EMT Induces Cell State–Specific Signaling Networks in CSCs

Chemotherapeutics and radiotherapy effectively reduce tumor bulk but enrich for cancer stem cells (CSC) that stimulate tumor recurrence, emphasizing the importance of identifying CSC-specific pathways that may be exploited to selectively target these resistant cells. Induction of epithelial–mesenchymal transition (EMT) has been shown to generate CSCs with a mesenchymal phenotype and enhanced tumor-initiating potential, suggesting that EMT may activate cell state–specific signaling in CSCs. Tam and colleagues found that passage of human mammary epithelial cells (MEC) through EMT stimulated the overexpression of several kinases, including protein kinase C α (PKCα). Inhibition of PKCα preferentially induced CSC apoptosis and diminished the initiation and growth of tumors derived from these mesenchymal cells, suggesting that CSCs are dependent on PKCα signaling. PKCα was activated following EMT by a shift from EGF receptor (EGFR) signaling, which predominated in non-CSCs, to autocrine platelet-derived growth factor receptor (PDGFR) signaling in mesenchymal stem-like cells and basal breast cancer cell lines. Upregulation of PKCα resulted in induction of ERK1/2 and activation of the transcription factor FRA1, which was required for CSC viability and triggered a molecular switch from c-FOS to FRA1 as the preferred binding partner of c-JUN in CSCs. In addition, FRA1 expression was directly induced by the EMT transcription factors TWIST and SNAIL and was required for EMT in MECs, whereas FRA1 depletion induced mesenchymal–epithelial transition and impaired the tumor-initiating potential of basal breast cancer cells. Moreover, FRA1 and PKCα levels were elevated in triple-negative breast cancer (TNBC) and were correlated with poor survival, and PKCα blockade suppressed the growth of patient-derived TNBC xenografts. These findings identify PKCα and FRA1 as critical regulators of CSCs and suggest inhibition of this pathway as a potential strategy to specifically target CSCs in TNBC.

Tam WL, Lu H, Buikhuisen J, Soh BS, Lim E, Reinhardt F, et al. Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 2013;24:347–64.