Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis

Summary We report on a systematic analysis of genotype-specific melanocyte UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with Nras(Q61K) to transform melanocytes. We previously reported that melanocytes migrate from the follicular outer root sheath into the epidermis after neonatal UVR. Here we found that Arf or p53 loss markedly diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4(R24C) did not affect the melanocyte migration. Instead, independent of UVR exposure, interfollicular dermal melanocytes were more prevalent in Cdk4(R24C) mice. Subsequently, in adulthood these mutants developed dermal melanocyte proliferations reminiscent of superficial congenital naevi. Two types of melanoma were observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression.