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Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice

Oncogene volume 28, pages 2289–2298 (2009)Cite this article

Abstract

BRAF, a cellular oncogene and effector of RAS-mediated signaling, is activated by mutation in ∼60% of melanomas. Most of these mutations consist of a V600E substitution resulting in constitutive kinase activation. Mutant BRAF thus represents an important therapeutic target in melanoma. In an effort to produce a pre-clinical model of mutant BRAF function in melanoma, we have generated a mouse expressing BRAF V600E targeted to melanocytes. We show that in these transgenic mice, widespread benign melanocytic hyperplasia with histological features of nevi occurs, with biochemical evidence of senescence. Melanocytic hyperplasia progresses to overt melanoma with an incidence dependent on BRAF expression levels. Melanomas show CDKN2A loss, and genetic disruption of the CDKN2A locus greatly enhances melanoma formation, consistent with collaboration between BRAF activation and CDKN2A loss suggested from studies of human melanoma. The development of melanoma also involves activation of the Mapk and Akt signaling pathways and loss of senescence, findings that faithfully recapitulate those seen in human melanomas. This murine model of mutant BRAF-induced melanoma formation thus provides an important tool for identifying further genetic alterations that cooperates with BRAF and that may be useful in enhancing susceptibility to BRAF-targeted therapeutics in melanoma.

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Acknowledgements

This work was supported by NIH grant CA095798 to FGH. We thank Mohammad Miri for technical assistance, Dr Louis Montoliu for the tyrosinase promoter, Dr Lynda Chin for the mouse strains, and Dr Philip Tsichlis, Dr Amit Deshpande and Dr Trevor Pemberton for useful discussions.

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Authors and Affiliations

  1. Molecular Oncology Research Institute, Tufts New England Medical Center, Boston, MA, USA

    V K Goel, N Ibrahim, G Jiang, M Singhal, P W Hinds & F G Haluska

  2. Massachusetts General Hospital, Boston, MA, USA

    S Fee, T Flotte & F S Haluska

  3. New England Primate Research Center, Harvard Medical School, Boston, MA, USA

    S Westmoreland

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  1. V K Goel
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  2. N Ibrahim
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  3. G Jiang
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  4. M Singhal
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  5. S Fee
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  6. T Flotte
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  8. F S Haluska
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  10. F G Haluska
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Correspondence to V K Goel or F G Haluska.

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

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Goel, V., Ibrahim, N., Jiang, G. et al. Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice. Oncogene 28, 2289–2298 (2009). https://doi.org/10.1038/onc.2009.95

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