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1.
Oncogene ; 38(7): 950-964, 2019 02.
Article in English | MEDLINE | ID: mdl-30478447

ABSTRACT

Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-of-function analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases.


Subject(s)
Bone Neoplasms/metabolism , Breast Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Mammary Neoplasms, Animal/metabolism , Neoplasm Proteins/metabolism , Receptor Activator of Nuclear Factor-kappa B/biosynthesis , Receptors, Estrogen/metabolism , Animals , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Bone Neoplasms/secondary , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Mammary Neoplasms, Animal/genetics , Mammary Neoplasms, Animal/pathology , Mice , Mice, Inbred BALB C , Neoplasm Proteins/genetics , Receptor Activator of Nuclear Factor-kappa B/genetics , Receptors, Estrogen/genetics , ERRalpha Estrogen-Related Receptor
3.
J Neuroinflammation ; 13(1): 111, 2016 05 18.
Article in English | MEDLINE | ID: mdl-27193196

ABSTRACT

BACKGROUND: Devic's neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central nervous system inflammation, demyelination, and neuronal injury. Several studies confirmed that autoantibodies directed against aquaporin-4 (AQP4-IgG) are relevant in the pathogenesis of NMO, mainly through complement-dependent toxicity leading to astrocyte death. However, the effect of the autoantibody per se and the exact role of intrathecal AQP4-IgG are still controversial. METHODS: To explore the intrinsic effect of intrathecal AQP4-IgG, independent from additional inflammatory effector mechanisms, and to evaluate its clinical impact, we developed a new animal model, based on a prolonged infusion of purified immunoglobulins from NMO patient (IgG(AQP4+), NMO-rat) and healthy individual as control (Control-rat) in the cerebrospinal fluid (CSF) of live rats. RESULTS: We showed that CSF infusion of purified immunoglobulins led to diffusion in the brain, spinal cord, and optic nerves, the targeted structures in NMO. This was associated with astrocyte alteration in NMO-rats characterized by loss of aquaporin-4 expression in the spinal cord and the optic nerves compared to the Control-rats (p = 0.001 and p = 0.02, respectively). In addition, glutamate uptake tested on vigil rats was dramatically reduced in NMO-rats (p = 0.001) suggesting that astrocytopathy occurred in response to AQP4-IgG diffusion. In parallel, myelin was altered, as shown by the decrease of myelin basic protein staining by up to 46 and 22 % in the gray and white matter of the NMO-rats spinal cord, respectively (p = 0.03). Loss of neurofilament positive axons in NMO-rats (p = 0.003) revealed alteration of axonal integrity. Then, we investigated the clinical consequences of such alterations on the motor behavior of the NMO-rats. In a rotarod test, NMO-rats performance was lower compared to the controls (p = 0.0182). AQP4 expression, and myelin and axonal integrity were preserved in AQP4-IgG-depleted condition. We did not find a major immune cell infiltration and microglial activation nor complement deposition in the central nervous system, in our model. CONCLUSIONS: We establish a link between motor-deficit, NMO-like lesions and astrocytopathy mediated by intrathecal AQP4-IgG. Our study validates the concept of the intrinsic effect of autoantibody against surface antigens and offers a model for testing antibody and astrocyte-targeted therapies in NMO.


Subject(s)
Aquaporin 4/immunology , Astrocytes/drug effects , Cerebrospinal Fluid/physiology , Immunoglobulin G/administration & dosage , Neuromyelitis Optica/cerebrospinal fluid , Neuromyelitis Optica/etiology , Animals , Animals, Newborn , Aquaporin 4/metabolism , Astrocytes/ultrastructure , Axons/pathology , Axons/ultrastructure , Cells, Cultured , Cerebrospinal Fluid/drug effects , Disease Models, Animal , Glial Fibrillary Acidic Protein/metabolism , Glutamic Acid/metabolism , Humans , Movement Disorders/complications , Myelin Basic Protein/metabolism , Myelin Sheath/metabolism , Myelin Sheath/pathology , Neuromyelitis Optica/complications , Neuromyelitis Optica/pathology , Optic Nerve/pathology , Optic Nerve/ultrastructure , Rats , Spinal Cord/pathology , Spinal Cord/ultrastructure
4.
Mol Psychiatry ; 21(12): 1768-1780, 2016 12.
Article in English | MEDLINE | ID: mdl-26728568

ABSTRACT

Vascular endothelial growth factor (VEGF) is known to be required for the action of antidepressant therapies but its impact on brain synaptic function is poorly characterized. Using a combination of electrophysiological, single-molecule imaging and conditional transgenic approaches, we identified the molecular basis of the VEGF effect on synaptic transmission and plasticity. VEGF increases the postsynaptic responses mediated by the N-methyl-D-aspartate type of glutamate receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B subunit (GluNR-2B). VEGF induces a rapid redistribution of GluNR-2B at synaptic sites by increasing the surface dynamics of these receptors within the membrane. Consistently, silencing the expression of the VEGF receptor 2 (VEGFR2) in neural cells impairs hippocampal-dependent synaptic plasticity and consolidation of emotional memory. These findings demonstrated the direct implication of VEGF signaling in neurons via VEGFR2 in proper synaptic function. They highlight the potential of VEGF as a key regulator of GluNR synaptic function and suggest a role for VEGF in new therapeutic approaches targeting GluNR in depression.


