RelA-induced interferon response negatively regulates proliferation

Bose S. Kochupurakkal, Zhigang C. Wang, Tony Hua, Aedin C. Culhane, Scott J. Rodig, Koraljka Rajkovic-Molek, Jean Bernard Lazaro, Andrea L. Richardson, Debajit K. Biswas, J. Dirk Iglehart

Research output: Contribution to journalArticle

Abstract

Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-κB) pathway. Moreover, NF-κB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-κB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-ã elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-ã converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumorsuppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors.

Original languageEnglish (US)
Article numbere0140243
JournalPloS one
Volume10
Issue number10
DOIs
StatePublished - Oct 13 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Kochupurakkal, B. S., Wang, Z. C., Hua, T., Culhane, A. C., Rodig, S. J., Rajkovic-Molek, K., Lazaro, J. B., Richardson, A. L., Biswas, D. K., & Iglehart, J. D. (2015). RelA-induced interferon response negatively regulates proliferation. PloS one, 10(10), [e0140243]. https://doi.org/10.1371/journal.pone.0140243