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G DeBlaquiere, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, United Kingdom
F May, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, NE2 4HH, United Kingdom
B Westley, Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, United Kingdom

Correspondence: Felicity May, Email: F.E.B.May{at}ncl.ac.uk

Abstract

Insulin-like growth factors (IGFs) are thought to promote tumour progression and metastasis in part by stimulating cell migration. IRS-1 and IRS-2 are multisite docking proteins positioned immediately downstream from the type I IGF and insulin receptors. IRS-2 but not IRS-1 has been reported to be involved in the migratory response of breast cancer cells to IGFs. The purpose of this investigation was to determine if IRS-1 is involved in, and to assess the contributions of IRS-1 and IRS-2 to, the migratory response of breast cancer cells to IGFs. The expression of IRS-1 and IRS-2 varied considerably between ten breast cancer cell lines. Oestrogens may control the sensitivity of breast cancer cells to IGFs by regulating the expression of components of the IGF signal transduction pathway. Oestrogen increased expression of the type I IGF receptor, IRS-1 and IRS-2 in MCF-7 and ZR-75 cells. The migratory response to a range of IGF-1 concentrations was measured in MCF-7 and MDA-MB-231 breast cancer cells in which IRS-1 and IRS-2 levels were modulated using a doxycycline-inducible expression system. Induction of both IRS-1 and IRS-2 expression increased the sensitivity of the migratory response to IGF-1 but did not increase the magnitude of the response stimulated at higher concentrations of IGF-1. Knockdown of IRS-1, IRS-2 and the type I IGF receptor in MCF-7 and MDA-MB-2231 cells decreased sensitivity to IGF-1. We conclude that both IRS-1 and IRS-2 control the migratory response of breast cancer cells to IGF-1 and may, therefore, be key molecules in determining breast cancer spread.