Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity.
| Autor: | D'Angelo RC, Ouzounova M, Davis A, Choi D; Georgia Regents University Cancer Center, Department of Biochemistry and Molecular Biology 1410 Laney Walker Blvd. CN2136 Augusta, GA 30912., Tchuenkam SM; Georgia Regents University Cancer Center, Department of Biochemistry and Molecular Biology 1410 Laney Walker Blvd. CN2136 Augusta, GA 30912., Kim G, Luther T, Quraishi AA, Senbabaoglu Y, Conley SJ, Clouthier SG, Hassan KA, Wicha MS, Korkaya H |
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| Jazyk: | angličtina |
| Zdroj: | Molecular cancer therapeutics [Mol Cancer Ther] 2015 Mar; Vol. 14 (3), pp. 779-787. Date of Electronic Publication: 2015 Feb 11. |
| DOI: | 10.1158/1535-7163.MCT-14-0228 |
| Abstrakt: | Developmental pathways such as Notch play a pivotal role in tissue-specific stem cell self-renewal as well as in tumor development. However, the role of Notch signaling in breast cancer stem cells (CSC) remains to be determined. We utilized a lentiviral Notch reporter system to identify a subset of cells with a higher Notch activity (Notch(+)) or reduced activity (Notch(-)) in multiple breast cancer cell lines. Using in vitro and mouse xenotransplantation assays, we investigated the role of the Notch pathway in breast CSC regulation. Breast cancer cells with increased Notch activity displayed increased sphere formation as well as expression of breast CSC markers. Interestingly Notch(+) cells displayed higher Notch4 expression in both basal and luminal breast cancer cell lines. Moreover, Notch(+) cells demonstrated tumor initiation capacity at serial dilutions in mouse xenografts, whereas Notch(-) cells failed to generate tumors. γ-Secretase inhibitor (GSI), a Notch blocker but not a chemotherapeutic agent, effectively targets these Notch(+) cells in vitro and in mouse xenografts. Furthermore, elevated Notch4 and Hey1 expression in primary patient samples correlated with poor patient survival. Our study revealed a molecular mechanism for the role of Notch-mediated regulation of breast CSCs and provided a compelling rationale for CSC-targeted therapeutics. (©2015 American Association for Cancer Research.) |
| Databáze: | MEDLINE |
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