Shared signaling pathways in normal and breast cancer stem cells

Abstract

Recent advances in our understanding of breast cancer biology have led to the identification of a subpopulation of cells within tumors that appear to be responsible for initiating and propagating the cancer. These tumor initiating cells are not only unique in their ability to generate tumors, but also share many similarities with elements of normal adult tissue stem cells, and have therefore been termed cancer stem cells (CSCs). These CSCs often inappropriately use many of the same signaling pathways utilized by their normal stem cell counterparts which may present a challenge to the development of CSC specific therapies. Here, we discuss three major stem cell signaling pathways (Notch, Wnt, and Hedgehog); with a focus on their function in normal mammary gland development and their misuse in breast cancer stem cell fate determination.

Keywords: Cancer stem cell; Wnt; hedgehog; mammary stem cell; notch.

Figure 1

Notch, Wnt, and Hedgehog signaling pathways regulate normal and stem cell fate. (a) Notch signaling pathway. Upon binding of Notch ligands (Jag / Delta) to the Notch receptor, the cleaved intracellular domain (NICD) translocates to the nucleus where it binds with co-activators to induce transcription of its target genes. Notch 1 and 3 show higher expression in luminal committed progenitors, whereas Notch4 is expressed in bipotent MaSCs, and significantly downregulated upon luminal and myoepithelial cell differentiation. (b) Wnt signaling pathway. Canonical Wnt signaling occurs through the stabilization and nuclear accumulation of β-catenin. One of the 19 secreted Wnt ligands binds to the frizzled receptor and the LRP co-receptor. This activation recruits the Axin degradation complex to the LRP receptor and away from β-catenin, preventing its degradation. β-catenin is then free to translocate to the nucleus and associate with the transcription factors LCF / LEF and co-activators (e.g., CBP) to initiate transcription of target genes, which are essential for normal mammary gland development and stem cell renewal. (c) Hedgehog signaling. Hedgehog is a secreted ligand that binds to its receptor, Patched (Ptch). When Ptch is activated by Hh binding, its inhibition of the Smoothened (Smo) receptor is relieved, which allows the Smo receptor to localize to the primary cilium. Smo is then able to inhibit the phosphorylation and cleavage of Gli (by GSK3, CK1α, and PKA), which prevents the formation of repressive Gli (GliR) and instead promotes the formation of activated Gli (GliA). GliA then translocates into the nucleus and initiates transcription of target genes, which play a role in stem cell regulation