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Science. 2017 Jan 6;355(6320):78-83. doi: 10.1126/science.aah4199.

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

Author information

1
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
2
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
3
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
5
Department of Biostatistics and Bioinformatics, RPCI, Buffalo, NY 14263, USA.
6
Department of Pathology, RPCI, Buffalo, NY 14263, USA.
7
Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, MA 02115, USA.
8
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, MA 02115, USA.
9
Division of Cancer Studies, King's College London, London SE1 9RT, UK.
10
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
11
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA. david.goodrich@roswellpark.org leigh.ellis@roswellpark.org.

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.

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PMID:
28059767
PMCID:
PMC5367887
DOI:
10.1126/science.aah4199
[Indexed for MEDLINE]
Free PMC Article

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