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- Aguilar, Helena, et al.
(author)
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VAV3 mediates resistance to breast cancer endocrine therapy
- 2014
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In: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 16:3, s. R53-
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
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| 4. |
- Aguilar, J. A., et al.
(author)
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Design and sensitivity of the Radio Neutrino Observatory in Greenland (RNO-G)
- 2021
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In: Journal of Instrumentation. - : Institute of Physics Publishing (IOPP). - 1748-0221. ; 16:3
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Journal article (peer-reviewed)abstract
- This article presents the design of the Radio Neutrino Observatory Greenland (RNO-G) and discusses its scientific prospects. Using an array of radio sensors, RNO-G seeks to measure neutrinos above 10 PeV by exploiting the Askaryan effect in neutrino-induced cascades in ice. We discuss the experimental considerations that drive the design of RNO-G, present first measurements of the hardware that is to be deployed and discuss the projected sensitivity of the instrument. RNO-G will be the first production-scale radio detector for in-ice neutrino signals.
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| 5. |
- Agerman, K, et al.
(author)
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BDNF gene replacement reveals multiple mechanisms for establishing neurotrophin specificity during sensory nervous system development
- 2003
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In: Development (Cambridge, England). - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 130:8, s. 1479-1491
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Journal article (peer-reviewed)abstract
- Neurotrophins have multiple functions during peripheral nervous system development such as controlling neuronal survival, target innervation and synaptogenesis. Neurotrophin specificity has been attributed to the selective expression of the Trk tyrosine kinase receptors in different neuronal subpopulations. However, despite overlapping expression of TrkB and TrkC in many sensory ganglia, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) null mutant mice display selective losses in neuronal subpopulations. In the present study we have replaced the coding part of theBDNF gene in mice with that of NT3 (BDNFNT3/NT3)to analyse the specificity and selective roles of BDNF and NT3 during development. Analysis of BDNFNT3/NT3 mice showed striking differences in the ability of NT3 to promote survival, short-range innervation and synaptogenesis in different sensory systems. In the cochlea, specificity is achieved by a tightly controlled spatial and temporal ligand expression. In the vestibular system TrkB or TrkC activation is sufficient to promote vestibular ganglion neuron survival, while TrkB activation is required to promote proper innervation and synaptogenesis. In the gustatory system, NT3 is unable to replace the actions of BDNF possibly because of a temporally selective expression of TrkB in taste neurons. We conclude that there is no general mechanism by which neurotrophin specificity is attained and that specificity is achieved by (i) a tightly controlled spatial and temporal expression of ligands, (ii) different Trk receptors playing distinct roles within the same neuronal subpopulation, or (iii) selective receptor expression in sensory neuron subpopulations.
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