RAS-induced transformation of mammary epithelial cells relies on ZEB1-dependent cellular reprogramming via a paracrine process

While uncommon in breast cancers, oncogenic activation of the RAS/MAPK signalling pathway is frequent in claudin-low (CL) tumours, a subtype of breast malignancies enriched in features of epithelial-mesenchymal transition (EMT), suggesting an interplay between RAS activation and EMT. Using inducible models of human mammary epithelial cells, we show that RAS-mediated transformation relies on cellular reprogramming governed by the EMT-inducing transcription factor ZEB1. The path to ZEB1 induction involves a paracrine process: cells entering a senescent state following RAS activation release proinflammatory cytokines, notably IL-6 and IL-1 which promote ZEB1 expression and activity in neighbouring cells, thereby fostering their malignant transformation. Collectively, our findings unveil a previously unprecedented role for senescence in bridging RAS activation and EMT over the course of malignant transformation of human mammary epithelial cells.