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

R. A. Jones, C. I. Campbell, Edward Gunther, L. A. Chodosh, J. J. Petrik, R. Khokha, R. A. Moorehead

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1636-1644
Number of pages9
JournalOncogene
Volume26
Issue number11
DOIs
Publication statusPublished - Mar 8 2007

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Jones, R. A., Campbell, C. I., Gunther, E., Chodosh, L. A., Petrik, J. J., Khokha, R., & Moorehead, R. A. (2007). Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene, 26(11), 1636-1644. https://doi.org/10.1038/sj.onc.1209955