Expression of ANRIL-Polycomb Complexes-CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value
Expression of ANRIL-Polycomb Complexes-CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value
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DOI：
10.1158/1541-7786.mcr-15-0418
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发表时间：
2016-07-01
影响因子：
5.2
通讯作者：
Bieche, Ivan
中科院分区：
文献类型：
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作者：
Meseure, Didier;Vacher, Sophie;Bieche, Ivan
ANRIL是一种长链非编码RNA（lncRNA），最近报道其在募集多梳抑制复合物PRC 2和PRC 1以调节p15/CDKN 2B-p16/CDKN 2A-p14/ARF基因簇的表达中具有直接作用。通过qRT-PCR在一个大的浸润性乳腺癌（IBC，n = 456）队列中评价ANRIL、EZH 2、SUZ 12、EED、JARID 2、CBX 7、BMI 1、p16、p15和p14/ARF基因的表达分析，并对CBX 7、EZH 2、p14、p15、p16、H3 K27 me 3和H3 K27 ac进行免疫组织化学（IHC）。我们观察到ANRIL（19.7%）和EZH 2（77.0%）在IBC中显著过表达，而CBX 7（39.7%）表达不足。这些基因之间的相关性，其表达模式，和几个经典的临床和病理参数，分子亚型，和患者的结果，以及与增殖，上皮间质转化，乳腺癌干细胞标志物。多因素分析显示，EZH 2/CBX 7联合状态是独立的预后因素（P = 0.001）。此外，几种miRNA与CBX 7低表达和EZH 2过表达负相关。这些数据证明了lncRNA ANRIL、几种miRNA、PRC 2/PRC 1亚基和p15/CDKN 2B-p16/CDKN 2A-p14/ARF基因座之间复杂的相互作用模式，并表明应将它们的表达一起考虑以评估抗肿瘤药物，特别是BET布罗莫结构域抑制剂。这项研究表明，在定义压抑性Polycomb的功能时，应考虑整体表达模式，而不是单个家族成员的表达复合物和治疗靶向潜力。（C）2016年AACR。
ANRIL, a long noncoding RNA (lncRNA), has recently been reported to have a direct role in recruiting polycomb repressive complexes PRC2 and PRC1 to regulate the expression of the p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster. Expression analysis of ANRIL, EZH2, SUZ12, EED, JARID2, CBX7, BMI1, p16, p15, and p14/ARF genes was evaluated in a large cohort of invasive breast carcinomas (IBC, n = 456) by qRT-PCR and immunohistochemistry (IHC) was performed on CBX7, EZH2, p14, p15, p16, H3K27me3, and H3K27ac. We observed significant overexpression in IBCs of ANRIL (19.7%) and EZH2 (77.0%) and an underexpression of CBX7 (39.7%). Correlations were identified between these genes, their expression patterns, and several classical clinical and pathologic parameters, molecular subtypes, and patient outcomes, as well as with proliferation, epithelial-mesenchymal transition, and breast cancer stem cell markers. Multivariate analysis revealed that combined EZH2/CBX7 status is an independent prognostic factor (P = 0.001). In addition, several miRNAs negatively associated with CBX7 underexpression and EZH2 overexpression. These data demonstrate a complex pattern of interactions between lncRNA ANRIL, several miRNAs, PRC2/PRC1 subunits, and p15/CDKN2B-p16/CDKN2A-p14/ARF locus and suggest that their expression should be considered together to evaluate antitumoral drugs, in particular the BET bromodomain inhibitors.Implications: This study suggests that the global pattern of expression rather than expression of individual family members should be taken into account when defining functionality of repressive Polycomb complexes and therapeutic targeting potential. (C)2016 AACR.