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Molecular and Cellular Biology, April 2007, p. 3165-3175, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01315-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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-{kappa}B and Snail{triangledown}

Hyun-Jung Kim,3,{dagger} Beate C. Litzenburger,3 Xiaojiang Cui,3 David A. Delgado,3 Brian C. Grabiner,1 Xin Lin,1 Michael T. Lewis,3 Marco M. Gottardis,2 Tai W. Wong,2 Ricardo M. Attar,2 Joan M. Carboni,2 and Adrian V. Lee3*

Breast Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine and the Methodist Hospital, Houston, Texas,3 Department of Molecular and Cellular Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas,1 Oncology Drug Discovery, Bristol-Myers Squibb Research Institute, Princeton, New Jersey2

Received 18 July 2006/ Returned for modification 1 September 2006/ Accepted 23 January 2007

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

* Corresponding author. Mailing address: Baylor College of Medicine, Breast Center MS:600, One Baylor Plaza, Room N1110, Houston, TX 77030. Phone: (713) 798-1624. Fax: (713) 798-1642. E-mail: avlee{at}breastcenter.tmc.edu

{triangledown} Published ahead of print on 12 February 2007.

{dagger} Present address: Craniomaxillofacial Life Science 21, School of Dentistry, Seoul National University, 28 Yeongeon-dong, Jongno-gu, Seoul 110-749, South Korea. Phone: 82-2-740-8690. Fax: 82-2-741-3193. E-mail: hkim7{at}snu.ac.kr.

Molecular and Cellular Biology, April 2007, p. 3165-3175, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01315-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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