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Identification of genes responsible for RelA-dependent proliferation arrest in human mammary epithelial cells

Bose S Kochupurakkal1, J Dirk Iglehart2

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Genomics Data
|March 17, 2016
PubMed

Insights

Nuclear factor-kappa B (NF-kB) factor RelA suppresses tumor growth by activating the Interferon pathway, downregulating CDK4, and halting cell cycle progression. This uncovers a novel tumor-suppressor role for NF-kB.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Cycle Regulation

Background:

  • The dual role of Nuclear Factor-kappa B (NF-kB) as both an oncogene and tumor suppressor is not fully understood.
  • Previous studies indicated a negative correlation between RelA (a key NF-kB factor) levels and proliferation markers (Ki67, AURKA) in estrogen receptor-positive/HER2-negative (ER+/HER2-) breast tumors.
  • Conditional expression of RelA in Human Mammary Epithelial Cells (HRA cells) induced proliferation arrest, which was reversible upon RelA suppression.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the tumor-suppressive function of NF-kB, specifically RelA.
  • To identify genes mediating the negative correlation between RelA levels and cell proliferation.

Main Methods:

  • Semi-quantitative immunohistochemistry of primary breast tumors.
  • Analysis of The Cancer Genome Atlas (TCGA) data for ER+/HER2- tumors.
  • Genome-wide gene expression analysis using a Tetracycline-inducible RelA system in HRA cells under various induction and withdrawal conditions.
  • Data submission to Gene Expression Omnibus (GEO) under accession number GSE65040.

Main Results:

  • A negative correlation was observed between RelA levels and Ki67-index in ER+/HER2- breast tumors.
  • Gene expression analysis revealed cross-talk between RelA activity and the Interferon pathway, mediated by IRF1.
  • Activation of the Interferon pathway led to decreased CDK4 expression, resulting in RB1 hypo-phosphorylation and cell cycle arrest.

Conclusions:

  • NF-kB, particularly RelA, exhibits tumor-suppressor activity through its interaction with the Interferon pathway.
  • The identified pathway (RelA -> IRF1 -> Interferon pathway -> CDK4 downregulation -> RB1 hypo-phosphorylation) explains the antiproliferative effect of RelA.
  • This finding provides novel insights into the complex role of NF-kB in cancer and suggests potential therapeutic targets.

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