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

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 ␤-catenin signaling pathway. Consistent with this, IRSs were found to bind ␤-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.Insulin receptor substrates (IRSs) are a family of intracellular proteins that integrate and coordinate hormone, cytokine, and growth factor signaling. To date, four IRS proteins (IRS-1 to IRS-4) have been identified (27). All IRSs contain multiple tyrosine phosphorylation sites that act as binding sites for SH2-containing proteins (27). The IRS proteins were first identified as substrates and presumed signaling intermediates of the insulin receptor. However, it is now clear that the IRS proteins can be activated and phosphorylated by a number of other signaling pathways, including those that are critical for mammary gland development, such as growth hormone and prolactin (2, 56).Much research has focused on the roles of IRSs in both metabolic and mitogenic signaling; however, the last several years have seen an emergence of literature implicating IRSs in human cancer. IRS-1 is constitutively active and phosphorylated in many tumors (6). IRS-1 levels are increased in patients with pancreatic cancer (1), and both IRS-1 and IRS-2 levels are increased in patients with hepatocellular cancer (3, 36). We previously reported that high IRS-1 levels are associated with poor outcomes for patients with breast cancer (25, 41), and this is supported by further studies showing that IRS-1 is expressed in patients with primary breast cancer and metastases, and its levels correlate with poor differentiation and lymph node involvement (22). One study, however, found that IRS-1 levels in advanced primary breast cancers were reduced compared to breasts from healthy patients (44).The mouse mammary gland has served as a useful area for the identification and characterization of oncogenes and tumor suppressor genes important in human breast cancer (15). For example, transgenic mice overexpressing the HER-2 oncogene develop mammary cancer with biological and phenotypic variances similar to those observed in human breast cancer patients (23).To date, there have been no re...

The Prolyl Peptidases PRCP/PREP Regulate IRS-1 Stability Critical for Rapamycin-induced Feedback Activation of PI3K and AKT

“…Overexpression of IRS-1 has been found in a number of human tumors including pancreatic cancer and its overexpression is associated with tumor progression (33,41). Transgenic overexpression of IRS-1 and IRS-2 in mammary glands of mice can induce breast tumorigenesis and metastasis (42).…”

Growth inhibition by microRNAs that target the insulin receptor substrate-1

“…9,15,16 IRS-1 expression is often increased in human cancers 22 and increased or ectopic expression of IRS-1 causes cell transformation, i.e., ability to form colonies in soft agar and tumors in mice. 15,[23][24][25][26][27][28][29][30] Conversely, downregulation of IRS-1 (by antisense or siRNA) reverses the transformed phenotype. [30][31][32][33] One intriguing aspect of IRS-1 downregulation is that cells that do not express IRS-1 survive, although they have a tendency to differentiate (see above).…”

Association Of Insulin Receptor Substrate-2 Gene Polymorphism With Ovarian Cancer

“…In recent reports, IRS-2 expression has been linked to specific cancers, such as breast cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer (3,(21)(22)(23)(24). Slattery et al found that a variant of IRS-2 was associated with colon cancer risk and the IRS-2 GD genotype reduced the risk of colon cancer (3).…”