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Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.

TitleRb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.
Publication TypeJournal Article
Year of Publication2017
AuthorsKu SYu, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, Goodrich MM, Labbé DP, Gomez ECortes, Wang J, Long HW, Xu B, Brown M, Loda M, Sawyers CL, Ellis L, Goodrich DW
JournalScience
Volume355
Issue6320
Pagination78-83
Date Published2017 01 06
ISSN1095-9203
KeywordsAdenocarcinoma, Androgen Antagonists, Animals, Cell Line, Tumor, Cell Lineage, Cell Plasticity, Drug Resistance, Neoplasm, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Humans, Male, Mice, Mutation, Neoplasm Metastasis, Neoplasms, Experimental, Neuroendocrine Tumors, Prostatic Neoplasms, PTEN Phosphohydrolase, Retinoblastoma-Like Protein p107, SOXB1 Transcription Factors, Tumor Suppressor Protein p53
Abstract

Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.

DOI10.1126/science.aah4199
Alternate JournalScience
PubMed ID28059767
PubMed Central IDPMC5367887
Grant ListP30 CA016056 / CA / NCI NIH HHS / United States
R01 CA193837 / CA / NCI NIH HHS / United States
R01 CA070292 / CA / NCI NIH HHS / United States
P50 CA092629 / CA / NCI NIH HHS / United States
R01 CA207757 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA155169 / CA / NCI NIH HHS / United States
R25 GM095459 / GM / NIGMS NIH HHS / United States
R21 CA179907 / CA / NCI NIH HHS / United States