Hedgehog signaling (Hh) has been shown to be hyper-activated in several cancers. However, active Hh signaling can promote or inhibit tumor growth; thus identification of markers beyond main canonical Hh target genes is needed to improve patient selection and clinical outcome in response to Hh inhibitors. Cancer-associated fibroblasts (CAFs) have been linked with tumor progression and beneficial response to Hh inhibitors. Thus, we hypothesized that genes associated with Hh-activated CAFs can be used for stratification of tumors that will benefit from Hh inhibitors. In this work, we evaluated a 15-gene fingerprint that combines Hh and mesenchymal genes associated with CAF phenotype to profile breast cancer sub-types based on gene expression patterns among clustered groups. About 3800 cancer samples were evaluated using random forest models and linear discriminant analysis to sort breast cancer by subtypes and therapeutic approach. The results showed that the Hh-mesenchyme gene fingerprint has a highly sensitive and differential expression pattern among basal and luminal A sub-groups. Basal samples with high levels of Hh target genes had better prognosis than luminal A samples. Luminal A samples with a tendency towards Hh signaling suppression had higher overall and disease-free survival rates particularly if deprived of hormone therapy. Hh transcriptional repressor GLI3 and signaling activator SMO were the top 2 genes for discriminating among samples with active Hh signaling in human breast cancer subtypes and Hh-inhibitor resistant tumors. Caveolin-1 (CAV1), a gene with low expression in CAFs, shows strong correlation with active Hh signaling and discrimination among survival curves in luminal A patients with active or inactive Hh signaling. Our data suggest that CAV1 is an important gene for monitoring Hh inhibition in tumors and support further stratification by hormone therapy status prior to use of Hh inhibitors.

中文翻译：

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刺猬间质基因签名确定管腔和基础乳腺癌亚型的双峰预后

刺猬信号（Hh）已被证明在几种癌症中被过度激活。但是，活跃的Hh信号传导可以促进或抑制肿瘤的生长。因此，需要鉴定主要的规范Hh靶基因以外的标记物，以改善对Hh抑制剂的反应和对患者的选择。癌症相关的成纤维细胞（CAF）已与肿瘤进展和对Hh抑制剂的有益反应相关。因此，我们假设与Hh活化的CAF相关的基因可用于对将从Hh抑制剂中受益的肿瘤进行分层。在这项工作中，我们评估了15个基因的指纹，该指纹结合了Hh和与CAF表型相关的间充质基因，以基于聚类组之间的基因表达模式来分析乳腺癌亚型。使用随机森林模型和线性判别分析对大约3800个癌症样品进行了评估，以按照亚型和治疗方法对乳腺癌进行分类。结果表明，Hh-间质基因指纹在基础和管腔A亚群之间具有高度敏感和差异表达模式。具有高Hh靶基因水平的基础样品比管腔A样品具有更好的预后。具有Hh信号抑制趋势的Luminal A样品具有更高的总体生存率和无病生存率，尤其是在缺乏激素治疗的情况下。Hh转录阻遏物GLI3和信号激活因子SMO是区分人类乳腺癌亚型和Hh抑制剂耐药肿瘤中具有活跃Hh信号的样品的前2个基因。Caveolin-1（CAV1），一种在CAF中低表达的基因，显示与活跃的Hh信号密切相关，并在具有活跃或不活跃的Hh信号的腔A患者中区分生存曲线。我们的数据表明，CAV1是监测肿瘤中Hh抑制的重要基因，并在使用Hh抑制剂之前通过激素治疗状态支持进一步分层。