Glucocorticoids promote breast cancer metastasis
Glucocorticoids promote breast cancer metastasis
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DOI：
10.1038/s41586-019-1019-4
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发表时间：
2019-03-28
期刊：
影响因子：
64.8
通讯作者：
Bentires-Alj, Mohamed
中科院分区：
文献类型：
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作者：
Obradovic, Milan M. S.;Hamelin, Baptiste;Bentires-Alj, Mohamed
在疾病进展过程中出现的肿瘤和转移瘤内部或之间的多样性（称为患者内肿瘤异质性）是治疗的严重障碍（1-3）。转移是癌症的致命标志，而作为转移级联反应中最复杂步骤的定殖机制（4）仍不清楚。更清楚地了解患者体内肿瘤异质性和转移的细胞和分子过程对于个性化癌症治疗的成功至关重要。在这里，使用肿瘤的转录谱和小鼠患者来源的异种移植模型中的匹配转移，我们显示了癌症位点特异性表型和远处转移中糖皮质激素受体活性的增加。糖皮质激素受体介导应激激素和这些激素的合成衍生物的作用，这些激素的合成衍生物在临床上广泛用作抗炎剂和免疫抑制剂。我们发现，乳腺癌进展过程中应激激素的增加导致远处转移部位糖皮质激素受体的激活，增加定植和降低生存率。我们的转录组学、蛋白质组学和磷酸化蛋白质组学研究表明，糖皮质激素受体参与了转移中多个过程的激活和激酶ROR 1表达的增加，这两者都与生存率降低相关。在临床前模型中，ROR 1的消融减少了转移性生长并延长了生存期。我们的研究结果表明，糖皮质激素受体的激活增加了异质性和转移，这表明在使用糖皮质激素治疗已发生癌症相关并发症的乳腺癌患者时需要谨慎。
Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy(1-3). Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade(4), remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.