Prolactin Pro-Differentiation Pathway in Triple Negative Breast Cancer: Impact on Prognosis and Potential Therapy.
Prolactin Pro-Differentiation Pathway in Triple Negative Breast Cancer: Impact on Prognosis and Potential Therapy.
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DOI：
10.1038/srep30934
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发表时间：
2016-08-02
影响因子：
4.6
通讯作者：
Ali S
中科院分区：
文献类型：
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作者：
López-Ozuna VM;Hachim IY;Hachim MY;Lebrun JJ;Ali S
三阴性乳腺癌（TNBC）是一种异质性疾病，临床结局差，缺乏靶向治疗。在这里，我们表明，催乳素（PRL）及其信号通路作为一个亚分类和预测促分化治疗TNBC。使用免疫组织化学和二氧化硅分析中的各种基因表达，我们观察到催乳素受体（PRLR）蛋白和mRNA水平在TNBC病例中下调。此外，检查PRLR基因表达与TNBC亚型（580例）的多基因的相关性，我们发现PRLR基因表达将TNBC患者细分为特征为上皮-管腔分化的新亚组（TNBC-PRLR）。重要的是，PRL信号通路组分的基因表达单独（PRL、PRLR、Jak 2和Stat 5a）或作为基因标签能够预测具有显著更好的生存结果的TNBC患者。由于PRL激素是一种可药物化的靶标，我们确定了PRL在TNBC生物学中的生物学作用。值得注意的是，在代表间充质或TNBC-PRLR亚组的TNBC细胞中PRL途径的恢复/激活导致上皮表型的诱导和肿瘤发生的抑制。总之，这些结果为TNBC分层和基于PRL通路激活的个性化治疗的开发提供了潜在的新模式。
Triple negative breast cancer (TNBC) is a heterogeneous disease associated with poor clinical outcome and lack of targeted therapy. Here we show that prolactin (PRL) and its signaling pathway serve as a sub-classifier and predictor of pro-differentiation therapy in TNBC. Using immunohistochemistry and various gene expression in silica analyses we observed that prolactin receptor (PRLR) protein and mRNA levels are down regulated in TNBC cases. In addition, examining correlation of PRLR gene expression with metagenes of TNBC subtypes (580 cases), we found that PRLR gene expression sub-classifies TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial-luminal differentiation. Importantly, gene expression of PRL signaling pathway components individually (PRL, PRLR, Jak2 and Stat5a), or as a gene signature is able to predict TNBC patients with significantly better survival outcomes. As PRL hormone is a druggable target we determined the biological role of PRL in TNBC biology. Significantly, restoration/activation of PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of epithelial phenotype and suppression of tumorigenesis. Altogether, these results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation.