Abstract
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.
Highlights
Breast cancer is the most common malignancy in women, accounting for more than 400,000 deaths per year worldwide [1]
Zheng et al found that heterozygosity at rs2046210, a single nucleotide polymorphisms (SNPs) in the region between C6ORF97 and ESR1, increased breast cancer risk by an odds ratio of 1.59 in a Chinese population and that this risk was present in a European population, albeit to a weaker extent [6]
We found that three open reading frames within this region are tightly co-expressed with ESR1
Summary
Breast cancer is the most common malignancy in women, accounting for more than 400,000 deaths per year worldwide [1]. 80% of human breast carcinomas present as oestrogen receptor a-positive (ER+ve) disease and ER status is arguably the most clinically important biological factor in all oncology [2]. Recent genome wide studies have identified SNPs around C6ORF97, an open reading frame (ORF) immediately upstream of the gene encoding ER (ESR1) to be associated with increased risk of breast cancer. Zheng et al found that heterozygosity at rs2046210, a SNP in the region between C6ORF97 and ESR1, increased breast cancer risk by an odds ratio of 1.59 in a Chinese population and that this risk was present in a European population, albeit to a weaker extent [6]. Our studies have revealed unexpected relationships in the expression patterns in breast carcinomas between ESR1, C6ORF97 and the two genes immediately upstream (C6ORF211 and C6ORF96 [RMND1])
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