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Sci. STKE, 12 December 2006
Vol. 2006, Issue 365, p. tw417
[DOI: 10.1126/stke.3652006tw417]

EDITORS' CHOICE

Cancer Biology IRS Cancer Connection

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

Two groups (Dearth et al. and Ma et al.) examined the role of insulin receptor substrate (IRS) in mouse mammary gland tumorigenesis and metastasis. Dearth et al. used transgenic mice forced to overexpress IRS-1 or IRS-2, or an immortalized but nontumorigenic cell line (MCF-10A) also forced to overexpress one of these two proteins. In the MCF-10A cells, overexpression of either protein caused an increase in phosphorylation (and activation) of Akt and an increase in proliferation in response to insulin growth factor-1 (IGF-1). Only the IRS-1-overexpressing cells showed enhanced phosphorylation of extracellular signal-related kinases 1 and 2. Both IRS proteins disrupted acinar formation in three-dimensional Matrigel cultures, and both IRS proteins coimmunoprecipitated with beta-catenin. In the transgenic mice, there was no effect on lactational capacity, but both groups of mice formed tumors in the mammary glands. The IRS-2-overexpressing mice had more rapid tumor formation than did the IRS-1-overexpressing mice; however, IRS-2 was overexpressed to a greater extent than was IRS-1. Both groups exhibited lung metastasis. The histology of the tumors was quite diverse, and many contained cells that were highly differentiated, which is similar to phenotypes associated with activation of beta-catenin. In the tumors from the IRS-1- or IRS-2-overexpressing mice, beta-catenin coimmunoprecipitated with the IRS proteins, and there was increased abundance of cyclin D, which is encoded by a beta-catenin target gene. In the overexpressing MCF-10A cells, IGF-1 stimulated the association between IRS-1 or IRS-2 and beta-catenin.

Ma et al. examined the different functions of IRS-1 and IRS-2 in tumorigenesis and metastasis by generating tumors in IRS-1-deficient mice using polyoma virus middle-T (PyV-MT::Irs1–/–) and comparing these tumors to those formed in wild-type mice (PyV-MT) or in IRS-2-deficient mice (PyV-MT::Irs2–/–). It was previously known that mammary tumors formed in PyV-MT::Irs2–/– mice exhibited decreased metastasis. The tumors from the PyV-MT::Irs1–/– mice showed increased lung metastasis compared with PyV-MT mice. This effect was intrinsic to the PyV-MT::Irs1–/– tumors, because the tumors grew faster and showed increased lung metastasis even when injected into wild-type mice. The PyV-MT::Irs1–/– tumors showed elevated microvascular density compared with the PyV-MT tumors and the PyV-MT::Irs1–/– tumors, and serum from these mice had increased concentrations of vascular endothelial growth factor A (VEGF-A). The tumors from the PyV-MT::Irs1–/– mice also showed increased signaling through the mTOR pathway, which regulates protein production and may explain the increase in VEGF-A production. The tumors from the PyV-MT::Irs1–/– mice also showed decreased abundance of apoptotic cells compared with tumors from the PyV-MT mice. IRS-2 abundance and tyrosine phosphorylation were increased in the tumors from the PyV-MT::Irs1–/– mice, and there was increased interaction between IRS-2 and the p85 regulatory subunit of phosphinositide 3-kinase, suggesting that in the absence of IRS-1, signaling through IRS-2 is enhanced. Further, these results suggest that IRS-1 may have an inhibitory effect of tumor metastasis, yet promote tumor formation and growth. Metastatic tumors from PyV-MT::Irs2–/– or PyV-MT mice had increased serine phosphorylation of IRS-1, which prevents tyrosine phosphorylation and thereby inhibits IRS-1 function. Small interfering RNA (SiRNA) used to decrease IRS-1 in cells from PyV-MT tumors increased IRS-2 abundance in those cells, suggesting that IRS-1 may inhibit IRS-2 signaling, and siRNA of IRS-2 in cells from PyV-MT::Irs1–/– decreased the phosphorylation of S6 kinase, a marker for activation of the mTOR pathway. Thus, it appears that IRS-1 and IRS-2 antagonize each other's activity and that inactivation of IRS-1 may contribute to the increased metastatic potential of mammary tumors.

R. K. Dearth, X. Cui, H.-J. Kim, I. Kuiatse, N. A. Lawrence, X. Zhang, J. Divisova, O. L. Britton, S. Mohsin, D. C. Allred, D. L. Hadsell, A. V. Lee, Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Mol. Cell. Biol. 26, 9302-9314 (2006). [Abstract] [Full Text]

Z. Ma, S. L. Gibson, M. A. Byrne, J. Zhang, M. F. White, L. M. Shaw, Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis. Mol. Cell. Biol. 26, 9338-9351 (2006). [Abstract] [Full Text]

Citation: N. R. Gough, IRS Cancer Connection. Sci. STKE 2006, tw417 (2006).



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