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

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. 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 60 PI3K/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 wildtype levels. PyV-MT::Irs1-/-tumors also exhibited a significant increase in VEGF 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.