on the topic "Estrogen receptor. eng"
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Test No. 457: BG1Luc Estrogen Receptor Transactivation Test Method for Identifying Estrogen Receptor Agonists and Antagonists. OECD, 2012. http://dx.doi.org/10.1787/9789264185395-en.
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Test No. 455: The Stably Transfected Human Estrogen Receptor-alpha Transcriptional Activation Assay for Detection of Estrogenic Agonist-Activity of Chemicals. OECD, 2009. http://dx.doi.org/10.1787/9789264076372-en.
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Test No. 455: Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists. OECD, 2012. http://dx.doi.org/10.1787/9789264185388-en.
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Test No. 455: Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists. OECD, 2016. http://dx.doi.org/10.1787/9789264265295-en.
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Test No. 455: Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists. OECD, 2015. http://dx.doi.org/10.1787/9789264243040-en.
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Test No. 250: EASZY assay - Detection of Endocrine Active Substances, acting through estrogen receptors, using transgenic tg(cyp19a1b:GFP) Zebrafish embrYos. OECD, 2021. http://dx.doi.org/10.1787/0a39b48b-en.
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Test No. 493: Performance-Based Test Guideline for Human Recombinant Estrogen Receptor (hrER) In Vitro Assays to Detect Chemicals with ER Binding Affinity. OECD, 2015. http://dx.doi.org/10.1787/9789264242623-en.
Full textConference papers on the topic "Estrogen receptor. eng"
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Davies, Julia, Deyarina Gonzalez, and R. Steven Conlan. "Abstract 5504: Regulation of the receptor for advanced glycation end products by estrogen receptor ligands in endometrial cancer." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-5504.
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