Jun 缺失促进了腔乳腺癌中 Myc 信号对组蛋白去乙酰化酶抑制剂恩替诺特的耐药性。
Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer.
机构信息
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.
出版信息
Genome Med. 2018 Nov 30;10(1):86. doi: 10.1186/s13073-018-0597-3.
BACKGROUND
Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. Predictors of sensitivity and resistance, however, remain unknown.
METHODS
A total of eight cell lines and nine mouse models of breast cancer were treated with entinostat. Luminal cell lines were treated with or without entinostat at their IC doses, and MMTV/Neu luminal mouse tumors were untreated or treated with entinostat until progression. We investigated these models using their gene expression profiling by microarray and copy number by arrayCGH. We also utilized the network-based DawnRank algorithm that integrates DNA and RNA data to identify driver genes of resistance. The impact of candidate drivers was investigated in The Cancer Genome Atlas and METABRIC breast cancer datasets.
RESULTS
Luminal models displayed enhanced sensitivity to entinostat as compared to basal-like or claudin-low models. Both in vitro and in vivo luminal models showed significant downregulation of Myc gene signatures following entinostat treatment. Myc gene signatures became upregulated on tumor progression in vivo and overexpression of Myc conferred resistance to entinostat in vitro. Further examination of resistance mechanisms in MMTV/Neu tumors identified a portion of mouse chromosome 4 that had DNA copy number loss and low gene expression. Within this region, Jun was computationally identified to be a driver gene of resistance. Jun knockdown in cell lines resulted in upregulation of Myc signatures and made these lines more resistant to entinostat. Jun-deleted samples, found in 17-23% of luminal patients, had significantly higher Myc signature scores that predicted worse survival.
CONCLUSIONS
Entinostat inhibited luminal breast cancer through Myc signaling, which was upregulated by Jun DNA loss to promote resistance to entinostat in our models. Jun DNA copy number loss, and/or high MYC signatures, might represent biomarkers for entinostat responsiveness in luminal breast cancer.
背景
基于有前景的二期数据，组蛋白去乙酰化酶抑制剂恩替诺特正在进行转移性雌激素受体阳性乳腺癌患者的三期临床试验。然而，敏感性和耐药性的预测因素仍然未知。
方法
共对 8 种细胞系和 9 种乳腺癌小鼠模型进行了恩替诺特治疗。腔细胞系在其 IC 剂量下用或不用恩替诺特治疗，MMTV/Neu 腔乳腺癌小鼠肿瘤未经处理或用恩替诺特治疗直至进展。我们使用微阵列的基因表达谱和 arrayCGH 的拷贝数对这些模型进行了研究。我们还利用基于网络的 DawnRank 算法，该算法整合 DNA 和 RNA 数据来识别耐药的驱动基因。在 The Cancer Genome Atlas 和 METABRIC 乳腺癌数据集上研究了候选驱动基因的影响。
结果
与基底样或 Claudin-low 模型相比，腔模型对恩替诺特的敏感性增强。在体外和体内腔模型中，恩替诺特治疗后 Myc 基因谱明显下调。Myc 基因谱在体内肿瘤进展中上调，Myc 过表达使体外对恩替诺特产生耐药性。在 MMTV/Neu 肿瘤中进一步研究耐药机制时，发现部分小鼠染色体 4 存在 DNA 拷贝数丢失和低基因表达。在该区域内，Jun 被计算为耐药的驱动基因。在细胞系中敲低 Jun 导致 Myc 谱上调，并使这些细胞系对恩替诺特更具耐药性。在 17-23%的腔型患者中发现的 Jun 缺失样本具有明显更高的 Myc 谱评分，这预示着预后更差。
结论
恩替诺特通过 Myc 信号通路抑制腔型乳腺癌，而 Jun DNA 缺失通过上调 Myc 信号通路促进了我们模型中对恩替诺特的耐药性。Jun DNA 拷贝数丢失和/或高 MYC 谱可能代表腔型乳腺癌对恩替诺特反应的生物标志物。
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