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|a urn:nbn:de:hbz:6-98199544976
|2 urn
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|a 10.1186/s12943-017-0621-z
|2 doi
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|a eng
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|a 610 Medizin und Gesundheit
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|a Ibrahim, Sherif
|u FB 13: Biologie
|0 http://d-nb.info/gnd/1015600905
|4 aut
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|a Universitäts- und Landesbibliothek Münster
|0 http://d-nb.info/gnd/5091030-9
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|a Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways
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|a [Electronic ed.]
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|c 2017-03-07
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|b Universitäts- und Landesbibliothek Münster
|c 2018-04-11
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|a 1-19
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|a free access
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|a Molecular Cancer 16 (2017) 57, 1-19
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|a BACKGROUND: Inflammatory breast cancer (IBC), a particularly aggressive form of breast cancer, is characterized by cancer stem cell (CSC) phenotype. Due to a lack of targeted therapies, the identification of molecular markers of IBC is of major importance. The heparan sulfate proteoglycan Syndecan-1 acts as a coreceptor for growth factors and chemokines, modulating inflammation, tumor progression, and cancer stemness, thus it may emerge as a molecular marker for IBC. METHODS: We characterized expression of Syndecan-1 and the CSC marker CD44, Notch-1 & -3 and EGFR in carcinoma tissues of triple negative IBC (n = 13) and non-IBC (n = 17) patients using qPCR and immunohistochemistry. Impact of siRNA-mediated Syndecan-1 knockdown on the CSC phenotype of the human triple negative IBC cell line SUM-149 and HER-2-overexpressing non-IBC SKBR3 cells employing qPCR, flow cytometry, Western blotting, secretome profiling and Notch pharmacological inhibition experiments. Data were statistically analyzed using Student’s t-test/Mann-Whitney U-test or one-way ANOVA followed by Tukey’s multiple comparison tests. RESULTS: Our data indicate upregulation and a significant positive correlation of Syndecan-1 with CD44 protein, and Notch-1 & -3 and EGFR mRNA in IBC vs non-IBC. ALDH1 activity and the CD44(+)CD24(-/low) subset as readout of a CSC phenotype were reduced upon Syndecan-1 knockdown. Functionally, Syndecan-1 silencing significantly reduced 3D spheroid and colony formation. Intriguingly, qPCR results indicate downregulation of the IL-6, IL-8, CCL20, gp130 and EGFR mRNA upon Syndecan-1 suppression in both cell lines. Moreover, Syndecan-1 silencing significantly downregulated Notch-1, -3, -4 and Hey-1 in SUM-149 cells, and downregulated only Notch-3 and Gli-1 mRNA in SKBR3 cells. Secretome profiling unveiled reduced IL-6, IL-8, GRO-alpha and GRO a/b/g cytokines in conditioned media of Syndecan-1 knockdown SUM-149 cells compared to controls. The constitutively activated STAT3 and NFκB, and expression of gp130, Notch-1 & -2, and EGFR proteins were suppressed upon Syndecan-1 ablation. Mechanistically, gamma-secretase inhibition experiments suggested that Syndecan-1 may regulate the expression of IL-6, IL-8, gp130, Hey-1, EGFR and p-Akt via Notch signaling. CONCLUSIONS: Syndecan-1 acts as a novel tissue biomarker and a modulator of CSC phenotype of triple negative IBC via the IL-6/STAT3, Notch and EGFR signaling pathways, thus emerging as a promising therapeutic target for IBC.<br>
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|a specialized
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|a Finanziert durch den Open-Access-Publikationsfonds 2017 der Westfälischen Wilhelms-Universität Münster (WWU Münster).
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|a CC BY 4.0
|u http://creativecommons.org/licenses/by/4.0/
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|a Inflammatory breast cancer
|a Syndecan-1
|a Proteoglycan
|a Cancer stem cell
|a IL-6/STAT3
|a Notch
|a EGFR
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|2 DRIVER Types
|a Artikel
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|a Text
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|a Gadalla, Ramy
|0 http://d-nb.info/gnd/1128879050
|4 aut
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|a El-Ghonaimy, Eslam A.
|0 http://d-nb.info/gnd/110948965X
|0 http://viaf.org/viaf/90147093665925001388
|4 aut
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|a Samir, Omnia
|0 http://d-nb.info/gnd/1128879069
|4 aut
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|a Mohamed, Hossam Taha
|0 http://d-nb.info/gnd/1122722427
|0 http://viaf.org/viaf/121148389417210712312
|4 aut
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|a Hassan, Hebatallah
|0 http://d-nb.info/gnd/1030128227
|0 http://viaf.org/viaf/295530515
|4 aut
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|a Greve, Burkhard
|4 aut
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|a El-Shinawi, Mohamed
|0 http://d-nb.info/gnd/1096682397
|4 aut
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|a Mohamed, Mona Mostafa
|0 http://d-nb.info/gnd/1109489668
|0 http://viaf.org/viaf/120147093665625001375
|4 aut
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|a Götte, Martin
|0 http://d-nb.info/gnd/120035715
|4 aut
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|3 Zum Volltext
|q text/html
|u https://nbn-resolving.de/urn:nbn:de:hbz:6-98199544976
|u urn:nbn:de:hbz:6-98199544976
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|3 Zum Volltext
|q application/pdf
|u https://repositorium.uni-muenster.de/document/miami/ef5a6cbe-2f09-4d84-87d8-c8aaef308a36/2017_artikel_goette.pdf
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