Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast

Cell. 2011 Jun 10;145(6):926-40. doi: 10.1016/j.cell.2011.04.029.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autocrine Communication*
  • Bone Morphogenetic Proteins / metabolism
  • Breast / cytology*
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Movement
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / drug effects
  • Mesoderm / metabolism
  • Mice
  • Neoplastic Stem Cells / metabolism*
  • Paracrine Communication*
  • Signal Transduction
  • Stem Cells / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Wnt Proteins / metabolism


  • Bone Morphogenetic Proteins
  • Transforming Growth Factor beta
  • Wnt Proteins

Associated data

  • GEO/GSE28681