TNFα signaling exposes latent estrogen receptor binding sites to alter the breast cancer cell transcriptome

Mol Cell. 2015 Apr 2;58(1):21-34. doi: 10.1016/j.molcel.2015.02.001. Epub 2015 Mar 5.

Abstract

The interplay between mitogenic and proinflammatory signaling pathways plays key roles in determining the phenotypes and clinical outcomes of breast cancers. Using GRO-seq in MCF-7 cells, we defined the immediate transcriptional effects of crosstalk between estradiol (E2) and TNFα, identifying a large set of target genes whose expression is rapidly altered with combined E2 + TNFα treatment, but not with either agent alone. The pleiotropic effects on gene transcription in response to E2 + TNFα are orchestrated by extensive remodeling of the ERα enhancer landscape in an NF-κB- and FoxA1-dependent manner. In addition, expression of the de novo and synergistically regulated genes is strongly associated with clinical outcomes in breast cancers. Together, our genomic and molecular analyses indicate that TNFα signaling, acting in pathways culminating in the redistribution of NF-κB and FoxA1 binding sites across the genome, creates latent ERα binding sites that underlie altered patterns of gene expression and clinically relevant cellular responses.

Publication types

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

MeSH terms

  • Binding Sites
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Humans
  • MCF-7 Cells
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Protein Binding / drug effects
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Survival Analysis
  • Transcriptome*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Estrogen Receptor alpha
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • NF-kappa B
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • estrogen receptor alpha, human
  • Estradiol

Associated data

  • GEO/GSE59530
  • GEO/GSE59531
  • GEO/GSE59532