Constitutively Active Type I Insulin-Like Growth Factor Receptor Causes Transformation and Xenograft Growth of Immortalized Mammary Epithelial Cells and Is Accompanied by an Epithelial-to-Mesenchymal Transition Mediated by NF-κB and Snail

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-κB was highly active in CD8-IGF-IR-MCF10A cells, and both increased levels of Snail and the EMT were partially reversed by blocking NF-κB 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.

We thank Ora Britton for help with the xenograft studies, Craig Allred and the Pathology core of the Breast Center at Baylor College of Medicine for IHC, and Steffi Oesterreich for critical reading of the manuscript. Flag-Snail-pCMV-Tag 2B was a gift from Mien-Chie Hung at the M. D. Anderson Cancer Center, Houston, TX.

This work was supported in part by Public Health Service grants R01CA94118 (A.V.L.) and P01CA30195 (C.K.O./A.V.L.). A.V.L. is the recipient of a T. T. Chao Scholar award (Department of Medicine, Baylor College of Medicine). X.C. is the recipient of a Career Development Award (P50CA58183).