Genes Regulated by miRNA in Endocrine-Resistant Breast Tumours.

Abstract

Abstract RationaleChange in genes expression is one of the major molecular drivers of tumour growth. Mechanisms controlling genes expression include transcriptional factors, mutations, aberrations in gene copy number, epigenetic mechanisms and micro-RNA (miRNA) regulation. The last mechanism has been discovered recently and there is a need to investigate its involvement in genes regulation in endocrine resistant breast tumours.Methods and ResultsTo identify genes regulated by miRNA in endocrine resistant breast tumours we collected frozen biopsies from a series of 51 tumours growing on endocrine treatment (aromatase inhibitors or tamoxifen, post-menopausal patients). Gene expression profiles were obtained using Illumina HT-12 micro-arrays; miRNA expression profiles were obtained using Illumina DASL® Sentrix Array Matrix.Unsupervised hierarchical clustering using 50 most variable miRNAs split tumours into two major clusters (25 and 26 tumours each). We suggest that genes differentially expressed between these two clusters can be potentially regulated by miRNA. The top differentially expressed genes included SAA1, VTCN1, SLC40A1, FBLN1, COL17A1, HDC and CD59.An alternative bioinformatics approach was based on correlations between mRNA and miRNA in the studied tumours. Initially we identified 66 genes negatively correlated with at least one miRNA (r<-0.6). Then we screened the correlated pairs to identify those in which miRNA has target sequence within the corresponding gene. This approach yielded just 2 genes: RAG1 and USP19: RAG1 being potentially regulated by mir92 and USP19 regulated by miR15a.DiscussionEndocrine resistance is a major obstacle in treatment of many breast cancer patients. Molecular mechanisms of the resistance are yet unclear. The abstract presents a sub-group analysis within a larger study, aimed to investigate molecular mechanisms underlying endocrine resistance at both mRNA and miRNA levels. Most of the identified potential miRNA-regulated genes have not been previously reported in the context of breast cancer biology. On our knowledge, this study represents the first systematic attempt to identify genes regulated by miRNA in endocrine-resistant breast cancers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5149.