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Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

Oncogene volume 26, pages 662–672 (2007)Cite this article

Abstract

Transgenic mice overexpressing Notch4 intracellular domain (Int3) under the control of the whey acidic protein (WAP) or mouse mammary tumor virus-long terminal repeat promoters, develop mammary tumors. Microarray analysis of these tumors revealed high levels of c-Kit expression. Gleevec is a tyrosine kinase inhibitor that targets c-Kit, platelet-derived growth factor receptors (PDGFRs) and c-Abl. This led us to speculate that tyrosine kinase receptor activity might be a driving force in the development of Int3 mammary tumors. WAP-Int3 tumor-bearing mice were treated with continuous release of Gleevec using subcutaneously implanted Alzet pumps. Phoshorylation of c-Kit, PDGFRs and c-Abl is inhibited in Int3 transgenic mammary tumors by Gleevec. Inhibition of these enzymes is associated with a decrease in cell proliferation and angiogenesis, and an induction of apoptosis. To examine the signaling mechanisms underlying Notch4/Int3 tumorigenesis, we employed small interfering RNA (siRNA) to knock down c-Kit, PDGFRs and c-Abl alone or in combination and observed the effects on soft agar growth of HC11 cells overexpressing Int3. Only siRNA constructs for c-Kit and/or PDGFR-α were able to inhibit HC11-Int3 colony formation in soft agar. Our data demonstrate an inhibitory effect of Gleevec on Int3-induced transformation of HC11 cells and mammary tumors and indicate an oncogenic role for c-Kit and PDGFR-α tyrosine kinases in the context of Int3 signaling.

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Acknowledgements

We thank Dr Barbara Vonderhaar and Dr Gilbert H Smith for their critical review of the manuscript. We specially thank Novartis Pharmaceuticals for providing Gleevec.

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  1. A Raafat and A Zoltan-Jones: These authors contributed equally to this work

Authors and Affiliations

  1. Oncogenetics Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    A Raafat, A Zoltan-Jones, L Strizzi, S Bargo, K Kimura, D Salomon & R Callahan

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  1. A Raafat
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Correspondence to R Callahan.

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Raafat, A., Zoltan-Jones, A., Strizzi, L. et al. Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis. Oncogene 26, 662–672 (2007). https://doi.org/10.1038/sj.onc.1209823

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