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• W4367675057 endingPage "114800" @default.
• W4367675057 startingPage "114800" @default.
• W4367675057 abstract "Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer characterized by drug resistance and distant metastasis. Cancer stem cells (CSCs) are considered a major contributor to TNBC's drug resistance. Thus targeting and eliminating CSCs have been vigorously researched. However, the precise targetable molecular networks responsible for CSC genesis remain unclear; this conundrum is mainly due to the high heterogeneity of the TNBC tumor microenvironment (TME). The cancer-associated fibroblasts (CAFs) are one of the most abundant cellular components of the TME. Emerging studies indicate that CAFs facilitate TNBC's progression by establishing a pro-tumor TME. Hence, identifying the molecular networks involved in CAF transformation and CAF-associated oncogenesis are essential areas to be explored. Through a bioinformatics approach, we identified INFG/STAT1/NOTCH3 as a molecular link between CSCs and CAF. DOX-resistant TNBC cell lines showed increased expression of INFG/STAT1/NOTCH3 and CD44 and were associated with increased self-renewal ability and CAF-transformative ability. Downregulation of STAT1 significantly reduced the tumorigenic properties of MDA-MB-231 and -468 cells and their CAF-transforming potential. Our molecular docking analysis suggested that gamma mangostin (gMG), a xanthone, formed complexes with INFG/STAT1/NOTCH3 better than celecoxib. We then demonstrated that gMG treatment reduced the tumorigenic properties similarly observed in STAT1-knocked down conditions. Finally, we utilized a DOX-resistant TNBC tumoroid-bearing mouse model to demonstrate that gMG treatment significantly delayed tumor growth, reduced CAF generation, and improved DOX sensitivity. Further investigations are warranted for clinical translation." @default.
• W4367675057 created "2023-05-03" @default.
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• W4367675057 date "2023-07-01" @default.
• W4367675057 modified "2023-10-04" @default.
• W4367675057 title "Identification of INFG/STAT1/NOTCH3 as γ-Mangostin's potential targets for overcoming doxorubicin resistance and reducing cancer-associated fibroblasts in triple-negative breast cancer" @default.
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• W4367675057 doi "https://doi.org/10.1016/j.biopha.2023.114800" @default.
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