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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

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

Hector L Franco1, Anusha Nagari1, W Lee Kraus1

  • 1Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Molecular Cell
|March 11, 2015
PubMed

Insights

Combined estradiol (E2) and tumor necrosis factor alpha (TNFα) signaling rapidly alters gene expression in breast cancer cells. This crosstalk creates new estrogen receptor alpha (ERα) binding sites, influencing cancer phenotypes and clinical outcomes.

Area of Science:

  • Molecular biology
  • Cancer research
  • Genomics

Background:

  • Mitogenic and proinflammatory pathways significantly impact breast cancer phenotypes and outcomes.
  • Understanding the crosstalk between estradiol (E2) and tumor necrosis factor alpha (TNFα) signaling is crucial for breast cancer research.

Purpose of the Study:

  • To define the immediate transcriptional effects of E2 and TNFα crosstalk in breast cancer cells.
  • To investigate the genomic mechanisms underlying gene expression changes induced by combined E2 + TNFα treatment.

Main Methods:

  • Utilized GRO-seq (Global Run-On sequencing) in MCF-7 breast cancer cells.
  • Analyzed transcriptional responses to individual and combined E2 and TNFα treatments.
  • Investigated enhancer remodeling and transcription factor binding site redistribution (NF-κB, FoxA1).

Main Results:

  • Identified a large set of target genes rapidly altered by combined E2 + TNFα, but not by either agent alone.
  • Demonstrated extensive remodeling of the estrogen receptor alpha (ERα) enhancer landscape dependent on NF-κB and FoxA1.
  • Found that expression of synergistically regulated genes is strongly associated with breast cancer clinical outcomes.

Conclusions:

  • TNFα signaling, through NF-κB and FoxA1, creates latent ERα binding sites, altering gene expression patterns.
  • This crosstalk influences clinically relevant cellular responses in breast cancer.
  • Genomic and molecular analyses reveal a novel mechanism of gene regulation in breast cancer.

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