TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer

Nat Commun. 2012;3:1055. doi: 10.1038/ncomms2039.

Abstract

The role of transforming growth factor-beta (TGFβ) in the progression of different molecular subtypes of breast cancer has not been clarified. Here we show that TGFβ increases breast tumour-initiating cell (BTIC) numbers but only in claudin(low) breast cancer cell lines by orchestrating a specific gene signature enriched in stem cell processes that predicts worse clinical outcome in breast cancer patients. NEDD9, a member of the Cas family of integrin scaffold proteins, is necessary to mediate these TGFβ-specific effects through a positive feedback loop that integrates TGFβ/Smad and Rho-actin-SRF-dependent signals. In normal human mammary epithelium, TGFβ induces progenitor activity only in the basal/stem cell compartment, where claudin(low) cancers are presumed to arise. These data show opposing responses to TGFβ in both breast malignant cell subtypes and normal mammary epithelial cell subpopulations and suggest therapeutic strategies for a subset of human breast cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Chromatin Immunoprecipitation
  • Claudins / genetics
  • Claudins / metabolism*
  • Female
  • Humans
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / drug effects
  • Mammary Glands, Human / metabolism
  • Mice
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Adaptor Proteins, Signal Transducing
  • Claudins
  • NEDD9 protein, human
  • Phosphoproteins
  • Transforming Growth Factor beta