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.
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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.
Science (New York, N.Y.). 2017 Jan 06 [Epub]
Sheng Yu Ku, Spencer Rosario, Yanqing Wang, Ping Mu, Mukund Seshadri, Zachary W Goodrich, Maxwell M Goodrich, David P Labbé, Eduardo Cortes Gomez, Jianmin Wang, Henry W Long, Bo Xu, Myles Brown, Massimo Loda, Charles L Sawyers, Leigh Ellis, David W Goodrich
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA., Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Department of Biostatistics and Bioinformatics, RPCI, Buffalo, NY 14263, USA., Department of Pathology, RPCI, Buffalo, NY 14263, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA. .