title: Fascin Is Critical for the Maintenance of Breast Cancer Stem Cell Pool Predominantly via the Activation of the Notch Self-Renewal Pathway.
abstract: An emerging dogma shows that tumors are initiated and maintained by a subpopulation of cancer cells that hijack some stem cell features and thus referred to as "cancer stem cells" (CSCs). The exact mechanism that regulates the maintenance of CSC pool remains largely unknown. Fascin is an actin-bundling protein that we have previously demonstrated to be a major regulator of breast cancer chemoresistance and metastasis, two cardinal features of CSCs. Here, we manipulated fascin expression in breast cancer cell lines and used several in vitro and in vivo approaches to examine the relationship between fascin expression and breast CSCs. Fascin knockdown significantly reduced stem cell-like phenotype (CD44hi/CD24loand ALDH+) and reversal of epithelial to mesenchymal transition. Interestingly, expression of the embryonic stem cell transcriptional factors (Oct4, Nanog, Sox2, and Klf4) was significantly reduced when fascin expression was down-regulated. Functionally, fascin-knockdown cells were less competent in forming colonies and tumorspheres, consistent with lower basal self-renewal activity and higher susceptibility to chemotherapy. Fascin effect on CSC chemoresistance and self-renewability was associated with Notch signaling. Activation of Notch induced the relevant downstream targets predominantly in the fascin-positive cells. Limiting-dilution xenotransplantation assay showed higher frequency of tumor-initiating cells in the fascin-positive group. Collectively, our data demonstrated fascin as a critical regulator of breast CSC pool at least partially via activation of the Notch self-renewal signaling pathway and modification of the expression embryonic transcriptional factors. Targeting fascin may halt CSCs and thus presents a novel therapeutic approach for effective treatment of breast cancer. Stem Cells 2016;34:2799-2813 Video Highlight: https://youtu.be/GxS4fJ_Ow-o.
authors: Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Rayanah
authors: R
authors: Barnawi
authors: National Genome Center, King Abdulaziz City for Sciences and Technology, Riyadh, Saudi Arabia.
authors: Samiyah
authors: S
authors: Al-Khaldi
authors: Collage of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
authors: Ghida
authors: G
authors: Majed Sleiman
authors: Collage of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
authors: Abdullah
authors: A
authors: Sarkar
authors: Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Abdullah
authors: A
authors: Al-Dhfyan
authors: Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Falah
authors: F
authors: Al-Mohanna
authors: Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.|Collage of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
authors: Hazem
authors: H
authors: Ghebeh
authors: Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.|Collage of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
authors: Monther
authors: M
authors: Al-Alwan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000066449:Human Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014410:Tumor Stem Cell Assay
chemical_list: D015703:Antigens, CD; D002352:Carrier Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D008840:Microfilament Proteins; D051880:Receptors, Notch; C020324:fascin
keywords: Breast cancer; Cancer stem cell; Chemoresistance; Fascin; Metastasis