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Start Over Author "Mélanie Mestdagt" Topic 0302 clinical medicine
7 results on '"Mélanie Mestdagt"'

1. Regulation of CXCL8/IL-8 expression by Zonula Occludens-1 in human breast cancer cells

Author

Agnès Noël, Jean-Michel Foidart, Emilie Luczka, Walter Hunziker, Myriam Polette, Christine Gilles, Philippe Birembaut, Mélanie Mestdagt, and Anne Brysse

Subjects
musculoskeletal diseases, Cancer Research, Chemokine, Breast Neoplasms, Transfection, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Humans, Neoplasm Invasiveness, Interleukin 8, RNA, Small Interfering, Molecular Biology, Cells, Cultured, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, biology, Gene Expression Profiling, Carcinoma, Interleukin-8, Membrane Proteins, Microarray Analysis, Phosphoproteins, medicine.disease, Cell biology, Gene Expression Regulation, Neoplastic, Oncology, SKBR3, Tumor progression, 030220 oncology & carcinogenesis, Cancer cell, Disease Progression, Zonula Occludens-1 Protein, biology.protein, Cancer research, Female
Abstract

Accumulating data now suggest that ZO-1, once delocalized from tight junctions, could be implicated in the regulation of tumor-promoting genes. Because of their major implication in different steps of tumor progression, we investigated here the influence of ZO-1 on chemokines expression in breast cancer cells. Using GeneArray analysis to compare chemokine mRNA expression in breast tumor cells transfected with a siRNA against ZO-1, we identified CXCL-8IL-8 as a major potential target of ZO-1 signaling, being strongly downregulated following ZO-1 siRNA transfection. Examining further the relationship between ZO-1 and interleukin-8 (CXCL8/IL-8), we first showed that CXCL8/IL-8 expression correlates with a relocalization of ZO-1 in several breast cancer cell lines. Moreover, CXCL8/IL-8 is downregulated in invasive BT549 cells transfected with three different ZO-1 siRNA and overexpressed in noninvasive BT20 and SKBR3 cells transfected with vectors expressing ZO-1. We also provide evidence for an activation of the CXCL8/IL-8 promoter by ZO-1. Finally, we show that the regulation of CXCL8/IL-8 by ZO-1 is independent of the β-catenin pathway. Our results thus clearly show an implication of ZO-1 in CXCL8/IL-8 regulation. Because of the major implications of CXCL8/IL-8 in tumor invasion, such a regulation could play an important role in breast cancer progression. Mol Cancer Res; 10(1); 121–32. ©2011 AACR.

Published
2012
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2. Transactivation of MCP-1/CCL2 by β-catenin/TCF-4 in human breast cancer cells

Author

Christine Gilles, Agnès Noël, Myriam Polette, Atsuhisa Ueda, Giovanna Butticè, Mélanie Mestdagt, Jean-Michel Foidart, Laboratory of Developmental and Tumour Biology (LDTB), Université de Liège, Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry, Boston University School of Medicine (BUSM), Boston University [Boston] (BU)-Boston University [Boston] (BU), Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Communauté française de Belgique (Actions de Recherches Concert2es), Commission of European Communities (FP6 Brecosm), Fonds de la Recherche Scientifique Médicale, Fonds National de la Recherche Scientifique (FNRS, Belgium), Fédération Belge Contre le Cancer, C.G.R.I.-F.N.R.S.-INSERM Coopération, Fonds spéciaux de la Recherche (University of Liège, Centre Anticancéreux près l'Université de Liège, Fortis Banque Assurances, Fondation Léon Frédéricq (University of Liège), D.G.T.R.E. from the ‘‘Région Wallonne', Fonds d'Investissements de la Recherche Scientifique (CHU, Liège, Belgium), Interuniversity Attraction Poles Programme-Belgian Science Policy (Brussels, Belgium)., and Birembaut, Philippe

