Identification of novel genes involved in prostate and Schwann cell malignancies utilizing a sleeping beauty transposon somatic cell mutagenesis screen

Abstract

The focus of this thesis was identification of new genes and genetic pathways altered in prostate cancer and malignant peripheral nerve sheath tumor formation utilizing a Sleeping Beauty somatic mutagenesis forward genetic screen. Mutagenesis of prostate epithelial cells gave rise to proliferative cell lesions that resembled early stages of prostate cancer. From these lesions, Pde4d, Klhl13, Braf, and Nras were identified as CISs. Moreover, Pde4d was shown to be a pro-proliferative factor in human prostate cancer cell lines and to be overexpressed in human prostate cancers. SB mutagenesis in Schwann cells gave rise to all stages of Schwann cell tumorigenesis including benign neurofibromas, plexiform neurofibromas, and aggressive MPNSTs. From these tumors, hundreds of CISs were identified including known tumor suppressors Nf1, Pten, and Cav1. Experiments with loss of Cav1 demonstrated cooperativity with EGFR overexpression in vivo for Schwann cell tumorigenesis.