Open AccessHeterogeneity of breast cancer stem cells as evidenced with N otch‐dependent and N otch‐independent populations
Author(s) -
Wong Nelson K. Y.,
Fuller Megan,
Sung Sandy,
Wong Fred,
Karsan Aly
Publication year - 2012
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.18
Subject(s) - notch signaling pathway , cancer stem cell , population , cancer research , stem cell , biology , cell , cancer , cancer cell , in vivo , microbiology and biotechnology , signal transduction , medicine , biochemistry , genetics , environmental health
Studies have suggested the potential importance of Notch signaling to the cancer stem cell population in some tumors, but it is not known whether all cells in the cancer stem cell fraction require Notch activity. To address this issue, we blocked Notch activity in MCF ‐7 cells by expressing a dominant‐negative MAML ‐ GFP (dn MAML ) construct, which inhibits signaling through all Notch receptors, and quantified the effect on tumor‐initiating activity. Inhibition of Notch signaling reduced primary tumor sphere formation and side population. Functional quantification of tumor‐initiating cell numbers in vivo showed a significant decrease, but not a complete abrogation, of these cells in dn MAML ‐expressing cells. Interestingly, when assessed in secondary assays in vitro or in vivo, there was no difference in tumor‐initiating activity between the dn MAML ‐expressing cells and control cells. The fact that a subpopulation of dn MAML ‐expressing cells was capable of forming primary and secondary tumors indicates that there are Notch‐independent tumor‐initiating cells in the breast cancer cell line MCF ‐7. Our findings thus provide direct evidence for a heterogeneous cancer stem cell pool, which will require combination therapies against multiple oncogenic pathways to eliminate the tumor‐initiating cell population.