Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

There is increasing support for the hypothesis that most tumors contain a subpopulation of cells, referred to here as tumor initiating cells (TICs), with the ability to self-renew and to regenerate all the cell types within the tumor. TICs are enriched in breast cancer patients after common treatments, indicating their intrinsic therapeutic resistance. Two independently-derived gene transcription "signatures" of TICs from different studies indicate enrichment of TICs within the recently-identified "claudin-low" intrinsic molecular subtype of breast cancer. These are characterized by high expression of markers associated with epithelial-mesenchymal transition (EMT), suggesting that claudin-low cells may arise from more immature stem or progenitor cells than other breast cancers. EMT is a process by which cells acquire molecular alterations that facilitate dysfunctional cell-cell adhesive interactions and junctions, as well as a more spindle-shaped morphology. These processes may promote cancer cell progression and invasion into the surrounding microenvironment. Induction of EMT in immortalized human mammary epithelial cells results in an increased ability to form mammospheres, and in the expression of stem cell and TIC markers, suggesting that there may be a direct link between the EMT and the gain of TIC properties. Targeting specific molecular pathways-such as Notch, Wnt, and TGF-associated with development and EMT in the TIC subpopulation, in addition to conventional chemo- and radiation therapies that target the bulk tumor, may ultimately provide a more effective strategy in treating breast cancer. Here, we review recent evidence of the involvement of EMT in breast cancer TICs, focusing on clinical studies.