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Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems

Oncogene volume 34, pages 4109–4117 (2015)Cite this article

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Abstract

The non-receptor tyrosine kinase Fer belongs to a distinct subfamily of F-BAR domain containing kinases implicated in vesicular trafficking and signaling downstream of adhesion and growth factor receptors. Targeted inactivation of the fer gene in a transgenic mouse model of HER2+, breast cancer was associated with delayed tumor onset and reduced proliferative rates in tumor cells. Fer deficiency was associated with increased rates of epidermal growth factor (EGF)-induced epidermal growth factor receptor (EGFR) internalization and amplified Ras-Raf-Mek-Erk (Ras-MAPK) signaling in primary mammary tumor epithelial cells, as well as increased cytotoxic and anti-proliferative sensitivity to the dual EGFR/HER2 inhibitor Lapatinib (LPN). These observations suggest a model in which accelerated ligand-induced EGFR internalization in Fer-deficient cells hypersensitizes the Ras-MAPK pathway to EGF, resulting in MAPK signal amplification to levels that induce cytostasis, rather than proliferation. Thus, Ras-MAPK cytostatic signaling delays HER2 tumor initiation and increases LPN cytotoxicity in Fer-deficient model systems. Taken together, these data suggest that targeting Fer alone, or in combination with LPN, may be of therapeutic benefit in HER2+ breast cancer.

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Acknowledgements

We are grateful to Lee Boudreau, Christine Hall and Yan Gao for technical assistance. This work was funded by operating grants from the Canadian Breast Cancer Foundation, the Canadian Institutes for Health Research, and the Canadian Cancer Society Research Institute to PAG.

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Authors and Affiliations

  1. Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada

    W Sangrar, C Shi, G Mullins, D LeBrun & P A Greer

  2. Department of Pathology and Molecular Medicine, Queen's Cancer Research Institute, Queen’s University, Kingston, Ontario, Canada

    W Sangrar, G Mullins, D LeBrun & P A Greer

  3. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    W Sangrar

  4. Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada

    B Ingalls

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  1. W Sangrar
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Correspondence to W Sangrar or P A Greer.

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Sangrar, W., Shi, C., Mullins, G. et al. Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems. Oncogene 34, 4109–4117 (2015). https://doi.org/10.1038/onc.2014.340

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