Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1

Basal cell carcinoma is the most prevalent cancer in the western world, sho wing a rapid increase in incidence. Activation of the Sonic hedgehog/Patche d (PTCH) signaling pathway because of PTCH1 inactivation is a key event in sporadic and familial basal cell carcinoma development in humans and is ass ociated with transcriptional activation of specific target genes, including PTCH1 itself. These changes are analogous to the situation in Drosophila w here hedgehog activates the zinc-finger transcription factor Cubitus interr uptus, leading to increased transcription of target genes. In the present s tudy, we show that mice ectopically expressing the human Cubitus interruptu s homolog GLI-1 in the skin develop tumors closely resembling human BCCs as well as other hair follicle-derived neoplasias, such as trichoepitheliomas , cylindromas, and trichoblastomas. Furthermore, examination of the tumors revealed wild-type p53 and Ha ras genes. These findings firmly establish th at increased GLI-1 expression is central and probably sufficient for tumor development and suggest that GLI-1-induced tumor development does not depen d on additional p53 or Ha ras mutations.