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.
Copyright © 2017, American Association for the Advancement of Science.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma* / drug therapy
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Adenocarcinoma* / genetics
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Adenocarcinoma* / secondary
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Androgen Antagonists / therapeutic use*
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Animals
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Cell Line, Tumor
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Cell Lineage
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Cell Plasticity
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Drug Resistance, Neoplasm / genetics*
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Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
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Enhancer of Zeste Homolog 2 Protein / genetics
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Epigenesis, Genetic
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Humans
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Male
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Mice
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Mutation
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Neoplasm Metastasis
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / pathology
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Neuroendocrine Tumors / drug therapy
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Neuroendocrine Tumors / genetics
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Neuroendocrine Tumors / pathology
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PTEN Phosphohydrolase / genetics
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Prostatic Neoplasms* / drug therapy
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Prostatic Neoplasms* / genetics
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Prostatic Neoplasms* / pathology
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Retinoblastoma-Like Protein p107 / genetics*
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SOXB1 Transcription Factors / antagonists & inhibitors
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SOXB1 Transcription Factors / genetics
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Tumor Suppressor Protein p53 / genetics*
Substances
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Androgen Antagonists
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Rbl1 protein, mouse
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Retinoblastoma-Like Protein p107
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SOXB1 Transcription Factors
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Sox2 protein, mouse
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Tumor Suppressor Protein p53
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Enhancer of Zeste Homolog 2 Protein
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Ezh2 protein, mouse
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PTEN Phosphohydrolase
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Pten protein, mouse