Increased Expression of a Set of Genes Enriched in Oxygen Binding Function Discloses a Predisposition of Breast Cancer Bone Metastases to Generate Metastasis Spread in Multiple Organs
Increased Expression of a Set of Genes Enriched in Oxygen Binding Function Discloses a Predisposition of Breast Cancer Bone Metastases to Generate Metastasis Spread in Multiple Organs
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DOI：
10.1002/jbmr.1686
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发表时间：
2012-11-01
影响因子：
6.2
通讯作者：
Rucci, Nadia
中科院分区：
文献类型：
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作者：
Capulli, Mattia;Angelucci, Adriano;Rucci, Nadia
骨是乳腺癌（BrCa）远处转移的首选部位。局限于骨转移（BO）的患者通常比迅速发展为肝和肺多发转移的患者总体生存期更长。因此，产生骨和内脏转移（BV）的分子易感是不良临床结果的明确指示。我们使用Affymetrix和Agilent两种不同的芯片平台对BO和BV患者的骨转移样本进行了微阵列分析。由此产生的转录组的无监督分层聚类与临床进展相关，将BO从BV谱中分离出来。匹配Affymetrix和Agilent芯片的双重显著调控基因，在BV和BO骨转移样本中发现了15个基因特征，其中13个基因上调，2个基因下调。为了验证结果的特征，我们分离了不同的MDA-MB-231克隆亚群，这些克隆亚群只转移到骨（MDA-BO）或骨和内脏组织（MDA-BV）。与MDA-BO克隆相比，MDA-BV中6个特征基因也显著上调。包括血红蛋白B （HBB）在内的一组上调基因参与氧代谢，HBB的体外功能分析显示，其在MDA亚群中的表达与过氧化氢的产生减少有关。在原代BrCa组织中检测到HBB的表达，但在正常乳腺上皮细胞中未检测到。与相应的原发肿瘤相比，转移淋巴结中HBB的阳性表达往往更高，而BO转移的表达低于BV转移，这表明HBB与骨转移迅速扩散到其他器官的能力呈正相关。我们认为，HBB与其他参与氧代谢的基因一起，赋予了BrCa细胞弥散到骨的更具攻击性的转移表型。(C) 2012年美国骨与矿物研究学会。
Bone is the preferential site of distant metastasis in breast carcinoma (BrCa). Patients with metastasis restricted to bone (BO) usually show a longer overall survival compared to patients who rapidly develop multiple metastases also involving liver and lung. Hence, molecular predisposition to generate bone and visceral metastases (BV) represents a clear indication of poor clinical outcome. We performed microarray analysis with two different chip platforms, Affymetrix and Agilent, on bone metastasis samples from BO and BV patients. The unsupervised hierarchical clustering of the resulting transcriptomes correlated with the clinical progression, segregating the BO from the BV profiles. Matching the twofold significantly regulated genes from Affymetrix and Agilent chips resulted in a 15-gene signature with 13 upregulated and two downregulated genes in BV versus BO bone metastasis samples. In order to validate the resulting signature, we isolated different MDA-MB-231 clonal subpopulations that metastasize only in the bone (MDA-BO) or in bone and visceral tissues (MDA-BV). Six of the signature genes were also significantly upregulated in MDA-BV compared to MDA-BO clones. A group of upregulated genes, including Hemoglobin B (HBB), were involved in oxygen metabolism, and in vitro functional analysis of HBB revealed that its expression in the MDA subpopulations was associated with a reduced production of hydrogen peroxide. Expression of HBB was detected in primary BrCa tissue but not in normal breast epithelial cells. Metastatic lymph nodes were frequently more positive for HBB compared to the corresponding primary tumors, whereas BO metastases had a lower expression than BV metastases, suggesting a positive correlation between HBB and ability of bone metastasis to rapidly spread to other organs. We propose that HBB, along with other genes involved in oxygen metabolism, confers a more aggressive metastatic phenotype in BrCa cells disseminated to bone. (C) 2012 American Society for Bone and Mineral Research.