Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.
Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.
复制标题
DOI：
10.1126/science.aah4199
复制
发表时间：
2017-01-06
期刊：
影响因子：
--
通讯作者：
Goodrich DW
中科院分区：
文献类型：
--
作者：
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
抗雄激素治疗复发的前列腺癌可能表现出组织学变异，谱系标记物表达发生改变，这表明谱系可塑性促进了治疗耐药性。前列腺癌谱系可塑性的潜在机制尚不完全清楚。通过研究小鼠模型，我们证明 Rb1 缺失促进 Pten 突变引发的前列腺腺癌的谱系可塑性和转移。 Trp53 的额外损失会导致抗雄激素治疗产生抵抗。基因表达谱表明小鼠肿瘤与人类前列腺癌神经内分泌变异相似；小鼠和人类肿瘤均表现出 Ezh2 和 Sox2 等表观遗传重编程因子表达增加。临床相关的 Ezh2 抑制剂可恢复雄激素受体表达和对抗雄激素治疗的敏感性。这些发现揭示了导致前列腺癌进展的基因突变；确定用于研究前列腺癌谱系可塑性的小鼠模型；并提出了一种表观遗传学方法来延长抗雄激素治疗的临床反应。
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.