A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours

Nat Commun. 2019 Jul 19;10(1):3210. doi: 10.1038/s41467-019-11278-7.

Abstract

Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7, VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast / pathology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism
  • Extracellular Matrix / metabolism
  • Female
  • Fibroblast Growth Factor 2 / metabolism
  • Fibroblast Growth Factor 7 / metabolism
  • Fibroblasts / metabolism*
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Interleukin-6
  • Male
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Knockout
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasms, Experimental
  • Neoplasms, Glandular and Epithelial / metabolism*
  • Neoplasms, Glandular and Epithelial / pathology
  • Signal Transduction*
  • Tumor Microenvironment
  • Tumor Suppressor Protein p53 / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*

Substances

  • Fgf7 protein, mouse
  • Interleukin-6
  • Tumor Suppressor Protein p53
  • Vascular Endothelial Growth Factor A
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • vascular endothelial growth factor A, mouse
  • Fibroblast Growth Factor 2
  • Fibroblast Growth Factor 7