A time- and matrix-dependent TGFBR3-JUND-KRT5 regulatory circuit in single breast epithelial cells and basal-like premalignancies

Nat Cell Biol. 2014 Apr;16(4):345-56. doi: 10.1038/ncb2930. Epub 2014 Mar 23.


Basal-like breast carcinoma is characterized by poor prognosis and high intratumour heterogeneity. In an immortalized basal-like breast epithelial cell line, we identified two anticorrelated gene-expression programs that arise among single extracellular matrix (ECM)-attached cells during organotypic three-dimensional culture. The first contains multiple TGF-β-related genes including TGFBR3, whereas the second contains JUND and the basal-like marker KRT5. TGFBR3 and JUND interconnect through four negative-feedback loops to form a circuit that exhibits spontaneous damped oscillations in three-dimensional culture. The TGFBR3-JUND circuit is conserved in some premalignant lesions that heterogeneously express KRT5. The circuit depends on ECM engagement, as detachment causes a rewiring that is triggered by RPS6 dephosphorylation and maintained by juxtacrine tenascin C, which is critical for intraductal colonization of basal-like breast cancer cells in vivo. Intratumour heterogeneity need not stem from partial differentiation and could instead reflect dynamic toggling of cells between expression states that are not cell autonomous.

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
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Carcinoma, Intraductal, Noninfiltrating / genetics
  • Carcinoma, Intraductal, Noninfiltrating / metabolism*
  • Cell Differentiation
  • Cell Line, Tumor
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Extracellular Matrix / metabolism
  • Female
  • Humans
  • Keratin-5 / metabolism*
  • Mice
  • Mice, SCID
  • Phosphorylation
  • Proteoglycans / genetics
  • Proteoglycans / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Ribosomal Protein S6 / metabolism
  • Signal Transduction
  • Tenascin / metabolism
  • Transcription, Genetic


  • JunD protein, human
  • KRT5 protein, human
  • Keratin-5
  • Proteoglycans
  • Proto-Oncogene Proteins c-jun
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta
  • Ribosomal Protein S6
  • Tenascin
  • betaglycan

Associated data

  • GEO/GSE41527