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

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

Research output: Contribution to journalArticle

210 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberaah4199
JournalScience
Volume355
Issue number6320
DOIs
StatePublished - Jan 6 2017
Externally publishedYes

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Androgen Antagonists
Prostatic Neoplasms
Neoplasm Metastasis
Epigenomics
Therapeutics
Mutation
Androgen Receptors
Gene Expression Profiling
Prostate
Neoplasms
Histology
Adenocarcinoma

ASJC Scopus subject areas

  • General

Cite this

Ku, S. Y., Rosario, S., Wang, Y., Mu, P., Seshadri, M., Goodrich, Z. W., ... Goodrich, D. W. (2017). Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science, 355(6320), [aah4199]. https://doi.org/10.1126/science.aah4199

Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. / Ku, Sheng Yu; Rosario, Spencer; Wang, Yanqing; Mu, Ping; Seshadri, Mukund; Goodrich, Zachary W.; Goodrich, Maxwell M.; Labbé, David P.; Gomez, Eduardo Cortes; Wang, Jianmin; Long, Henry W.; Xu, Bo; Brown, Myles; Loda, Massimo; Sawyers, Charles L.; Ellis, Leigh; Goodrich, David W.

In: Science, Vol. 355, No. 6320, aah4199, 06.01.2017.

Research output: Contribution to journalArticle

Ku, SY, Rosario, S, Wang, Y, Mu, P, Seshadri, M, Goodrich, ZW, Goodrich, MM, Labbé, DP, Gomez, EC, Wang, J, Long, HW, Xu, B, Brown, M, Loda, M, Sawyers, CL, Ellis, L & Goodrich, DW 2017, 'Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance', Science, vol. 355, no. 6320, aah4199. https://doi.org/10.1126/science.aah4199
Ku, Sheng Yu ; Rosario, Spencer ; Wang, Yanqing ; Mu, Ping ; Seshadri, Mukund ; Goodrich, Zachary W. ; Goodrich, Maxwell M. ; Labbé, David P. ; Gomez, Eduardo Cortes ; Wang, Jianmin ; Long, Henry W. ; Xu, Bo ; Brown, Myles ; Loda, Massimo ; Sawyers, Charles L. ; Ellis, Leigh ; Goodrich, David W. / Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. In: Science. 2017 ; Vol. 355, No. 6320.
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