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Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2
Robert K. Dearth,1,
Xiaojiang Cui,1,
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 thatplay a major role in the metabolic and mitogenic actions ofinsulin and insulin-like growth factors. Reports have recentlynoted increased levels, or activity, of IRSs in many human cancers,and some have linked this to poor patient prognosis. We foundthat overexpressed IRS-1 was constitutively phosphorylated invitro and in vivo and that transgenic mice overexpressing IRS-1or IRS-2 in the mammary gland showed progressive mammary hyperplasia,tumorigenesis, and metastasis. Tumors showed extensive squamousdifferentiation, a phenotype commonly seen with activation ofthe canonical ß-catenin signaling pathway. Consistentwith this, IRSs were found to bind ß-catenin in vitroand in vivo. IRS-induced tumorigenesis is unique, given thatthe IRSs are signaling adaptors with no intrinsic kinase activity,and this supports a growing literature indicating a role forIRSs in cancer. This study defines IRSs as oncogene proteinsin vivo and provides new models to develop inhibitors againstIRSs 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.
Published ahead of print on 9 October 2006.
These authors contributed equally to the work.
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EDITORS' CHOICE
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[DOI: 10.1126/stke.3652006tw417] |Abstract »
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Xiaojiang Cui,1
Published ahead of print on 9 October 2006. 
These authors contributed equally to the work. 
