Skip to main content

Volume 12 Supplement 1

Breast Cancer Research 2010

Recruitment of insulin receptor substrate-1 by erbB3 impacts on IGF-IR signalling in oestrogen receptor-positive breast cancer cells

Insulin-like growth factor receptor (IGF-IR) signalling classically involves phosphorylation of insulin receptor substrate-1 (IRS-1) to recruit key down-stream signalling pathways effecting breast cancer cell proliferation and survival. Recently, we have shown a further capacity for IRS-1 to associate with the epidermal growth factor receptor (EGFR/erbB1), with activation of EGFR promoting recruitment and phosphorylation of IRS-1 in an oestrogen receptor (ER)-positive tamoxifen-resistant breast cancer cell line. In this study, we examined recruitment of IRS-1 by another member of the erbB receptor family, erbB3, in three ER-positive breast cancer cell lines. Our studies revealed an interaction between erbB3 and IRS-1 in MCF-7, T47D and BT474 cells with HRGβ1 treatment significantly enhancing this recruitment and promoting IRS-1 phosphorylation at tyrosine (Y) 612, a specific phosphoinositide 3-kinase (PI3K) binding site. IRS-1 appears to play a key role in erbB3 signalling in MCF-7 and T47D cells as its knockdown using siRNA greatly impaired HRGβ1 signalling via PI3K/AKT in these cell lines. This novel interaction may have clinical relevance as immunohistochemical analysis of ER-positive breast cancer patient samples revealed IRS-1 Y612 expression positively correlated with total erbB3, p-AKT and Ki67 expression. Importantly, we found that recruitment of IRS-1 by erbB3 impaired IRS-1 recruitment by IGF-IR in both MCF-7 and T47D cells, whilst blockade of IGF-1R enhanced erbB3/IRS-1 interaction and sensitised both cell lines to HRGβ1. Consequently, blockade of erbB3 signalling enhanced the effects of IGF-IR inhibition in these cells. In conclusion, these and previous findings suggest that IRS-1 can be recruited to IGF-1R, EGFR and erbB3 in ER-positive breast cancer cells and this may provide an adaptive resistance mechanism when these receptors are targeted individually. Consequently co-targeting of IGF-IR and erbB receptors may prove to be a more effective strategy for the treatment of ER-positive breast cancer.

Author information

Authors and Affiliations


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Knowlden, J., Gee, J., Barrow, D. et al. Recruitment of insulin receptor substrate-1 by erbB3 impacts on IGF-IR signalling in oestrogen receptor-positive breast cancer cells. Breast Cancer Res 12 (Suppl 1), P49 (2010).

Download citation

  • Published:

  • DOI:


  • T47D Cell
  • erbB Receptor
  • erbB3 Signalling
  • erbB Receptor Family
  • Breast Cancer Patient Sample