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Reversibility and recurrence of IGF-IR-induced mammary tumors

Oncogene volume 28, pages 2152–2162 (2009)Cite this article

Abstract

The type-I insulin-like growth factor receptor (IGF-IR) is frequently overexpressed in breast cancer and therapeutic agents targeting IGF-IR are currently in development. The ultimate success of anti-IGF-IR therapies will depend on the extent to which established tumors remain dependent upon IGF-IR signaling for sustained growth. To investigate the potential benefits and pitfalls of targeting IGF-IR, we used a doxycycline inducible mouse model of IGF-IR initiated breast cancer. We found that downregulation of IGF-IR results in tumor-size-dependent regression to an undetectable state. Partially regressed tumors almost always resumed growth in the absence of doxycycline and a proportion of tumors that regressed to an undetectable state ultimately recurred. This re-emergence of tumor growth in the absence of doxycycline was facilitated by IGF-IR-dependent and IGF-IR-independent mechanisms. Tumor escape from IGF-IR dependence was associated with an epithelial to mesenchymal transition and upregulation of transcriptional repressors of E-cadherin. These results suggest that tumors initiated by IGF-IR have the ability to become independent of this initiating oncogene, and IGF-IR independence is associated with characteristics consistent with an epithelial to mesenchymal transition.

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Acknowledgements

We thank Katrina Watson, Helen Coates and Michelle Ross for excellent technical assistance. This work was supported by operating grants from the Canadian Institutes of Health Research, the Canadian Breast Cancer Research Alliance, the Cancer Research Society as well as a New Investigator Salary Award from the Canadian Institutes of Health Research (RA Moorehead) and Ontario Graduate Scholarships (RA Jones and CI Campbell).

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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. Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada

    G A Wood

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Correspondence to R A Moorehead.

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Jones, R., Campbell, C., Wood, G. et al. Reversibility and recurrence of IGF-IR-induced mammary tumors. Oncogene 28, 2152–2162 (2009). https://doi.org/10.1038/onc.2009.79

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