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| dc.contributor.author | Abdelaziz Ibrahim, Sherif | |
| dc.contributor.author | Gadalla, Ramy | |
| dc.contributor.author | A. El-Ghonaimy, Eslam | |
| dc.contributor.author | Samir, Omnia | |
| dc.contributor.author | Taha Mohamed, Hossam | |
| dc.contributor.author | Hassan, Hebatallah | |
| dc.contributor.author | Greve, Burkhard | |
| dc.contributor.author | El-Shinawi, Mohamed | |
| dc.contributor.author | Mostafa Mohamed, Mona | |
| dc.contributor.author | Götte, Martin | |
| dc.date.accessioned | 2020-02-29T08:32:30Z | |
| dc.date.available | 2020-02-29T08:32:30Z | |
| dc.date.issued | 2017 | |
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| dc.identifier.uri | https://t.ly/XAq3b | |
| dc.description | MSA Google Scholar | en_US |
| dc.description.abstract | 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. | en_US |
| dc.description.sponsorship | BioMed Central | en_US |
| dc.language.iso | en | en_US |
| dc.publisher | BioMed Central | en_US |
| dc.relation.ispartofseries | Molecular cancer;Volume: 16 Issue: 1 Pages: 57 | |
| dc.subject | University of Inflammatory; breast cancer; Syndecan-1; Proteoglycan; Cancer stem cell; IL-6/STAT3; Notch; EGFR | en_US |
| dc.title | 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 | en_US |
| dc.type | Article | en_US |
| dc.Affiliation | October University for modern sciences and Arts (MSA) |
