Cell
Volume 145, Issue 6, 10 June 2011, Pages 926-940
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Article
Paracrine and Autocrine Signals Induce and Maintain Mesenchymal and Stem Cell States in the Breast

https://doi.org/10.1016/j.cell.2011.04.029Get rights and content
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Summary

The epithelial-mesenchymal transition (EMT) has been associated with the acquisition of motility, invasiveness, and self-renewal traits. During both normal development and tumor pathogenesis, this change in cell phenotype is induced by contextual signals that epithelial cells receive from their microenvironment. The signals that are responsible for inducing an EMT and maintaining the resulting cellular state have been unclear. We describe three signaling pathways, involving transforming growth factor (TGF)-β and canonical and noncanonical Wnt signaling, that collaborate to induce activation of the EMT program and thereafter function in an autocrine fashion to maintain the resulting mesenchymal state. Downregulation of endogenously synthesized inhibitors of autocrine signals in epithelial cells enables the induction of the EMT program. Conversely, disruption of autocrine signaling by added inhibitors of these pathways inhibits migration and self-renewal in primary mammary epithelial cells and reduces tumorigenicity and metastasis by their transformed derivatives.

Highlights

► Induction of EMT in mammary epithelial cells depends on collaborating pathways ► Pathways that induce EMT also maintain the resultant cellular state ► Autocrine signaling maintains the mesenchymal and stem-cell traits induced by EMT ► Similar signals maintain both normal and neoplastic mammary stem cells

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