Royal Marsden Hospital, London, United Kingdom.
PLoS Genet. 2011 Apr;7(4):e1001382. doi: 10.1371/journal.pgen.1001382. Epub 2011 Apr 28.
Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast cancer risk. Our investigation of factors associated with the level of expression of ESR1 in ER+ve tumours has revealed unexpected associations between genes in this region and ESR1 expression that are important to consider in studies of the genetic causes of breast cancer risk. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with an aromatase (oestrogen synthase) inhibitor was analyzed on Illumina 48K microarrays. Multiple-testing corrected Spearman correlation revealed that three previously uncharacterized open reading frames (ORFs) located immediately upstream of ESR1, C6ORF96, C6ORF97, and C6ORF211 were highly correlated with ESR1 (Rs = 0.67, 0.64, and 0.55 respectively, FDR<1 × 10(-7)). Publicly available datasets confirmed this relationship in other groups of ER+ve tumours. DNA copy number changes did not account for the correlations. The correlations were maintained in cultured cells. An ERα antagonist did not affect the ORFs' expression or their correlation with ESR1, suggesting their transcriptional co-activation is not directly mediated by ERα. siRNA inhibition of C6ORF211 suppressed proliferation in MCF7 cells, and C6ORF211 positively correlated with a proliferation metagene in tumours. In contrast, C6ORF97 expression correlated negatively with the metagene and predicted for improved disease-free survival in a tamoxifen-treated published dataset, independently of ESR1. Our observations suggest that some of the biological effects previously attributed to ER could be mediated and/or modified by these co-expressed genes. The co-expression and function of these genes may be important influences on the recently identified relationship between SNPs in this region and breast cancer risk.
大约 80%的人类乳腺癌呈雌激素受体 α 阳性（ER+ve）疾病，而 ER 状态是治疗决策的关键因素。最近，位于 6q25.1 上 ER 基因（ESR1）上游区域的单核苷酸多态性（SNP）与乳腺癌风险相关。我们对与 ER+ve 肿瘤中 ESR1 表达水平相关的因素的研究揭示了该区域基因与 ESR1 表达之间的意外关联，这些关联在研究乳腺癌风险的遗传原因时需要考虑。对 104 名绝经后妇女在接受芳香酶（雌激素合成酶）抑制剂治疗前和治疗后 2 周的肿瘤活检组织进行了 RNA 分析，使用 Illumina 48K 微阵列进行分析。经多重检验校正的 Spearman 相关分析显示，位于 ESR1 上游的三个先前未描述的开放阅读框（ORF），C6ORF96、C6ORF97 和 C6ORF211 与 ESR1 高度相关（Rs 分别为 0.67、0.64 和 0.55，FDR<1×10(-7)）。来自其他 ER+ve 肿瘤组的公共数据集证实了这种关系。DNA 拷贝数变化并不能解释这些相关性。在培养的细胞中，这种相关性仍然存在。ERα 拮抗剂不影响 ORF 的表达或它们与 ESR1 的相关性，这表明它们的转录共激活不是直接由 ERα 介导的。C6ORF211 的 siRNA 抑制抑制了 MCF7 细胞的增殖，并且 C6ORF211 与肿瘤中的增殖元正相关。相比之下，C6ORF97 的表达与元负相关，并在一个接受他莫昔芬治疗的已发表数据集独立于 ESR1 预测疾病无进展生存。我们的观察结果表明，先前归因于 ER 的一些生物学效应可能由这些共表达的基因介导和/或修饰。这些基因的共表达和功能可能对该区域的 SNP 与乳腺癌风险之间最近发现的关系产生重要影响。
