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Fascin Is Critical for the Maintenance of Breast Cancer Stem Cell Pool Predominantly via the Activation of the Notch Self-Renewal Pathway
- Source :
- Stem Cells. 34:2799-2813
- Publication Year :
- 2016
- Publisher :
- Oxford University Press (OUP), 2016.
-
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/CD24lo and 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. Video Highlight: https://youtu.be/GxS4fJ_Ow-o
- Subjects :
- 0301 basic medicine
Homeobox protein NANOG
Epithelial-Mesenchymal Transition
Human Embryonic Stem Cells
Notch signaling pathway
Mice, Nude
Breast Neoplasms
macromolecular substances
Kruppel-Like Factor 4
03 medical and health sciences
0302 clinical medicine
SOX2
Antigens, CD
Cancer stem cell
Cell Line, Tumor
Spheroids, Cellular
Animals
Humans
Cell Self Renewal
Tumor Stem Cell Assay
Fascin
Receptors, Notch
biology
Microfilament Proteins
Cell Biology
Gene Expression Regulation, Neoplastic
Phenotype
030104 developmental biology
KLF4
030220 oncology & carcinogenesis
Cancer cell
Immunology
Neoplastic Stem Cells
biology.protein
Cancer research
Molecular Medicine
Female
Stem cell
Carrier Proteins
Signal Transduction
Developmental Biology
Subjects
Details
- ISSN :
- 15494918 and 10665099
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Stem Cells
- Accession number :
- edsair.doi.dedup.....d019b494c8c382e5098d4eca276e28ee