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| Status |
Public on Feb 24, 2017 |
| Title |
Rb and p53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting lineage plasticity facilitates therapeutic resistance. Mechanisms underlying prostate cancer lineage plasticity are unknown, and relevant experimental models are needed. We demonstrate Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation in the mouse. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates mouse tumors are comparable to human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors like Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations enabling prostate cancer progression, identify mouse models for studying prostate cancer lineage plasticity, and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.
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| Overall design |
27 mouse samples; 4 wild type and 23 with floxed alleles. The purpose of the experiment was to compare the gene expression profile of prostate tumors from mice with different genotypes. The genotypes compared include PBCre4:Ptenfl/fl, PBCre4:Ptenfl/fl:Rb1fl/fl, and PBCre4:Ptenfl/fl:Rb1fl/fl:Trp53fl/fl where fl=floxed alleles of the indicated genes. Tumors, either primary or metastatic, from individual mice were dissected, RNA extracted, and RNA analyzed by RNA-seq. Castrate recurrent tumors were dissected from mice that had been surgically castrated at 30 weeks of age, and tumors collected at relapse as mice became moribund.
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| Contributor(s) |
Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, Goodrich MM, Labbe DP, Cortes E, Wang J, Long HW, Xu B, Brown M, Loda M, Sawyers CL, Ellis L, Goodrich DW |
| Citation(s) |
28059767, 33481853, 37875657 |
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| Submission date |
Dec 05, 2016 |
| Last update date |
Jan 16, 2024 |
| Contact name |
David W Goodrich |
| E-mail(s) |
david.goodrich@roswellpark.org
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| Phone |
7168454506
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| Fax |
7168458857
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| Organization name |
Roswell Park Cancer Institute
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| Department |
Pharmacology&Therapeutics
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| Street address |
Elm and Carlton
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| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14263 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (27)
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| Relations |
| BioProject |
PRJNA356285 |
| SRA |
SRP094570 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE90891_RPKMedgeR.csv.gz |
4.0 Mb |
(ftp)(http) |
CSV |
| GSE90891_RawCounts.csv.gz |
963.6 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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