Torres-García Wandaliz, Domenech Maribella
Department of Industrial Engineering, University of Puerto Rico Mayagüez, Mayagüez, Puerto Rico.
Mol Biosyst. 2017 Nov 21;13(12):2615-2624. doi: 10.1039/c7mb00416h.
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.
刺猬信号通路（Hh）在多种癌症中已被证明处于过度激活状态。然而，活跃的Hh信号通路既可以促进也可以抑制肿瘤生长；因此，需要识别除主要经典Hh靶基因之外的标志物，以改善患者选择和对Hh抑制剂的临床反应结果。癌症相关成纤维细胞（CAFs）与肿瘤进展以及对Hh抑制剂的有益反应有关。因此，我们假设与Hh激活的CAFs相关的基因可用于对将从Hh抑制剂中获益的肿瘤进行分层。在这项研究中，我们评估了一个15基因指纹图谱，该图谱结合了与CAF表型相关的Hh和间充质基因，以根据聚类组之间的基因表达模式对乳腺癌亚型进行分析。使用随机森林模型和线性判别分析对约3800个癌症样本进行评估，以按亚型和治疗方法对乳腺癌进行分类。结果表明，Hh-间充质基因指纹图谱在基底样和腔面A型亚组中具有高度敏感和差异表达模式。Hh靶基因水平高的基底样样本的预后优于腔面A型样本。倾向于Hh信号通路抑制的腔面A型样本的总生存率和无病生存率更高，尤其是在没有激素治疗的情况下。Hh转录抑制因子GLI3和信号激活因子SMO是区分人类乳腺癌亚型中活跃Hh信号通路样本和Hh抑制剂耐药肿瘤的前两个基因。小窝蛋白-1（CAV1）是一种在CAFs中低表达的基因，与活跃的Hh信号通路以及腔面A型患者中活跃或不活跃Hh信号通路的生存曲线差异密切相关。我们的数据表明，CAV1是监测肿瘤中Hh抑制的重要基因，并支持在使用Hh抑制剂之前根据激素治疗状态进行进一步分层。
