Breast Cancer Research and Treatment

, Volume 111, Issue 1, pp 79–91

Insulin receptor substrate-1 involvement in epidermal growth factor receptor and insulin-like growth factor receptor signalling: implication for Gefitinib (‘Iressa’) response and resistance

  • Janice M. Knowlden
  • Helen E. Jones
  • Denise Barrow
  • Julia M. W. Gee
  • Robert I. Nicholson
  • Iain R. Hutcheson
Preclinical Study

DOI: 10.1007/s10549-007-9763-9

Cite this article as:
Knowlden, J.M., Jones, H.E., Barrow, D. et al. Breast Cancer Res Treat (2008) 111: 79. doi:10.1007/s10549-007-9763-9

Abstract

Classically the insulin receptor substrate-1 (IRS-1) is an essential component of insulin-like growth factor type 1 receptor (IGF-IR) signalling, providing an interface between the receptor and key downstream signalling cascades. Here, however, we show that in tamoxifen-resistant MCF-7 (Tam-R) breast cancer cells, that are highly dependent on epidermal growth factor receptor (EGFR) for growth, IRS-1 can interact with EGFR and be preferentially phosphorylated on tyrosine (Y) 896, a Grb2 binding site. Indeed, phosphorylation of this site is greatly enhanced by exposure of these cells, and other EGFR-positive cell lines, to EGF. Importantly, while IGF-II promotes phosphorylation of IRS-1 on Y612, a PI3-K recruitment site, it has limited effect on Y896 phosphorylation in Tam-R cells. Furthermore, EGF and IGF-II co-treatment, reduces the ability of IGF-II to phosphorylate Y612, whilst maintaining Y896 phosphorylation, suggesting that the EGFR is the dominant recruiter of IRS-1 in this cell line. Significantly, challenge of Tam-R cells with the EGFR-selective tyrosine kinase inhibitor gefitinib, for 7 days, reduces IRS-1/EGFR association and IRS-1 Y896 phosphorylation, while promoting IRS-1/IGF-IR association and IRS-1 Y612 phosphorylation. Furthermore, gefitinib significantly enhances IGF-II-mediated phosphorylation of IRS-1 Y612 and AKT in Tam-R cells. Importantly, induction of this pathway by gefitinib can be abrogated by inhibition/downregulation of the IGF-IR. Our data would therefore suggest a novel association exists between the EGFR and IRS-1 in several EGFR-positive cancer cell lines. This association acts to promote phosphorylation of IRS-1 at Y896 and drive MAPK signalling whilst preventing recruitment of IRS-1 by the IGF-IR and inhibiting signalling via this receptor. Treatment with gefitinib alters the dynamics of this system, promoting IGF-IR signalling, the dominant gefitinib-resistant growth regulatory pathway in Tam-R cells, thus, potentially limiting its efficacy.

Keywords

IRS-1EGFRIGF-1RGefitinibTamoxifen resistanceMCF-7

Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Janice M. Knowlden
    • 1
  • Helen E. Jones
    • 1
  • Denise Barrow
    • 1
  • Julia M. W. Gee
    • 1
  • Robert I. Nicholson
    • 1
  • Iain R. Hutcheson
    • 1
  1. 1.Tenovus Centre for Cancer Research, Welsh School of PharmacyCardiff UniversityCardiffUK