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Increased expression of both insulin receptor substrates 1 and 2 confers increased sensitivity to IGF-1 stimulated cell migration

Lookup NU author(s): Dr Gail De Blaquiere, Dr Felicity May, Professor Bruce Westley

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Abstract

Insulin-like growth factors (IGFs) are thought to promote tumour progression and metastasis in part by stimulating cell migration. Insulin receptor substrate-1 (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. Oestrogen increases expression of the type I IGF receptor, IRS-1 and IRS-2 in MCF-7 and ZR-75 cells. Oestrogens may control the sensitivity of breast cancer cells to IGFs by regulating the expression of components of the IGF signal transduction pathway 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. Endocrine-Related Cancer (2009) 16 635-647


Publication metadata

Author(s): de Blaquière GE, May FEB, Westley BR

Publication type: Article

Publication status: Published

Journal: Endocrine-Related Cancer

Year: 2009

Volume: 16

Issue: 2

Pages: 635-647

Print publication date: 01/06/2009

Online publication date: 04/03/2009

ISSN (print): 1351-0088

ISSN (electronic): 1479-6821

Publisher: Society for Endocrinology

URL: http://dx.doi.org/10.1677/ERC-08-0216

DOI: 10.1677/ERC-08-0216


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Funding

Funder referenceFunder name
1999-88Breast Cencer Campaign
2003-737Breast Cencer Campaign

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