Subjects
MESH: Carcinoma, Cancer Research, Angiogenesis, TCF/LEF family, medicine.disease_cause, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Cadherins, MESH: Down-Regulation, Transactivation, 0302 clinical medicine, Tumor Cells, Cultured, Promoter Regions, Genetic, skin and connective tissue diseases, Chemokine CCL2, beta Catenin, 0303 health sciences, Neovascularization, Pathologic, Transfection, Cadherins, MESH: Tum, Up-Regulation, 3. Good health, MESH: Promoter Regions (Genetics), Cell Transformation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Disease Progression, MESH: Disease Progression, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Transcriptional Activation, Down-Regulation, Breast Neoplasms, Biology, Article, 03 medical and health sciences, breast cancer, Breast cancer, medicine, Humans, MESH: Chemokine CCL2, 030304 developmental biology, MESH: Humans, Carcinoma, β-catenin, medicine.disease, MESH: Trans-Activation (Genetics), MESH: Cell Transformation, Neoplastic, Tumor progression, Cancer cell, Cancer research, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Neovascularization, Pathologic, Carcinogenesis, MESH: Breast Neoplasms, MESH: TCF Transcription Factors, MCP-1
Abstract

International audience; The loss of E-cadherin expression and the translocation of beta-catenin to the nucleus are frequently associated with the metastatic conversion of epithelial cells. In the nucleus, beta-catenin binds to the TCF/LEF-1 (T-cell factor/ lymphoid enhancer factor) transcription factor family resulting in the activation of several genes, some of them having important implications in tumour progression. In our study, we investigated the potential regulation of monocyte chemotactic protein-1 (MCP-1/CCL2) expression by the beta-catenin/TCF pathway. This CC-chemokine has been implicated in tumour progression events such as angiogenesis or tumour associated macrophage (TAM) infiltration. We thus demonstrated that MCP-1 expression correlates with the reorganization of the E-cadherin/beta-catenin complexes. Indeed, MCP-1 was expressed by invasive breast cancer cells (MDA-MB-231, BT549 and Hs578T), which do not express E-cadherin but was not produced by noninvasive breast cancer cell lines (MCF7 and T47D) expressing high level of E-cadherin. In addition, the MCP-1 promoter was activated in BT549 breast cancer cells transfected with beta-catenin and TCF-4 cDNAs. The MCP-1 mRNA level was similarly upregulated. Moreover, we showed that MCP-1 mRNA was downregulated after transfection with a siRNA against beta-catenin in both BT549 and Hs578T cells. Our results therefore identify MCP-1 as a target of the beta-catenin/TCF/LEF pathway in breast tumour cells, a regulation which could play a key role in breast tumour progression.

Published
2005

3. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation

Author

Claude Knauf, Françoise Lenfant, Marine Adlanmerini, Muriel Laine, Shyamala S. Rajan, Isabelle Raymond-Letron, Anne Drougard, Isabelle Muller, Daniel Henrion, Philippe Valet, Christel Pequeux, Anne Abot, Romain Solinhac, Jean-François Arnal, Marie Cécile Valera, Aurelie Fabre, John A. Katzenellenbogen, Alain Milon, Mélanie Mestdagt, Gilles Flouriot, François Ferrière, Coralie Fontaine, Jean-Michel Foidart, Geoffrey L. Greene, Céline Gérard, Anne Gompel, Pierre Gourdy, Benita S. Katzenellenbogen, Melissa Buscato, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre national de référence des angioedemes, Laboratory of Tumor and Developmental Biology, Université de Liège-CHU Sart-Tilman, Department of Molecular and Integrative Physiology, University of Illinois System, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie des Tumeurs et du Développement), Université de Liège, The work at the INSERM unit U1048 was supported by INSERM, Université de Toulouse III and Faculté de Médecine Toulouse-Rangueil, Fondation de France, Conseil Régional Midi-Pyrénées and Fondation pour la Recherche Médicale (FRM). A. Abot was supported by a grant from the Groupe de Réflexion sur la Recherche Cardiovasculaire. The NMR facility is part of the genotoul-Ibisa PICT platform and was funded by CNRS, région Midi-Pyrénées, and European structural funds. The work at INSERM U1083-CNRS-UMR 6214 is supported by INSERM, CNRS, CHU and Université d'Angers, Fondation de France, Fondation de l'Avenir, and Conseil Régional Pays de la Loire. The work at ULg, GIGA-cancer was supported by grants from the F.R.S.-FNRS (Belgium), the DGO6 from SPW (Belgium), the IUAP (Belspo, Belgium). This work was supported by National Institutes of Health Grants PHS5R01 DK015556 to J.A.K., Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Models, Molecular, [SDV]Life Sciences [q-bio], Gene Expression, Estrogen receptor, Protein Structure, Secondary, chemistry.chemical_compound, 0302 clinical medicine, Research Articles, Mice, Knockout, 0303 health sciences, Molecular Structure, Reverse Transcriptase Polymerase Chain Reaction, Estetrol, Hep G2 Cells, Immunohistochemistry, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MCF-7 Cells, Molecular Medicine, Female, estrogen receptor, medicine.medical_specialty, endothelium, Endothelium, medicine.drug_class, Ovariectomy, Blotting, Western, Biology, 03 medical and health sciences, Internal medicine, Coactivator, medicine, Animals, Humans, Estrogen receptor beta, Cell Proliferation, 030304 developmental biology, Cell Nucleus, uterus, Cell Membrane, Estrogen Receptor alpha, Protein Structure, Tertiary, Mice, Inbred C57BL, Endocrinology, chemistry, Estrogen, Nuclear receptor coactivator 3, Endothelium, Vascular, Estrogen receptor alpha, HeLa Cells
Abstract

