Heterogeneity of breast cancer stem cells as evidenced with Notch-dependent and Notch-independent populations.
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 (dnMAML) 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 dnMAML-expressing cells. Interestingly, when assessed in secondary assays in vitro or in vivo, there was no difference in tumor-initiating activity between the dnMAML-expressing cells and control cells. The fact that a subpopulation of dnMAML-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.
Genome Sciences Centre, BC Cancer Agency Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia Vancouver, BC, Canada.
Nelson K Y
NK
Wong
Megan
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Fuller
Sandy
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Sung
Fred
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Wong
Aly
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Karsan
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D051927:CD24 Antigen / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D039503:Integrin alpha6 / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics
D051927:CD24 Antigen; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D039503:Integrin alpha6; C430872:MAML1 protein, human; D051880:Receptors, Notch; D014157:Transcription Factors; D049452:Green Fluorescent Proteins
Breast cancer; MCF-7; Notch; cancer stem cells; dominant-negative MAML