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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

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

Submitted to: Molecular and Cellular Biology
Publication Type: Review Article
Publication Acceptance Date: September 18, 2006
Publication Date: October 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.

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: 11/1/2014
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