1. Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2.
- Author
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Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA, Zhang X, Divisova J, Britton OL, Mohsin S, Allred DC, Hadsell DL, and Lee AV
- Subjects
- Adaptor Proteins, Signal Transducing biosynthesis, Adaptor Proteins, Signal Transducing genetics, Animals, Cell Line, Transformed, Female, Humans, Hyperplasia, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins physiology, Lung Neoplasms genetics, Lung Neoplasms pathology, Mammary Glands, Animal pathology, Mammary Neoplasms, Experimental pathology, Mice, Mice, Transgenic, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology, Phosphoproteins physiology, Signal Transduction physiology, Intracellular Signaling Peptides and Proteins genetics, Lung Neoplasms secondary, Mammary Neoplasms, Experimental genetics, Phosphoproteins biosynthesis, Phosphoproteins genetics
- 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.
- Published
- 2006
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