P53R245W Mutation Elicits Metastatic Phenotype In Pten Deficient Prostate Cancer

<p><em>Trp53</em> mutations are the most frequent genetic alterations in prostate cancer and are associated with more aggressive disease and worse overall survival. The majority of <em>Trp53</em> mutations in prostate cancer are missense mutations, resulting in amino acid substitutions with profound effect. In addition to the loss of wild type function, missense mutations in <em>Trp53</em> result in a gain-of-function (GOF) phenotype. This GOF phenotype confers biologic advantages to the tumor cells, enabling them to metastasize and invade distant organs. In this study, we generated mice carrying a conditional prostate-specific p53R245W mutant and Pten deletion to access the role of this common p53 mutant in the pathogenesis and metastasis of prostate cancer. We found that <em>Trp53^R245W/- Pten^-/-</em> mice have invasive prostate cancer with complete penetrance and showed stable expression of the mutant p53. In addition, we found metastasis in <em>Trp53^R245W/- Pten^-/-</em> mice (3/15), which was absent in <em>Trp53^-/- Pten^-/- </em>mice (0/14). Analysis of metastasis also showed stable expression of the mutant p53. Taken together, these results indicate that p53R245W mutation has GOF in Pten-deficient prostate cancer.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2019

Authors dc:creator

• Pham, Ky
• <p>https://orcid.org/0000-0001-9818-5012</p>

Contributors dc:contributor

• M. James You, MD, PhD
• Guillermina Lozano, PhD
• Sean Post, PhD

• Prostate cancer
• Pten
• p53
• PbCre
• missense mutations
• gain of function
• invasion
• metastasis
• p53 stability
• genetic heterogeneity
• Bioinformatics
• Genetics
• Molecular Genetics
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/973

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2020