Prostate cancer is the most commonly diagnosed cancer in American men. Although much progress has been made in identifying the genetic alterations that underlie this disease, there remains a gap in our understanding of how these genetic changes interact to lead to cancer. Modeling human cancers in vivo using mice is a critical part of cancer biology to better understand human carcinogenesis. Most human cancers are thought to initiate from a mutation in a single cell or a few cells, which expand and become cancerous with the accumulation of additional mutations. However, current mouse prostate cancer models do not accurately mimic this process as mutations are generally induced in entire cell populations rather than in a few cells. To more accurately model human prostate cancer, we generated novel transgenic mice with focal overexpression of the oncogene c-MYC in the prostatic epithelium. Focal c-MYC activation resulted in mild pathology despite expansion of the c-MYC-positive cells. When combined with heterozygous or homozygous deletion of the Pten tumor suppressor gene, however, focal c-MYC expression promoted the development of prostate cancer. Cells with concurrent activation of c-MYC and loss of Pten were of higher grade and out-proliferated cells with mutations in Pten alone. In the prostate, Pten deletion activates the p53 pathway, which can induce either apoptosis or senescence. We found that concurrent c-MYC expression shifted the p53 pathway response from senescence in favor of apoptosis. Thus cooperativity between c-MYC and Pten leads to increased tumorigenicity due to the high rates of proliferation and reduced senescence in c-MYC/Pten mutant cells in spite of elevated rates of apoptosis. Our model of focal c-MYC expression allowed us to examine the characteristics of cells with distinct mutations (c-MYC vs. wild type or Pten-null vs. c-MYC;Pten-null cells) in the same mouse prostate to gain insight into the interaction and competition between cells in the cancer progression. This system provides an important cancer model to investigate heterogeneous and incremental nature of human prostate carcinogenesis.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-09102009-151212 |
| Date | 11 September 2009 |
| Creators | Kim, Jongchan |
| Contributors | Dr. Stephen Hann, Dr. Gregory Sephel, Dr. Harold Moses, Dr. Richard Hoover, Dr. Neil Bhowmick |
| 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-09102009-151212/ |
| 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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