title: Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.
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.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
authors.forename: Sheng Yu
authors.initials: SY
authors.lastname: Ku
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Rosario
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Mu
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
authors.forename: Zachary W
authors.initials: ZW
authors.lastname: Goodrich
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
authors.forename: Maxwell M
authors.initials: MM
authors.lastname: Goodrich
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Labbé
authors.affiliation: Department of Biostatistics and Bioinformatics, RPCI, Buffalo, NY 14263, USA.
authors.forename: Eduardo Cortes
authors.initials: EC
authors.lastname: Gomez
authors.affiliation: Department of Biostatistics and Bioinformatics, RPCI, Buffalo, NY 14263, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Long
authors.affiliation: Department of Pathology, RPCI, Buffalo, NY 14263, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|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.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, MA 02115, USA.|Division of Cancer Studies, King's College London, London SE1 9RT, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.|Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA. david.goodrich@roswellpark.org leigh.ellis@roswellpark.org.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ellis
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA. david.goodrich@roswellpark.org leigh.ellis@roswellpark.org.
authors.forename: David W
authors.initials: DW
authors.lastname: Goodrich
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D019070:Cell Lineage; D000066670:Cell Plasticity; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics; D044127:Epigenesis, Genetic; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000726:Androgen Antagonists; C489485:Rbl1 protein, mouse; D050720:Retinoblastoma-Like Protein p107; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D016159:Tumor Suppressor Protein p53; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse