IRS Cancer Connection
Authors: Gough Nancy R. 
Published: December 2006

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 β-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 β-catenin. In the tumors from the IRS-1- or IRS-2-overexpressing mice, β-catenin coimmunoprecipitated with the IRS proteins, and there was increased abundance of cyclin D, which is encoded by a β-catenin target gene. In the overexpressing MCF-10A cells, IGF-1 stimulated the association between IRS-1 or IRS-2 and β-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]