Identification of signal transduction pathways involved in constitutive NF-κB activation in breast cancer cells

Poornima Bhat-Nakshatri, Christopher J. Sweeney, Harikrishna Nakshatri

Research output: Contribution to journalArticle

Abstract

Nuclear factor-κB (NF-κB) is usually maintained in an inactive form in the cytoplasm through its association with inhibitor of kappaB (IκB) proteins, and is activated upon stimulation of cells with a variety of signals. However, constitutive activation of NF-κB is observed in a number of cancers including breast cancer. The signaling pathways that are involved in constitutive NF-κB activation remain largely unknown. Using breast cancer cell lines derived from transgenic mice that overexpress specific oncogene/growth factors in the mammary gland, we show that heregulin but not her2/neu, c-Myc or v-Ha-ras plays a major role in constitutive NF-κB activation. Her2/neu potentiated tumor necrosis factor alpha (TNFα)-inducible NF-κB activation whereas c-Myc potentiated 12-o-tetracecanyolphorbol-13-acetate (TPA)-induced NF-κB activation. Heregulin-mediated NF-κB activation correlated with phosphorylation of epidermal growth factor receptor (EGFR) and ErbB3 but not her2/neu. Tryphostin AG1517, which inhibits heregulin-mediated phosphorylation of EGFR, her2/neu and ErbB3 reduced NF-κB activation. In contrast, emodin, which blocks phosphorylation of her2/neu by heregulin, failed to reduce NF-κB activation. These results suggest that heregulin induces NF-κB independent of her2/neu. PI3 kinase/AKT, protein kinase A (PKA) and IκB kinase appear to be downstream signaling molecules involved in NF-κB activation as specific inhibitors of these kinases but not inhibitors of ERK/MAP kinase or protein kinase C reduced heregulin-mediated NF-κB activation. Based on these results, we propose that heregulin increases the expression of pro-invasive, prometastatic and anti-apoptotic genes in cancer cells through autocrine activation of NF-κB, which leads to invasive and drug-resistant growth of breast cancer.

Original languageEnglish
Pages (from-to)2066-2078
Number of pages13
JournalOncogene
Volume21
Issue number13
DOIs
StatePublished - May 21 2002

Fingerprint

Neuregulin-1
Signal Transduction
Breast Neoplasms
Phosphorylation
Epidermal Growth Factor Receptor
Phosphotransferases
Emodin
Neoplasm Genes
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Human Mammary Glands
Cyclic AMP-Dependent Protein Kinases
Phosphatidylinositol 3-Kinases
Oncogenes
Protein Kinase C
Transgenic Mice
Intercellular Signaling Peptides and Proteins
Cytoplasm
Acetates
Tumor Necrosis Factor-alpha

Keywords

  • Breast cancer
  • ErbB
  • NF-κB
  • Oncogenes

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Identification of signal transduction pathways involved in constitutive NF-κB activation in breast cancer cells. / Bhat-Nakshatri, Poornima; Sweeney, Christopher J.; Nakshatri, Harikrishna.

In: Oncogene, Vol. 21, No. 13, 21.05.2002, p. 2066-2078.

Research output: Contribution to journalArticle

Bhat-Nakshatri, Poornima ; Sweeney, Christopher J. ; Nakshatri, Harikrishna. / Identification of signal transduction pathways involved in constitutive NF-κB activation in breast cancer cells. In: Oncogene. 2002 ; Vol. 21, No. 13. pp. 2066-2078.
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