Intricate regulation of breast cancer stemness, self-renewal and differentiation via ERK/CDK4/6 activation by Wnt signaling

The partial EMT program drives breast cancer stemness and metastasis. This process is governed by transcriptional regulators that maintain the epithelial/mesenchymal (E/M) bipotent stem cell state and by differential growth factor signaling driving self-renewal vs differentiation. Here we show that TCF1/Wnt signaling stimulates transient ERK/CDK4/6 activation which upregulates FOXC2, and in turn TAp63 and ΔNp63 isoforms, thereby maintaining the partial EMT state. In parallel, ERK/CDK4/6 promotes FOXC2 expression and S-phase transition while activating FOXM1 to drive E/M cell self-renewal. Interestingly, transient ERK activation by Wnt3a inactivates EGFR, thus preventing EGF from causing a robust and sustained ERK phosphorylation that causes E/M to M differentiation, resulting in CSC exhaustion. Consistent with these data, ERK/CDK4/6 inhibition suppressed CSC organoid forming ability. Collectively, these findings illustrate an intricate mechanism integrating cancer stemness with self-renewal and differentiation via Wnt-stimulated ERK/CDK4/6 activation, underscoring the implication of these findings for cancer stem cell therapy.