Steroid receptor coactivator 1 (SRC-1) interacts with nuclear receptors and other transcription factors (TFs) to initiate transcriptional networks and regulate downstream genes which enable the cancer cell to evade therapy and metastasise. Here we took a top-down discovery approach to map out the SRC-1 transcriptional network in endocrine resistant breast cancer. First, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) was employed to uncover new SRC-1 TF partners. Next, RNA sequencing (RNAseq) was undertaken to investigate SRC-1 TF target genes. Molecular and patient-derived xenograft studies confirmed STAT1 as a new SRC-1 TF partner, important in the regulation of a cadre of four SRC-1 transcription targets, NFIA, SMAD2, E2F7 and ASCL1. Extended network analysis identified a downstream 79 gene network, the clinical relevance of which was investigated in RNAseq studies from matched primary and local-recurrence tumours from endocrine resistant patients. We propose that SRC-1 can partner with STAT1 independently of the estrogen receptor to initiate a transcriptional cascade and control regulation of key endocrine resistant genes.

中文翻译：

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对SRC-1的网络分析揭示了一种新型的转录因子中枢，可调节耐内分泌的乳腺癌。

类固醇受体共激活因子1（SRC-1）与核受体和其他转录因子（TFs）相互作用以启动转录网络并调节下游基因，使癌细胞能够逃避治疗和转移。在这里，我们采用了自上而下的发现方法，以绘制出内分泌抗性乳腺癌中SRC-1转录网络的图谱。首先，采用内源蛋白（RIME）的快速免疫沉淀质谱法来发现新的SRC-1 TF伴侣。接下来，进行RNA测序（RNAseq）以研究SRC-1 TF靶基因。分子和患者来源的异种移植研究证实STAT1是新的SRC-1 TF伴侣，对调节四个SRC-1转录靶标NFIA，SMAD2，E2F7和ASCL1的干部非常重要。扩展网络分析确定了一个下游79基因网络，其临床相关性已在来自内分泌抗性患者的匹配原发和局部复发肿瘤的RNAseq研究中进行了研究。我们建议SRC-1可以独立于雌激素受体与STAT1结合，以启动转录级联反应并控制关键内分泌抗性基因的调控。