Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Oncogene. 2007 Mar 8;26(11):1636-44. doi: 10.1038/sj.onc.1209955. Epub 2006 Sep 4.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Doxycycline / administration & dosage
  • Immunohistochemistry
  • Mammary Glands, Animal / embryology*
  • Mammary Neoplasms, Experimental / genetics*
  • Mice
  • Mice, Transgenic
  • Morphogenesis*
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / physiology*
  • Transgenes


  • Receptor, IGF Type 1
  • Doxycycline