Expression of Nestin associates with BRCA1 mutations, a basal-like phenotype and aggressive breast cancer.
Expression of Nestin associates with BRCA1 mutations, a basal-like phenotype and aggressive breast cancer.
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DOI：
10.1038/s41598-017-00862-w
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发表时间：
2017-04-24
影响因子：
4.6
通讯作者：
Akslen LA
中科院分区：
文献类型：
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作者：
Krüger K;Wik E;Knutsvik G;Nalwoga H;Klingen TA;Arnes JB;Chen Y;Mannelqvist M;Dimitrakopoulou K;Stefansson IM;Birkeland E;Aas T;Tobin NP;Jonassen I;Bergh J;Foulkes WD;Akslen LA
我们通过蛋白质和mRNA水平研究了Nestin是否可以作为BRCA1相关乳腺癌、基底样表型和侵袭性肿瘤的预测因子。在独立的乳腺癌医院队列（系列I-V，共1257例）中进行Nestin的免疫组织化学染色。此外，还分析了TCGA蛋白质组学数据（n = 103）、TCGA mRNA微阵列数据（n = 520）、METABRIC （n = 1992）和6个开放获取乳腺癌数据集（n = 1908）。肿瘤细胞中Nestin蛋白表达的患者更常发生BRCA1种系突变（OR 8.7, p < 0.0005, Series III），尤其是年轻患者（诊断时<40岁）（OR 16.5, p = 0.003）。在我院9-28%的病例（I-IV系列）中观察到Nestin蛋白阳性与乳腺癌特异性生存率降低独立相关（HR = 2.0, p = 0.035），并与基底样分化一致（通过细胞角蛋白5，OR 8.7-13.8, p < 0.0005; p -cadherin OR 7.0-8.9, p < 0.0005； EGFR染色，OR 3.7-8.2, p≤0.05）。Nestin mRNA与Nestin蛋白表达显著相关（ρ = 0.6, p < 0.0005），且在基底样内征亚型中表达水平较高。研究人员探索了与高Nestin相关的基因表达信号通路，并揭示了与茎样肿瘤特征的关联。总之，Nestin与种系BRCA1相关乳腺癌、基底样表型、生存率降低和干性特征密切相关。
We here examined whether Nestin, by protein and mRNA levels, could be a predictor of BRCA1 related breast cancer, a basal-like phenotype, and aggressive tumours. Immunohistochemical staining of Nestin was done in independent breast cancer hospital cohorts (Series I-V, total 1257 cases). Also, TCGA proteomic data (n = 103), mRNA microarray data from TCGA (n = 520), METABRIC (n = 1992), and 6 open access breast cancer datasets (n = 1908) were analysed. Patients with Nestin protein expression in tumour cells more often had BRCA1 germline mutations (OR 8.7, p < 0.0005, Series III), especially among younger patients (<40 years at diagnosis) (OR 16.5, p = 0.003). Nestin protein positivity, observed in 9–28% of our hospital cases (Series I-IV), was independently associated with reduced breast cancer specific survival (HR = 2.0, p = 0.035) and was consistently related to basal-like differentiation (by Cytokeratin 5, OR 8.7–13.8, p < 0.0005; P-cadherin OR 7.0–8.9, p < 0.0005; EGFR staining, OR 3.7–8.2, p ≤ 0.05). Nestin mRNA correlated significantly with Nestin protein expression (ρ = 0.6, p < 0.0005), and high levels were seen in the basal-like intrinsic subtype. Gene expression signalling pathways linked to high Nestin were explored, and revealed associations with stem-like tumour features. In summary, Nestin was strongly associated with germline BRCA1 related breast cancer, a basal-like phenotype, reduced survival, and stemness characteristics.