Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation.
Overexpression and hyperactivation of the type I insulin-like growth factor receptor (IGF-IR) has been observed in human breast tumor biopsies. In addition, in vitro studies indicate that overexpression of IGF-IR is sufficient to transform cells such as mouse embryo fibroblasts and this receptor promotes proliferation and survival in breast cancer cell lines. To fully understand the function of the IGF-IR in tumor initiation and progression, transgenic mice containing human IGF-IR under a doxycycline-inducible MMTV promoter system were generated. Administration of 2 mg/ml doxycycline in the animals' water supply beginning at 21 days of age resulted in elevated levels of IGF-IR in mammary epithelial cells as detected by Western blotting and immunohistochemistry. Whole mount analysis of 55-day-old mouse mammary glands revealed that IGF-IR overexpression significantly impaired ductal elongation. Moreover, histological analyses revealed multiple hyperplasic lesions in the mammary glands of these 55-day-old mice. The formation of palpable mammary tumors was evident at approximately 2 months of age and was associated with increased levels of IGF-IR signaling molecules including phosphorylated Akt, Erk1/Erk2 and STAT3. Therefore, these transgenic mice provide evidence that IGF-IR overexpression is sufficient to induce mammary epithelial hyperplasia and tumor formation in vivo and provide a model to further understand the function of IGF-IR in mammary epithelial transformation.
Jones
R A
RA
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
Campbell
C I
CI
Gunther
E J
EJ
Chodosh
L A
LA
Petrik
J J
JJ
Khokha
R
R
Moorehead
R A
RA
D000818:Animals; D015153:Blotting, Western; D004318:Doxycycline / Q000008:administration & dosage; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000196:embryology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D019076:Transgenes
D017526:Receptor, IGF Type 1; D004318:Doxycycline