International audience; Estetrol (E4) is a natural estrogen with a long half-life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand-binding domain bound to 17β-estradiol (E2) and E4 are very similar, as well as their capacity to activate the two activation functions AF-1 and AF-2 and to recruit the coactivator SRC3. In vivo administration of high doses of E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane-initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS-dependent effects in endothelium but also in MCF-7 breast cancer cell line. This profile of ERα activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further.

Published
2014

4. B-Catenin and ZO-1: Shuttle Molecules Involved in Tumor Invasion-Associated Epithelial-Mesenchymal Trabsition Processes

Author

Philippe Birembaut, Myriam Polette, S Bindels, Christine Gilles, Walter Hunziker, Jean-Michel Foidart, Béatrice Nawrocki-Raby, Mélanie Mestdagt, Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Developmental and Tumour Biology, Université de Liège, Epithelial cell Biology Laboratory, Institute of Molecular and Cell Biology, Service d'anesthésie-réanimation [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Birembaut, Philippe

Subjects
Histology, Beta-catenin, Vimentin, Models, Biological, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Epithelium, Adherens junction, Mesoderm, 03 medical and health sciences, 0302 clinical medicine, Neoplasm Invasiveness, Epithelial–mesenchymal transition, beta Catenin, 030304 developmental biology, 0303 health sciences, Tight junction, biology, Chemistry, Membrane Proteins, Epithelial Cells, Phosphoproteins, Cell biology, Cytosol, Cytoplasm, 030220 oncology & carcinogenesis, biology.protein, Zonula Occludens-1 Protein, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Anatomy, Signal transduction
Abstract

The cytoplasmic/nuclear relocalization of β-catenin and ZO-1 from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumor invasion. Data are now accumulating to demonstrate that these molecules, which shuttle between the plasma membrane and the nucleus or the cytosol, are involved in signaling pathways, and contribute to the regulation of genes such as vimentin or matrix metalloproteinase-14 which are turned on during EMT.

