UMMS Affiliation

Department of Cancer Biology

Date

10-13-2006

Document Type

Article

Subjects

Animals; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Lung Neoplasms; Male; Mammary Neoplasms, Animal; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphoproteins

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: Mol Cell Biol. 2006 Dec;26(24):9338-51. Epub 2006 Oct 9. Link to article on publisher's site

DOI of Published Version

10.1128/MCB.01032-06

Related Resources

Link to Article in PubMed

Journal Title

Molecular and cellular biology

PubMed ID

17030605

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