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United States Department of Agriculture

Agricultural Research Service

Title: Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2)

item Dearth, Robert
item Cui, Xiaojiang
item Kim, Hyun-jung
item Kuiatse, Isere
item Lawrence, Nicole
item Zhang, Xiaomei
item Divisova, Jana
item Britton, Ora
item Mohsin, Syed
item Allred, D
item Hadsell, Darryl
item Lee, Adrian

Submitted to: Molecular and Cellular Biology
Publication Type: Review article
Publication Acceptance Date: 9/18/2006
Publication Date: 10/9/2006
Citation: Dearth, R.K., Cui, X., Kim, H., Kuiatse, I., Lawrence, N.A., Zhang, X., Divisova, J., Britton, O.L., Mohsin, S., Allred, D.C., Hadsell, D.L., Lee, A.V. 2006. Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Molecular and Cellular Biology. 26:9302-9314.

Interpretive Summary:

Technical Abstract: Insulin receptor substrates (IRSs) are signaling adaptors that play a major role in the metabolic and mitogenic actions of insulin and insulin-like growth factors. Reports have recently noted increased levels, or activity, of IRSs in many human cancers, and some have linked this to poor patient prognosis. We found that overexpressed IRS-1 was constitutively phosphorylated in vitro and in vivo, and that transgenic mice overexpressing IRS-1 or IRS-2 in the mammary gland showed progressive mammary hyperplasia, tumorigenesis, and metastasis. Tumors showed extensive squamous differentiation, a phenotype commonly seen with activation of the canonical beta-catenin signaling pathway. Consistent with this, IRSs were found to bind beta-catenin in vitro and in vivo. IRS-induced tumorigenesis is unique, given that the IRSs are signaling adaptors with no intrinsic kinase activity, and this supports a growing literature indicating a role for IRSs in cancer. This study defines IRSs as oncogene proteins in vivo and provides new models to develop inhibitors against IRSs for anticancer therapy.

Last Modified: 8/24/2016
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