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

被引：794

作者：

Ku, Sheng Yu ^{[1
]}

Rosario, Spencer ^{[1
,11
]}

Wang, Yanqing ^{[1
,5
]}

Mu, Ping ^{[2
]}

Seshadri, Mukund ^{[1
,7
,8
]}

Goodrich, Zachary W. ^{[1
,4
]}

Goodrich, Maxwell M. ^{[1
,5
]}

Labbe, David P. ^{[3
,4
,6
,7
,11
]}

Gomez, Eduardo Cortes ^{[8
,9
]}

Wang, Jianmin ^{[4
,8
,9
]}

Long, Henry W.

Xu, Bo ^{[6
,11
]}

Brown, Myles

Loda, Massimo ^{[7
,10
,11
]}

Sawyers, Charles L.

Ellis, Leigh ^{[1
]}

Goodrich, David W. ^{[1
]}

机构：

[1] RPCI, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA

[2] MSKCC, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[3] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[5] RPCI, Dept Biostat & Bioinformat, Buffalo, NY 14263 USA

[6] RPCI, Dept Pathol, Buffalo, NY 14263 USA

[7] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, Boston, MA 02115 USA

[8] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA

[9] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[10] Kings Coll London, Div Canc Studies, London SE1 9RT, England

[11] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

SCIENCE | 2017年 / 355卷 / 6320期

关键词：

SMALL-CELL CARCINOMA; MOUSE MODEL; PTEN; TUMORIGENESIS; DEFICIENCY; EXPRESSION; GENERATION; DELETION; PATHWAY; EZH2;

D O I：

10.1126/science.aah4199

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：78 / 83

页数：6

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