P53R245W Mutation Elicits Metastatic Phenotype In Pten Deficient Prostate Cancer

Author

Ky Pham, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

https://orcid.org/0000-0001-9818-5012

Date of Graduation

8-2019

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

M. James You, MD, PhD

Committee Member

Guillermina Lozano, PhD

Committee Member

Sean Post, PhD

Committee Member

Bin Wang, PhD

Committee Member

George Calin, MD, PhD

Abstract

Trp53 mutations are the most frequent genetic alterations in prostate cancer and are associated with more aggressive disease and worse overall survival. The majority of Trp53 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 Trp53 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 Trp53^R245W/- Pten^-/- mice have invasive prostate cancer with complete penetrance and showed stable expression of the mutant p53. In addition, we found metastasis in Trp53^R245W/- Pten^-/- mice (3/15), which was absent in Trp53^-/- Pten^-/- 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.

Keywords

Prostate cancer, Pten, p53, PbCre, missense mutations, gain of function, invasion, metastasis, p53 stability, genetic heterogeneity