An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells

Oncogene. 2002 Jan 17;21(3):460-74. doi: 10.1038/sj.onc.1205100.

Abstract

Oncostatin M (OSM), an interleukin-6 type cytokine, acts via the gp130 signaling receptor to inhibit proliferation and induce differentiation of breast cancer cells. EGF, a mitogen for breast cells, signals via EGFR/ErbB tyrosine kinase receptors which are implicated in breast cancer pathogenesis. Here we show paradoxically that EGF enhanced the OSM-induced inhibition of proliferation and induction of cellular differentiation in both estrogen receptor positive and negative breast cancer cells. This functional synergism was also seen with heregulin but not SCF, PDGF or IGF-1, indicating that it was specific to EGF-related growth factors. Immunoprecipitation experiments revealed that gp130 was constitutively associated with ErbB-2 and ErbB-3. There was a similar association between the OSMRbeta and ErbB-2. Furthermore, EGF unexpectedly induced tyrosine phosphorylation of gp130. We show that OSM induced phosphorylation of STAT3. Both OSM and EGF activated the p42/44 MAP kinases, but while the MEK inhibitor, PD98059, ablated the OSM-induced inhibition, it only partially ablated the inhibitory effects of OSM plus EGF. Thus, we have demonstrated that the receptors and signalling pathways of two apparently unrelated growth factors were intimately linked, resulting in an unexpected biological effect. This provides a new mechanism for generating signalling diversity and has potential clinical implications in breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • Cytokine Receptor gp130
  • DNA-Binding Proteins / metabolism
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Membrane Glycoproteins / metabolism*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Oncostatin M
  • Peptides / pharmacology
  • Phosphorylation / drug effects
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-3 / metabolism
  • Receptors, Estrogen / genetics
  • STAT3 Transcription Factor
  • Substrate Specificity
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • DNA-Binding Proteins
  • IL6ST protein, human
  • Membrane Glycoproteins
  • OSM protein, human
  • Peptides
  • RNA, Messenger
  • Receptors, Estrogen
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Oncostatin M
  • Cytokine Receptor gp130
  • Epidermal Growth Factor
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Mitogen-Activated Protein Kinase Kinases