Title | Rapid in vivo validation of candidate drivers derived from the PTEN-mutant prostate metastasis genome. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Cho H, Herzka T, Stahlhut C, Watrud K, Robinson BD, Trotman LC |
Journal | Methods |
Volume | 77-78 |
Pagination | 197-204 |
Date Published | 2015 May |
ISSN | 1095-9130 |
Keywords | Animals, Genetic Association Studies, Genome, Humans, Male, Mice, Mice, Knockout, Mutation, Prostate, Prostatic Neoplasms, PTEN Phosphohydrolase, Time Factors, Tumor Suppressor Proteins |
Abstract | Human genome analyses have revealed that increasing gene copy number alteration is a driving force of incurable cancer of the prostate (CaP). Since most of the affected genes are hidden within large amplifications or deletions, there is a need for fast and faithful validation of drivers. However, classic genetic CaP engineering in mouse makes this a daunting task because generation, breeding based combination of alterations and non-invasive monitoring of disease are too time consuming and costly. To address the unmet need, we recently developed RapidCaP mice, which endogenously recreate human PTEN-mutant metastatic CaP based on Cre/Luciferase expressing viral infection, that is guided to Pten(loxP)/Trp53(loxP) prostate. Here we use a sensitized, non-metastatic Pten/Trp53-mutant RapidCaP system for functional validation of human metastasis drivers in a much accelerated time frame of only 3-4months. We used in vivo RNAi to target three candidate tumor suppressor genes FOXP1, RYBP and SHQ1, which reside in a frequent deletion on chromosome 3p and show that Shq1 cooperates with Pten and p53 to suppress metastasis. Our results thus demonstrate that the RapidCaP system forms a much needed platform for in vivo screening and validation of genes that drive endogenous lethal CaP. |
DOI | 10.1016/j.ymeth.2014.12.022 |
Alternate Journal | Methods |
PubMed ID | 25592467 |
PubMed Central ID | PMC4429512 |
Grant List | 1R01 GM101647 / GM / NIGMS NIH HHS / United States 5T32CA148056 / CA / NCI NIH HHS / United States R01 CA137050 / CA / NCI NIH HHS / United States P30 CA045508 / CA / NCI NIH HHS / United States 5P30CA045508 / CA / NCI NIH HHS / United States T32 CA148056 / CA / NCI NIH HHS / United States |
Related Faculty:
Brian Robinson, M.D.