Mouse models for BRAF-induced cancers

Abstract

Oncogenic mutations in the BRAF gene are detected in approximately 7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas. Over 40 different missense BRAF mutations have been found, but the vast majority (>90%) represent a single nucleotide change resulting in a valine-->glutamate mutation at residue 600 ((V600E)BRAF). In cells cultured in vitro, (V600E)BRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumorigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA (small interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are attractive therapeutic targets in cancer samples with BRAF mutations. In order to fully understand the role of oncogenic BRAF in cancer development in vivo as well as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs (genetically engineered mouse models) have been generated in which expression of oncogenic BRaf is conditionally dependent on the Cre recombinase. The delivery/activation of the Cre recombinase can be regulated in both a temporal and spatial manner and therefore these mouse models can be used to recapitulate the somatic mutation of BRAF that occurs in different tissues in the development of human cancer. The data so far obtained following Cre-mediated activation in haemopoietic tissue and the lung indicate that (V600E)BRAF mutation can drive tumour initiation and that its primary effect is to induce high levels of cyclin D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced senescence) are evident that restrain further development of the tumour.

An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice

“…This confirmed the findings of an earlier study, in which overexpression of full-length WT BRAF or the full-length V600E variant alone did not result in tumor formation after 3 months, whereas overexpression of BRAF VE FL resulted in high-grade astrocytic tumors only on an Ink4/Arf-deficient background (16). This, in turn, is consistent with considerations on the role of Ink4/Arf in Ras-driven mouse models in the literature (17).…”

Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours

“…Their role in glioma formation, and the role of the MAPK cascade they trigger, have been identified in tumour samples and further confirmed in mouse models (Jeuken et al, 2007;Pritchard et al, 2007;Lyustikman et al, 2008;Pfister et al, 2008). NF1 encodes for a Ras-GTPAse and its loss of function may lead to activation of Ras/RAF signalling and coincides with formation of indolent JPA mainly within the optic pathway.…”

The RASopathies

“…Ras is somatically mutated in approximately 20% of malignancies (8), and BRAF is somatically mutated in approximately 7% of malignancies (for a review, see 39). Because of this, the RASopathies are considered cancer syndromes, with the majority of associated mutations resulting in enhanced pathway activation or dysregulated signaling.…”