SATB1 Reprogrammes Gene Expression to Promote Breast Tumour Growth and Metastasis

Nature. 2008 Mar 13;452(7184):187-93. doi: 10.1038/nature06781.

Abstract

Mechanisms underlying global changes in gene expression during tumour progression are poorly understood. SATB1 is a genome organizer that tethers multiple genomic loci and recruits chromatin-remodelling enzymes to regulate chromatin structure and gene expression. Here we show that SATB1 is expressed by aggressive breast cancer cells and its expression level has high prognostic significance (P < 0.0001), independent of lymph-node status. RNA-interference-mediated knockdown of SATB1 in highly aggressive (MDA-MB-231) cancer cells altered the expression of >1,000 genes, reversing tumorigenesis by restoring breast-like acinar polarity and inhibiting tumour growth and metastasis in vivo. Conversely, ectopic SATB1 expression in non-aggressive (SKBR3) cells led to gene expression patterns consistent with aggressive-tumour phenotypes, acquiring metastatic activity in vivo. SATB1 delineates specific epigenetic modifications at target gene loci, directly upregulating metastasis-associated genes while downregulating tumour-suppressor genes. SATB1 reprogrammes chromatin organization and the transcription profiles of breast tumours to promote growth and metastasis; this is a new mechanism of tumour progression.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers, Tumor / analysis
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Cell Line
  • Cell Line, Tumor
  • Cell Polarity
  • Disease Progression
  • Epigenesis, Genetic / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lymphatic Metastasis / diagnosis
  • Lymphatic Metastasis / genetics
  • Lymphatic Metastasis / pathology
  • Matrix Attachment Region Binding Proteins / deficiency
  • Matrix Attachment Region Binding Proteins / genetics
  • Matrix Attachment Region Binding Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / diagnosis
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology
  • Neoplasm Transplantation
  • Phenotype
  • Prognosis
  • RNA Interference

Substances

  • Biomarkers, Tumor
  • Matrix Attachment Region Binding Proteins
  • SATB1 protein, human

Associated data

  • GEO/GSE5417