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

Knowlden, Janice Mary, Jones, Helen E., Barrow, Denise, Gee, Julia Margaret Wendy, Nicholson, Robert Ian and Hutcheson, Iain Robert 2008. Insulin receptor substrate-1 involvement in epidermal growth factor receptor and insulin-like growth factor receptor signalling: implication for Gefitinib ('Iressa') response and resistance. Breast Cancer Research and Treatment 111 (1) , pp. 79-91. 10.1007/s10549-007-9763-9

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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.

Item Type: Article
Status: Published
Schools: Biosciences
Medicine
Pharmacy
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: IRS-1; EGFR; IGF-1R; Gefitinib; Tamoxifen resistance; MCF-7
Publisher: Kluwer
ISSN: 0167-6806
Last Modified: 02 Feb 2018 23:17
URI: http://orca-mwe.cf.ac.uk/id/eprint/6603

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