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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

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.

Titel: 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
Verfasser: Ibrahim, Sherif GND
Gadalla, Ramy
El-Ghonaimy, Eslam A.
Samir, Omnia
Mohamed, Hossam Taha
Hassan, Hebatallah GND
Greve, Burkhard GND
El-Shinawi, Mohamed
Mohamed, Mona Mostafa
Götte, Martin GND
Organisation: FB 13: Biologie
FB 05: Medizinische Fakultät
Dokumenttyp: Artikel
Medientyp: Text
Erscheinungsdatum: 07.03.2017
Publikation in MIAMI: 11.04.2018
Datum der letzten Änderung: 11.04.2018
Quelle: Molecular Cancer 16 (2017) 57, 1-19
Schlagwörter: Inflammatory breast cancer; Syndecan-1; Proteoglycan; Cancer stem cell; IL-6/STAT3; Notch; EGFR
Fachgebiete: Medizin und Gesundheit
Lizenz: CC BY 4.0
Sprache: Englisch
Förderung: Finanziert durch den Open-Access-Publikationsfonds 2017 der Westfälischen Wilhelms-Universität Münster (WWU Münster).
Format: PDF-Dokument
URN: urn:nbn:de:hbz:6-98199544976
DOI: 10.1186/s12943-017-0621-z