Reversing cancer stemness

lethality of malignant breast cancer in human patients. Although various targeted and non-targeted therapies can occasionally control the progress of breast cancer, a significant portion of patients develop resistance to chemotherapy and experience metastatic recurrence. The epithelial to mesenchymal transition (EMT), a key developmental program in embryogenesis, has been found to be closely intertwined with the occurrence of metastasis in various human cancers. EMT can be prompted by the expression of multiple transcriptional factors and is controlled by several signaling pathways including TGF-β, Wnt and Notch signaling. Moreover, a link between EMT and the onset of epithelial stem cell-like properties has been suggested. However, the mechanism underlining this relationship remains unrevealed, and whether cancer stemness is a consequence of EMT or they are two parallel phenomena refecting cell plasticity remains unknown. Towards the goal of understanding breast cancer metastasis, our group performed a cross-species expression profiling and identified Foxq1 as an EMT-and metastasis-promoting gene in breast cancer [1]. Following this discovery, Foxq1 expression has been shown to promote EMT and metastasis in a wide array of human cancers [2-4]. In line with the previously-mentioned link between EMT and stemness, we demonstrated that ectopic expression of FOXQ1 led to an increase in the stem-like phenotype and CD44+/CD24-population consists of over 90% of cells. This increase in the stem cell population correlated with the induction of EMT. Mechanistically, we identified the receptor tyrosine kinases PDGFR α and β as downstream targets of FoxQ1 [5]. Our study showed that knockdown of PDGFR α and β significantly decreased cell proliferation, migration and invasion in HMLE/FoxQ1 cells. The effects were greatest when both α and β were knocked down. Knockdown of PDGFR α and β in HMLER/FoxQ1 cells decreased lung metastases in vivo. Moreover, Knockdown of α and β, or β alone, decreased the CD44+/CD24-phenotype by 25% without reversing the FoxQ1-induced EMT at the molecular and morphological levels. These results strongly suggest that FoxQ1's role as a promoter of the CSC's phenotype is regulated in part by PDGFR activity. Editorial We used the RTK inhibitor imantinib to examine the effects of pharmacologic silencing of PDGFR expression. Although imantinib targets multiple RTK's, we demonstrated that only PDGFR α and β expression were significantly altered in FoxQ1-upregulated cells. High doses of imantinib significantly inhibited cell proliferation, while the low-dose treatment markedly inhibited cell migration and invasion in vitro. Either pharmacological treatment or genetic manipulation of PDGFR α …