Profiling the Roles of Insulin Receptor Substrate Isoforms 1 and 2 in Breast Cancer
Abstract
The insulin-like growth factor (IGF) system has been shown to play role in breast cancer tumorigenesis and metastasis. Insulin receptor substrate (IRS) adaptor proteins are recruited to the IGF-1 receptor (IGF-1R) in response to IGF-I to activate downstream MAPK and PI3K signaling. Data from our lab suggests that different isoforms (IRS-1 and IRS-2) exhibit a selective propensity for one of these signaling pathways to drive cellular behavior, where IRS-1 drives proliferation through Grb2/MAPK activation and IRS-2 stimulates motility through PI3K/Akt induction. Our findings suggest that overlapping and distinct sets of genes are driven by IRS-1 and IRS-2 following IGF-1 exposure. While both isoforms regulate expression, early (4h) IRS-2 genes linked to motility and late IRS-1 (24h) genes linked to proliferation. IGF-I-induced upregulation in the transforming growth factor beta 2 (TGF!2) gene suggested that IRS isoforms link the IGF and TGF! pathways. Comparative analysis and hierarchical clustering of our IRS-driven microarrays with published data sets uncovered numerous commonly regulated genes. Moreover, certain subsets were linked to poor patient survival. Our data suggest that IGF stimulation of breast cancer cells results in distinct profiles of gene expression that are dependent on IRS adaptor protein expression and these signatures may reveal poor prognosis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2010
- Accession Number
- ADA526529
Entities
People
- Marc A. Becker
Organizations
- University of Minnesota