Subject(s)
Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Animals , Behavior, Animal , Cell Culture Techniques , Excitatory Postsynaptic Potentials , Fear , Hippocampus/metabolism , Mice , Neuronal Plasticity/physiology , Neurons/metabolism , Protein Subunits , Receptors, Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Synapses/metabolism , Synaptic Transmission/physiology , Vascular Endothelial Growth Factor A/physiology , Vascular Endothelial Growth Factor Receptor-2/physiology
5.
J Biol Chem ; 274(17): 11564-72, 1999 Apr 23.
Article in English | MEDLINE | ID: mdl-10206963

ABSTRACT

Two lines of transgenic mice, hAIItg-delta and hAIItg-lambda, expressing human apolipoprotein (apo)A-II at 2 and 4 times the normal concentration, respectively, displayed on standard chow postprandial chylomicronemia, large quantities of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) but greatly reduced high density lipoprotein (HDL). Hypertriglyceridemia may result from increased VLDL production, decreased VLDL catabolism, or both. Post-Triton VLDL production was comparable in transgenic and control mice. Postheparin lipoprotein lipase (LPL) and hepatic lipase activities decreased at most by 30% in transgenic mice, whereas adipose tissue and muscle LPL activities were unaffected, indicating normal LPL synthesis. However, VLDL-triglyceride hydrolysis by exogenous LPL was considerably slower in transgenic compared with control mice, with the apparent Vmax of the reaction decreasing proportionately to human apoA-II expression. Human apoA-II was present in appreciable amounts in the VLDL of transgenic mice, which also carried apoC-II. The addition of purified apoA-II in postheparin plasma from control mice induced a dose-dependent decrease in LPL and hepatic lipase activities. In conclusion, overexpression of human apoA-II in transgenic mice induced the proatherogenic lipoprotein profile of low plasma HDL and postprandial hypertriglyceridemia because of decreased VLDL catabolism by LPL.


Subject(s)
Apolipoprotein A-II/genetics , Hypertriglyceridemia/genetics , Lipoproteins, VLDL/blood , Animals , Apolipoprotein A-II/blood , Female , Humans , Hypertriglyceridemia/blood , Lipoprotein Lipase/blood , Lipoproteins, HDL/blood , Liver/enzymology , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Transgenic , Protein Isoforms/blood , Protein Isoforms/genetics
6.
Eur J Biochem ; 242(3): 657-64, 1996 Dec 15.
Article in English | MEDLINE | ID: mdl-9022694

ABSTRACT

Human apolipoprotein A-II (apo A-II) consists of three potential amphipathic helices of 17 residues each, which contribute to the lipid-binding properties of this apolipoprotein. The conformation and lipid-binding properties of these peptides, either as single-helix or as two-helix peptides, were investigated by turbidity, fluorescence, electron-microscopy and circular-dichroism measurements, and are compared in this article. The lipid affinity of shorter C-terminal segments of apo A-II was compared with those of the single-helix or two-helix peptides, to define the minimal peptide length required for stable complex formation. The properties of the apo-A-II-(13-48)-peptide were further compared with those of the same segment after deletion of the Ser31 and Pro32 residues, because the deleted apo-A-II-(13-30)-(33-48)-peptide, is predicted to form a long uninterrupted helix. The single helices of apo A-II could not form stable complexes with phospholipids, and the helix-turn-helix segment spanning residues 13-48 was not active either. The apo-A-II-(37-77)-peptide and the apo-A-II-(40-73)-peptide could form complexes with lipids, which appear as discoidal particles by negative-staining electron microscopy. The shortest C-terminal domain of apo A-II able to associate with lipids to form stable complexes was the apo-A-II-(40-73)-peptide, which consisted of the C-terminal helix, a beta-turn and part of the preceding helix. The shorter apo-A-II-(49-77)-peptide, and the helical apo-A-II-(13-30)-(33-48)-peptide, could also associate with phospholipids. The complexes formed were, however, less stable, as they dissociated outside the transition temperature range of the phospholipid. These data suggest that the C-terminal pair of helices of apo A-II, which is the most hydrophobic pair, is responsible for the lipid-binding properties of the entire protein. The N-terminal pair of helices of apo A-II at residues 13-48 does not associate tightly with lipids. The degree of internal similarity and the cooperativity between the helical segments of apo A-II is thus less pronounced than in apo A-I or apo A-IV. The N-terminal and C-terminal domains of apo A-II appear to behave as two distinct entities with regard to lipid-protein association.


Subject(s)
Apolipoprotein A-II/metabolism , Amino Acid Sequence , Apolipoprotein A-II/chemistry , Humans , Microscopy, Electron , Models, Molecular , Molecular Sequence Data , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Phospholipids/chemistry , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , Structure-Activity Relationship
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