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

Oncogene volume 26, pages 1636–1644 (2007)Cite this article

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.

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Acknowledgements

We acknowledge the technical assistance of Nicolle Linnerth, Katrina Watson, Michelle Ross and Helen Coates and the preliminary pathology reports on some of the initial tumors by Dr Robert Cardiff. This work was supported by an Idea Award from the CBCRA and a CBCRA/CIHR operating grant awarded to RAM and grants from the NCI US Army BCRP to LAC.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada

    R A Jones, C I Campbell, J J Petrik & R A Moorehead

  2. Penn State Hershey Medical School, Hershey, PA, USA

    E J Gunther

  3. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    L A Chodosh

  4. University Health Network/Princess Margaret Hospital, Toronto, Ontario, Canada

    R Khokha

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  1. R A Jones
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  2. C I Campbell
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Correspondence to R A Moorehead.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Jones, R., Campbell, C., Gunther, E. et al. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene 26, 1636–1644 (2007). https://doi.org/10.1038/sj.onc.1209955

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