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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03262012-235115 |
| Date | 11 April 2012 |
| Creators | McKissic, Sydika Amari |
| Contributors | Simon Hayward, Ph.D., Gregory Sephel, Ph.D., Richard Hoover, Ph.D., Andries Zijlstra, Ph.D., Alissa Weaver, M.D., Ph.D. |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03262012-235115/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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