TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer.
TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-18-0653
复制
发表时间：
2018-09-15
期刊：
影响因子：
--
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Blee AM;He Y;Yang Y;Ye Z;Yan Y;Pan Y;Ma T;Dugdale J;Kuehn E;Kohli M;Jimenez R;Chen Y;Xu W;Wang L;Huang H
PTEN和TP 53肿瘤抑制基因的缺失或突变与治疗抵抗性前列腺癌的谱系可塑性有关。在大约50%的前列腺癌中观察到致癌转录因子ERG的融合驱动的过表达，其中许多前列腺癌还具有PTEN和TP 53改变。然而，ERG在PTEN/TP 53改变的肿瘤的谱系可塑性中的作用尚不清楚。了解一个肿瘤内多个突变的集体效应对于对抗可塑性驱动的治疗耐药性至关重要。我们建立了Pten阴性/Trp 53突变/ERG过表达的前列腺癌小鼠模型，并将RNA测序与ERG染色质免疫沉淀测序（ChIP-seq）相结合，以确定在Pten/Trp 53改变的背景下由ERG调节的途径。我们研究了人前列腺癌细胞系、异种移植瘤和同种异体移植小鼠肿瘤对抗雄激素Enzalutamide和细胞周期蛋白依赖性激酶4和6（CDK 4/6）抑制剂Palbociclib的ERG依赖性敏感性。在TCGA、SU 2C和Beltran 2016年发表的患者队列和人体组织微阵列中评价了趋势。转基因ERG在小鼠中的表达阻断Pten/Trp 53改变诱导的AR表达和下游管腔上皮基因的减少。ERG直接抑制细胞周期相关基因的表达，从而诱导RB磷酸化不足并抑制E2 F1介导的间充质谱系调节因子的表达，从而限制腺癌的可塑性并维持抗雄激素敏感性。在ERG阴性肿瘤中，CDK 4/6抑制延迟肿瘤生长。我们的研究确定了以前未定义的ERG功能，限制谱系可塑性和维持抗雄激素敏感性的PTEN/TP 53改变的前列腺癌。我们的研究结果表明，ERG融合作为一种生物标志物，以指导治疗PTEN/TP 53改变，RB 1完整的前列腺癌。
Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN/TP53-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance. We generated a Pten-negative/Trp53-mutated/ERG-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin-immunoprecipitation sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of Pten/Trp53 alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin dependent kinases 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray. Transgenic ERG expression in mice blocked Pten/Trp53 alteration-induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle-related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth. Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in PTEN/TP53-altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of PTEN/TP53-altered, RB1-intact prostate cancer.