Published
2007

5. Transactivation of vimentin by beta-catenin in human breast cancer cells

Author

Philippe Birembaut, Myriam Polette, Mélanie Mestdagt, Jean-Michel Foidart, Philippe Ruggeri, Béatrice Nawrocki-Raby, Christine Gilles, Laboratory of Tumor and Developmental Biology, Université de Liège-CHU Sart-Tilman, Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), Supported by grants from the Communauté Française de Belgique (Actions de Recherches Concertées), the Commission of European Communities, the Fonds de la Recherche Scientifique Médicale, the Fonds National de la Recherche Scientifique (FNRS, Belgium), the Fédération Belge Contre le Cancer, the CGRI-FNRS-ΓNSERM Coopération, the Fonds Spéciaux de la Recherche (University of Liège), the Centre Anticancéreux près l'Université de Liège, the FB Assurances, the Fondation Léon Frédéricq (University of Liège), the DGTRE from the Région Wallonne, the Fonds d'Investissements de la Recherche Scientifique (CHU, Liège, Belgium), the Interuniversity Attraction Poles (IAP) from the Federal Office for Scientific, Technical and Cultural Affairs (OSTC, Brussels, Belgium), Rhône-Poulenc Rorer Pharmaceuticals (Collegville, PA), and Roche Diagnostics GmbH (Penzberg, Germany). C. G. is a Research Associate from the FNRS (Belgium)., and Birembaut, Philippe

Subjects
Cytoplasm, MESH: Cytoskeletal Proteins, Vimentin, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Transactivation, 0302 clinical medicine, Tumor Cells, Cultured, Medicine, Promoter Regions, Genetic, beta Catenin, 0303 health sciences, biology, Obstetrics and Gynecology, Cell migration, MESH: Gene Expression Regulation, Neoplastic, Cell biology, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, MESH: Promoter Regions (Genetics), Oncology, 030211 gastroenterology & hepatology, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Transcriptional Activation, MESH: Cell Nucleus, Beta-catenin, MESH: Trans-Activators, Breast Neoplasms, Epithelial cell migration, Transfection, 03 medical and health sciences, MESH: Transcription Fa, Coactivator, Humans, Transcription factor, 030304 developmental biology, Cell Nucleus, MESH: Humans, business.industry, MESH: Cytoplasm, Cytoskeletal Proteins, MESH: Trans-Activation (Genetics), Cancer cell, biology.protein, Trans-Activators, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business, MESH: Breast Neoplasms, MESH: DNA-Binding Proteins, MESH: TCF Transcription Factors, Transcription Factors
Abstract

FREE FULL TEXT http://cancerres.aacrjournals.org/cgi/reprint/63/10/2658; International audience; The cytoplasmic and nuclear redistribution of beta-catenin and the de novo expression of vimentin are frequently involved in the epithelial-to-mesenchymal transition associated with increased invasive/migratory properties of epithelial cells. Because beta-catenin can act as a coactivator of transcription through its binding to the T-cell factor (TCF)/lymphoid enhancer factor 1 transcription factor family, we have explored the possibility that beta-catenin/TCF could directly transactivate vimentin. We first compared vimentin expression in relation with the localization of beta-catenin in eight breast cancer cell lines displaying various degrees of invasiveness and in a model of cell migration using human mammary MCF10A cells. We could thus show a cytoplasmic and/or nuclear distribution of beta-catenin in invasive/migratory cells expressing vimentin, but not in noninvasive/stationary vimentin-negative cell lines. In addition, the human vimentin promoter was found to be up-regulated by beta-catenin and TCF-4 cotransfection. Varying with the cellular background, a diminution of this up-regulation was observed when the putative beta-catenin/TCF binding site of the vimentin promoter was mutated. Our results therefore demonstrate that the vimentin promoter is a target of the beta-catenin/TCF pathway and strongly suggest an implication of this regulation in epithelial cell migration/invasion.

Published
2003

6. Reduction of brain metastases in plasminogen activator inhibitor-1 deficient mice with transgenic ocular tumors

Author

Agnès Noël, Friedrich Beermann, M.M. Petitjean, Paule Opolon, E Frau, Maud Jost, Michel Perricaudet, J.-M. Foidart, Catherine Maillard, Mélanie Mestdagt, Anne Masset, Marc Abitbol, Céline Bouquet, Laboratory of Tumor and Developmental Biology, Université de Liège-CHU Sart-Tilman, Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Swiss Institute for Experimental Cancer Research, ISREC, Centre d'Etudes et de Recherche Thérapeutique en Ophtalmologie (CERTO), Association RETINA France, Partenaires INRAE-Partenaires INRAE, Department of Gynecology and Obstetrics, and CHU Liège

