The role of NKX3.1 in the initiation and progression of prostate cancer
McKissic, Sydika Amari
This goal of this dissertation was to investigate the molecular mechanisms of prostate tumorigenesis initiated by loss of the tumor suppressor NKX3.1. In human prostate cancer, NKX3.1 is lost during disease progression. Deletion of Nkx3.1 in mouse models of prostate cancer have indicated that Nkx3.1 loss promotes initiation but require additional mutations for progression. Human clinical data and mouse models suggest that loss of NKX3.1 and overexpression of the oncogene c-MYC collaborate to promote prostate tumorigenesis. To evaluate cooperation between Nkx3.1 and c-Myc, I generated transgenic mice with concurrent, prostate specific loss of Nkx3.1 and activation of c-MYC. Cooperation was demonstrated by the development of high grade prostate intraepithelial neoplasia lesions with signs of micro-invasive cancer and increased proliferation. Using a combination of gene expression analysis, chromatin immunoprecipitation and immunohistochemistry, I demonstrate that Nkx3.1 and c-Myc cross-regulate cancer relevant target genes which facilitates tumor progression. These findings significantly improved our understanding of the role of NKX3.1 loss in tumor initiation and progression. In addition, these studies identified tumor contributing gene targets that may provide new molecular therapeutic targets.