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

Knowlden, Janice Mary, Gee, Julia Margaret Wendy, Barrow, Denise, Robertson, J. F., Ellis, I. O., Nicholson, Robert Ian and Hutcheson, Iain Robert 2010. Recruitment of insulin receptor substrate-1 by erbB3 impacts on IGF-IR signalling in oestrogen receptor-positive breast cancer cells [Abstract]. Breast Cancer Research 12 (S1) , S15. 10.1186/bcr2546

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Additional Information: This poster presentation abstract is part of the supplement: Breast Cancer Research 2010. Poster abstract no. P49.
Publisher: BioMed Central
ISSN: 1465-5411
Last Modified: 05 Mar 2019 21:02
URI: http://orca-mwe.cf.ac.uk/id/eprint/17111

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