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Mol. Cell. Biol. 26 (24): 9302-9314

Copyright © 2006 by the American Society for Microbiology. All rights reserved.

Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2{triangledown}

Robert K. Dearth,1,{dagger} Xiaojiang Cui,1,{dagger} Hyun-Jung Kim,1 Isere Kuiatse,1 Nicole A. Lawrence,2 Xiaomei Zhang,1 Jana Divisova,1 Ora L. Britton,1 Syed Mohsin,1 D. Craig Allred,1 Darryl L. Hadsell,2, and Adrian V. Lee1*

Breast Center, Baylor College of Medicine and Methodist Hospital, Departments of Medicine, Molecular and Cellular Biology, and Pathology, Houston, Texas 77030,1 USDA/ARS Children's Nutrition Research Center, Departments of Pediatrics and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas2

Received for publication 11 February 2006. Revision received 10 April 2006. Accepted for publication 18 September 2006.

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 ß-catenin signaling pathway. Consistent with this, IRSs were found to bind ß-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.

* Corresponding author. Mailing address: One Baylor Plaza MS:600, Room N1110, Baylor College of Medicine, Houston, TX 77030. Phone: (713) 798-1624. Fax: (713) 798-1642. E-mail: avlee{at}breastcenter.tmc.edu.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} These authors contributed equally to the work.

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