Potential Signaling Pathways Activated in Cancer Stem Cells in Breast Cancer

Accumulating evidence suggests that cancer stem cells—which make up only a small proportion of heterogeneous tumor cells—possess a greater ability to maintain tumor formation than other tumor cell types. It has been proposed that cancer stem cells have characteristics in common with normal stem cells from tumor-prone tissue. For instance, cancer stem cells can self-renew and simultaneously produce differentiated daughter cells that proliferate strongly until they reach their final differentiated state. Apparent differences also exist between cancer stem cells and normal stem cells. The latter are maintained under tight homeostatic regulation and are passively protected in the surrounding microenvironment or stem cell niche in adult tissues. However, the former may actively contribute to tumor formation. This concept was first proposed from the research of hematological malignancy, however, it is now believed that many solid tumors also have cancer stem-like cells. Although the concept of cancer stem cells greatly impacts cancer biology and evokes a reconsideration of cancer treatment, the molecular mechanisms involved in the contribution of cancer stem cells to tumorigenesis remain to be obscure. There have been many attempts to identify signaling pathways specifically activated in cancer stem cells. For example, it has been proposed that transforming growth factor (TGF)-β pathway, the epithelial-mesenchymal transition (EMT) pathway or nuclear factorkB (NF-kB) pathway may be activated in cancer stem cells. These potential pathways may contribute to self-renewal activity of cancer stem cells or have an influence on cancer stem cell niche. In this review, I would like to summarize our present understanding about potential signaling pathways activated in cancer stem cells in solid tumors, especially focusing on breast cancer, and then describe our recent findings about potential signaling pathways in breast cancer. Finally I would like to discuss how this increasing knowledge is utilized for developing novel molecularly targeting drugs for cancer treatment.