Abstract
Type I insulin-like growth factor receptor (IGF-IR) can transform mouse fibroblasts; however, little is known about the transforming potential of IGF-IR in human fibroblasts or epithelial cells. We found that overexpression of a constitutively activated IGF-IR (CD8-IGF-IR) was sufficient to cause transformation of immortalized human mammary epithelial cells and growth in immunocompromised mice. Furthermore, CD8-IGF-IR caused cells to undergo an epithelial-to-mesenchymal transition (EMT) which was associated with dramatically increased migration and invasion. The EMT was mediated by the induction of the transcriptional repressor Snail and downregulation of E-cadherin. NF-kappaB was highly active in CD8-IGF-IR-MCF10A cells, and both increased levels of Snail and the EMT were partially reversed by blocking NF-kappaB or IGF-IR activity. This study places IGF-IR among a small group of oncogenes that, when overexpressed alone, can confer in vivo tumorigenic growth of MCF10A cells and indicates the hierarchy in the mechanism of IGF-IR-induced EMT.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Benzimidazoles / pharmacology
- CD8 Antigens / metabolism
- Cadherins / genetics
- Cell Transformation, Neoplastic* / drug effects
- Collagen / drug effects
- Down-Regulation / drug effects
- Drug Combinations
- Epithelial Cells / cytology*
- Epithelial Cells / drug effects
- Genes, Regulator
- Humans
- Laminin / drug effects
- Mammary Glands, Human / cytology*
- Mammary Glands, Human / drug effects
- Mammary Glands, Human / growth & development
- Mesoderm / cytology*
- Mice
- Models, Biological
- Morphogenesis / drug effects
- NF-kappa B / metabolism*
- Proteoglycans / drug effects
- Pyridones / pharmacology
- Receptor, IGF Type 1 / antagonists & inhibitors
- Receptor, IGF Type 1 / metabolism*
- Recombinant Fusion Proteins / metabolism
- Snail Family Transcription Factors
- Transcription Factors / metabolism*
- Transplantation, Heterologous
Substances
- BMS 536924
- Benzimidazoles
- CD8 Antigens
- Cadherins
- Drug Combinations
- Laminin
- NF-kappa B
- Proteoglycans
- Pyridones
- Recombinant Fusion Proteins
- Snail Family Transcription Factors
- Transcription Factors
- matrigel
- Collagen
- Receptor, IGF Type 1