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 OSMRβ 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.
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Acknowledgements
The authors are grateful to Dr Francesca Walker from the Ludwig Institute for Cancer Research, Melbourne, for various reagents and advice and Dr David Clouston from The Rotary Bone Marrow Research Laboratories for histology expertise and for examining our slides. This work was supported by grants from the National Health and Medical Research Council, Canberra, The Anti-Cancer Council of Victoria, CRC for Cellular Growth Factors, The Government Employees Medical Research Fund, The Bone Marrow Donor Institute, The Felton Bequest and The Western Australian Institute for Medical Research. SL Grant is an Anti-Cancer Council of Victoria research scholar. The CRC for Cellular Growth Factors is established and supported by the Australian Government's Cooperative Research Centers Program.
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Grant, S., Hammacher, A., Douglas, A. et al. An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Oncogene 21, 460–474 (2002). https://doi.org/10.1038/sj.onc.1205100
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DOI: https://doi.org/10.1038/sj.onc.1205100
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