Summary
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-1α 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
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