Subjects
Genetically modified mouse, Cancer Research, Pathology, medicine.medical_specialty, Angiogenesis, Transgene, Blotting, Western, Mice, Transgenic, Retinal Pigment Epithelium, Biology, Metastasis, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Plasminogen Activator Inhibitor 1, medicine, Animals, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Brain Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Eye Neoplasms, General Medicine, medicine.disease, Primary tumor, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], chemistry, 030220 oncology & carcinogenesis, Plasminogen activator inhibitor-1, Plasminogen activator, Brain metastasis
Abstract

Plasminogen activator inhibitor-1 is known to play a paradoxical positive role in tumor angiogenesis, but its contribution to metastatic spread remains unclear. We studied the impact of plasminogen activator inhibitor (PAI)-1 deficiency in a transgenic mouse model of ocular tumors originating from retinal epithelial cells and leading to brain metastasis (TRP-1/SV40 Tag mice). PAI-1 deficiency did not affect primary tumor growth or vascularization, but was associated with a smaller number of brain metastases. Brain metastases were found to be differentially distributed between the two genotypes. PAI-1-deficient mice displayed mostly secondary foci expanding from local optic nerve infiltration, whereas wild-type animals displayed more disseminated nodules in the scissura and meningeal spaces. SuperArray GEarray analyses aimed at detecting molecules potentially compensating for PAI-1 deficiency demonstrated an increase in fibroblast growth factor-1 (FGF-1) gene expression in primary tumors, which was confirmed by reverse transcription-polymerase chain reaction and western blotting. Our data provide the first evidence of a key role for PAI-1 in a spontaneous model of metastasis and suggest that angiogenic factors, such as FGF-1, may be important for primary tumor growth and may compensate for the absence of PAI-1. They identify PAI-1 and FGF-1 as important targets for combined antitumor strategies.

7. 0218: The uterine and vascular actions of estetrol delineate an original distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation

Author

Isabelle Raymond-Letron, Françoise Lenfant, Anne Abot, Shyamala S. Rajan, Aurelie J Fabre, Geoffrey L. Greene, Muriel Laine, Alain Milon, Mélanie Mestdagt, Benita S. Katzenellenbogen, Coralie Fontaine, Jean-Michel Foidart, Daniel Henrion, Romain Solinhac, Gilles Flouriot, Melissa Buscato, Anne Drougard, Jean-François Arnal, John A. Katzenellenbogen, Claude Knauf, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Tumor and Developmental Biology, Université de Liège-CHU Sart-Tilman, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Molecular and Integrative Physiology, University of Illinois System, Institut de médecine moléculaire de Rangueil (I2MR), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie des Tumeurs et du Développement), Université de Liège, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
business.industry, medicine.drug_class, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Phospholipid, Uterus, Estrogen receptor, Hormone replacement therapy (menopause), 030204 cardiovascular system & hematology, Steroid, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Estetrol, medicine.anatomical_structure, chemistry, Estrogen, In vivo, Medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, ComputingMilieux_MISCELLANEOUS
Abstract

Estetrol (E4) is a natural estrogen produced by the human fetal liver only during pregnancy. Its distinctive biological profile offers potential benefits in women's health, such as contraception and hormone replacement therapy. The crystal structures of the estrogen receptor α (ERα) ligand binding domain with 17beta-estradiol (E2) and E4 were very similar, whereas these two estrogens showed distinct positioning within phospholipid bilayers. Using in vivo approaches, we demonstrated that high doses of E4 stimulate genomic, ERα-dependent effects in the uterus leading to epithelial proliferation and prevent atheroma in hypercholesterolemic mice to a similar extent as E2. In contrast to E2, however, E4 failed to promote membrane-initiated ERα signaling such as acceleration of endothelial healing. Moreover, E4 antagonized this endothelial effect of E2. We conclude that E4 is a weak estrogen able to modulate the nuclear/transcriptional activity of ERα, and is not only devoid of membrane-initiated steroid signal, but also able to antagonize the membrane effects of E2, thereby delineating a distinctive profile of ERα activation.

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