Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner.
Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner.
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Wnt-β-catenin途径在三阴性乳腺癌中的差异激活以PTEN依赖性方式增加了MMP7。
DOI：
10.1371/journal.pone.0077425
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Leyland-Jones B
中科院分区：
文献类型：
--
作者：
Dey N;Young B;Abramovitz M;Bouzyk M;Barwick B;De P;Leyland-Jones B
乳腺癌三阴性亚群（TNBC）肿瘤细胞中基因突变导致信号转导通路失调。肿瘤抑制基因PTEN的缺失是与基底样亚型相关的最常见的首发事件（Martins, De, Almendro, Gonen, and Park, 2012）。本研究首次报道了TNBC中Wnt-β-catenin信号通路的转录靶点分泌的mmp7的功能上调与PTEN的缺失有关。我们在两个独立队列TNBC患者的FFPE肿瘤样本中发现了Wnt-β-catenin通路（WP）的几个关键成分基因和转录靶基因的mrna表达差异，包括β-catenin、FZD7、DVL1、MMP7、c-MYC、BIRC5、CD44、PPARD、c-MET和NOTCH1。在TNBC细胞系模型中，β -catenin、WP的功能读数和β -catenin的转录靶基因MMP7的mRNA/蛋白也出现了类似的差异上调。在LY294002处理后，SiRNA或WP调节剂（XAV939和sulindac sulfide）对β -连环蛋白的遗传或药理学衰减以及PTEN的药理学模拟下调了MMP7水平以及MMP7阳性PTEN缺失TNBC细胞中分泌的MMP7的酶促功能。患者数据显示，MMP7 mRNA仅在TNBC的一个亚群中高表达，而该亚群的特征是PTEN mRNA同时低表达。在细胞系中，酪蛋白酶谱阳性的MMP7的高表达被区分为功能性PTEN的缺失。在PAM50数据集中，MMP7和PTEN mRNA水平之间也存在类似的负相关关系（相关系数为-0.54）。PAM50亚型和结果数据显示，与低MMP7组的高pCR（40%）和低残留病（Rd）（60%）相比，高MMP7组在临床T3期病理反应中具有低pCR（25%）和高Rd（74%）。
Mutations of genes in tumor cells of Triple Negative subset of Breast Cancer (TNBC) deregulate pathways of signal transduction. The loss of tumor suppressor gene PTEN is the most common first event associated with basal-like subtype (Martins, De, Almendro, Gonen, and Park, 2012). Here we report for the first time that the functional upregulation of secreted-MMP7, a transcriptional target of Wnt-β-catenin signature pathway in TNBC is associated to the loss of PTEN. We identified differential expression of mRNAs in several key-components genes, and transcriptional target genes of the Wnt-β-catenin pathway (WP), including beta-catenin, FZD7, DVL1, MMP7, c-MYC, BIRC5, CD44, PPARD, c-MET, and NOTCH1 in FFPE tumors samples from TNBC patients of two independent cohorts. A similar differential upregulation of mRNA/protein for beta-catenin, the functional readout of WP, and for MMP7, a transcriptional target gene of beta-catenin was observed in TNBC cell line models. Genetic or pharmacological attenuation of beta-catenin by SiRNA or WP modulators (XAV939 and sulindac sulfide) and pharmacological mimicking of PTEN following LY294002 treatment downregulated MMP7 levels as well as enzymatic function of the secreted MMP7 in MMP7 positive PTEN-null TNBC cells. Patient data revealed that MMP7 mRNA was high in only a subpopulation of TNBC, and this subpopulation was characterized by a concurrent low expression of PTEN mRNA. In cell lines, a high expression of casein-zymograph-positive MMP7 was distinguished by an absence of functional PTEN. A similar inverse relationship between MMP7 and PTEN mRNA levels was observed in the PAM50 data set (a correlation coefficient of -0.54). The PAM50 subtype and outcome data revealed that the high MMP7 group had low pCR (25%) and High Rd (74%) in clinical stage T3 pathologic response in contrast to the high pCR (40%) and low residual disease (RD) (60%) of the low MMP7 group.
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