ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1

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
Author Summary Recent genome-wide analysis has revealed that the way in which genes are arranged on chromosomes and the conformation of these chromosomes are crucial for the regulation of gene expression. Reflecting this arrangement, clusters of genes which are regulated together have been discovered. We have identified a previously unreported transcriptional activity hub spanning ESR1, the gene encoding the important breast cancer biomarker oestrogen receptor. Genetic variants immediately upstream of ESR1 have recently been linked to breast cancer risk. We found that three open reading frames within this region are tightly co-expressed with ESR1. We investigated the function of these genes and discovered that one of these co-expressed genes, C6ORF211, affects proliferation in cultured cells and is correlated with proliferation in breast tumours. Another of the genes, C6ORF97, is negatively correlated with proliferation in breast tumours and predicts for outcome on the anti-oestrogen drug tamoxifen. These findings suggest that the genes could contribute to the phenotype associated with oestrogen-receptor positivity. In addition, they may be involved in the mechanism by which genetic variation in this region of the genome contributes to breast cancer susceptibility.