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Molecular and Cellular Biology, December 2006, p. 9338-9351, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01032-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis

Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605,¹ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 63108,² Howard Hughes Medical Institute, Children's Hospital, Division of Endocrinology, Harvard Medical School, Boston, Massachusetts 02115³

Received 8 June 2006/ Returned for modification 15 August 2006/ Accepted 2 October 2006

The insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that organize signaling complexes downstream of activated cell surface receptors. Here, we show that IRS-1 and IRS-2, despite significant homology, play critical yet distinct functions in breast cancer, and we identify specific signaling pathways that are influenced by IRS-1 using the polyoma virus middle-T (PyV-MT) transgenic mouse model of mammary carcinoma and Irs-1 null (Irs1^–/–) mice. The absence of Irs-1 expression enhanced metastatic spread significantly without a significant effect on primary tumor growth. Orthotopic transplant studies revealed that the increased metastatic potential of Irs1-deficient tumor cells is cell autonomous. Mammary tumors that developed in PyV-MT::Irs1^–/– mice exhibited elevated Irs-2 function and enhanced phosphatidylinositol 3-kinase/Akt/mTor activity, suggesting that one mechanism by which Irs-1 impedes metastasis is to suppress Irs-2-dependent signaling. In support of this mechanism, reduction of Irs-2 expression in Irs1^–/– tumor cells restored mTor signaling to wild-type levels. PyV-MT::Irs1^–/– tumors also exhibited a significant increase in vascular endothelial growth factor expression and microvessel density, which could facilitate their dissemination. The significance of our findings for human breast cancer is heightened by our observation that Irs-1 is inactivated in wild-type, metastatic mammary tumors by serine phosphorylation. Collectively, our findings reveal that inactivation of IRS-1 enhances breast cancer metastasis and support the novel hypothesis that IRS-1 has metastasis suppressor functions for breast cancer.

Published ahead of print on 9 October 2006.

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