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

Autor: Zara Ghazoui, Sunil Pancholi, Anita K. Dunbier, Suzanne Drury, Lesley-Ann Martin, Kally Sidhu, Elena Lopez-Knowles, Ricardo Ribas, Helen Anderson, Mitch Dowsett, Alexandra Leary
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Transcriptional Activation
Cancer Research
Single-nucleotide polymorphism
Breast Neoplasms
Biology
QH426-470
Open Reading Frames
Breast cancer
Aromatase
Cell Line
Tumor
Gene expression
medicine
Genetics
Humans
ORFS
RNA
Small Interfering
Molecular Biology
Gene
Genetics and Genomics/Cancer Genetics
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
Genetics and Genomics/Genetics of Disease
Aromatase Inhibitors
Estrogen Antagonists
Estrogen Receptor alpha
Genetics and Genomics/Gene Expression
Genetics and Genomics/Bioinformatics
medicine.disease
Molecular biology
Gene Expression Regulation
Neoplastic
Genetics and Genomics/Gene Function
Genetic Loci
Gene Knockdown Techniques
Oncology/Breast Cancer
biology.protein
Chromosomes
Human
Pair 6
Female
DNA microarray
Estrogen receptor alpha
Research Article
Zdroj: PLoS Genetics, Vol 7, Iss 4, p e1001382 (2011)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: 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.
Databáze: OpenAIRE
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