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-kappaB and snail.
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.
Kim
Hyun-Jung
HJ
Baylor College of Medicine, Breast Center MS:600, One Baylor Plaza, Room N1110, Houston, TX 77030, USA.
Litzenburger
Beate C
BC
Cui
Xiaojiang
X
Delgado
David A
DA
Grabiner
Brian C
BC
Lin
Xin
X
Lewis
Michael T
MT
Gottardis
Marco M
MM
Wong
Tai W
TW
Attar
Ricardo M
RM
Carboni
Joan M
JM
Lee
Adrian V
AV
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D016827:CD8 Antigens / Q000378:metabolism; D015820:Cadherins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003094:Collagen / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D005809:Genes, Regulator; D006801:Humans; D007797:Laminin / Q000187:drug effects; D042361:Mammary Glands, Human / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D011509:Proteoglycans / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014183:Transplantation, Heterologous
C504983:BMS 536924; D001562:Benzimidazoles; D016827:CD8 Antigens; D015820:Cadherins; D004338:Drug Combinations; D007797:Laminin; D016328:NF-kappa B; D011509:Proteoglycans; D011728:Pyridones; D011993:Recombinant Fusion Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C059485:matrigel; D003094:Collagen; D017526:Receptor, IGF Type 1