Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice

V. K. Goel, N. Ibrahim, G. Jiang, M. Singhal, S. Fee, T. Flotte, S. Westmoreland, F. S. Haluska, P. W. Hinds, F. G. Haluska

Research output: Contribution to journalArticle

100 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2289-2298
Number of pages10
JournalOncogene
Volume28
Issue number23
DOIs
StatePublished - Jun 11 2009

Keywords

  • AKT
  • BRAF
  • CDKN2A
  • Melanoma
  • P53
  • Senescence

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Goel, V. K., Ibrahim, N., Jiang, G., Singhal, M., Fee, S., Flotte, T., Westmoreland, S., Haluska, F. S., Hinds, P. W., & Haluska, F. G. (2009). Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice. Oncogene, 28(23), 2289-2298. https://doi.org/10.1038/onc.2009.95