Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis

被引:71
作者
Ma, Zhefu
Gibson, Shannon L.
Byrne, Maura A.
Zhang, Junran
White, Morris F.
Shaw, Leslie M.
机构
[1] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA
[2] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO 63108 USA
[3] Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,Div Endocrinol, Boston, MA 02115 USA
关键词
D O I
10.1128/MCB.01032-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:9338 / 9351
页数:14
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