1. ¹Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
2. ²Department of Pathology, Vrije University Medical Center, Amsterdam, The Netherlands

Correspondence: Dr DS Peeper, Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands. E-mail: d.peeper@nki.nl

³These authors contributed equally to this work.

Received 3 July 2007; Accepted 4 July 2007; Published online 27 August 2007.

Abstract

Of the RAF family of protein kinases, BRAF is the only member to be frequently activated by mutation in cancer. A single amino acid substitution (V600E) accounts for the vast majority and results in constitutive activation of BRAF kinase function. Its expression is required to maintain the proliferative and oncogenic characteristics of BRAF^E600-expressing human tumour cells. Although BRAF^E600 acts as an oncogene in the context of additional genetic lesions, in primary cells it appears to be associated rather with transient stimulation of proliferation. Eventually, BRAF^E600 signalling triggers cell cycle arrest with the hallmarks of cellular senescence, as is illustrated by several recent studies in cultured cells, animal models and benign human lesions. In this review, we will discuss recent advances in our understanding of the role of BRAF^E600 in benign and malignant human tumours and the implications for therapeutic intervention.