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Cancer Medicine (1)
The Journal of Clinical Investigation (1)
Fuller, Megan (2)
Karsan, Aly (2)
Chari, Raj (1)
Deléhouzée, Sophie (1)
Gazdar, Adi F. (1)
Lam, Stephen (1)
Lam, Wan L. (1)
Lockwood, William W. (1)
Starczynowski, Daniel T. (1)
Sung, Sandy (1)
Tsao, Ming-Sound (1)
Wegrzyn, Joanna (1)
Wong, Fred (1)
Wong, Nelson K Y (1)
Year of Publication
Heterogeneity of breast cancer stem cells as evidenced with Notch-dependent and Notch-independent populations
Wong, Nelson K Y
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.
Breast cancer; cancer stem cells; dominant-negative MAML; MCF-7; Notch
TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer
Starczynowski, Daniel T.
Lockwood, William W.
Gazdar, Adi F.
Lam, Wan L.
The Journal of Clinical Investigation
Somatic mutations and copy number alterations (as a result of deletion or amplification of large portions of a chromosome) are major drivers of human lung cancers. Detailed analysis of lung cancer–associated chromosomal amplifications could identify novel oncogenes. By performing an integrative cytogenetic and gene expression analysis of non–small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) cell lines and tumors, we report here the identification of a frequently recurring amplification at chromosome 11 band p13. Within this region, only TNF receptor–associated factor 6 (TRAF6) exhibited concomitant mRNA overexpression and gene amplification in lung cancers. Inhibition of TRAF6 in human lung cancer cell lines suppressed NF-κB activation, anchorage-independent growth, and tumor formation. In these lung cancer cell lines, RAS required TRAF6 for its oncogenic capabilities. Furthermore, TRAF6 overexpression in NIH3T3 cells resulted in NF-κB activation, anchorage-independent growth, and tumor formation. Our findings show that TRAF6 is an oncogene that is important for RAS-mediated oncogenesis and provide a mechanistic explanation for the previously apparent importance of constitutive NF-κB activation in RAS-driven lung cancers.
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