Role of microRNAs in the regulation of breast cancer stem cells.

There is increasing evidence that many human cancers, including breast cancer, are driven and maintained by cancer stem cells (CSCs) which mediate tumor metastasis and contribute to treatment resistance and relapse. Our group was the first to describe "breast cancer stem cells" (BCSCs) characterized by expression of the cell surface markers ESA and CD44 and the absence of expression of the marker CD24. More recently, we have demonstrated that breast cancer cells contain subpopulations with stem cell properties that can be isolated by virtue of their expression of Aldehyde dehydrogenase (ALDH) as assessed by the Aldefluor assay. Interestingly, these markers identify overlapping, but not identical cell populations. Recent studies have suggested similarities between cancer stem cells and the epithelial mesenchymal transition (EMT) state. Our studies suggest that both normal and malignant breast stem cells exist in distinct, inter-convertible states (EMT and MET), the inter-conversion of which is regulated by microRNAs. EMT-like CSCs have a mesenchymal morphology, are largely quiescent, invasive and characterized by expression of the CSC markers CD24(-)CD44(+) and are EpCAM(-)CD49f(+). In contrast, the MET (mesenchymal epithelial transition) state of CSCs is characterized by active self-renewal and expression of the CSC markers ALDH and EpCAM(+)CD49f(+). A subpopulation of cells expressing both CD24(-)CD44(+) and ALDH may represent cells in transition between these states. This transition is regulated by signals originating in the microenvironment which in turn modulate microRNA networks in the CSC populations. The existence of multiple stem cell states suggests the necessity of developing therapeutic strategies capable of effectively targeting CSCs in all of these states. In addition, since CSC states are regulated by miRNAs, these small non-coding RNAs may be useful therapeutic agents to target CSCs.