Abstract P4-02-03: Gene Copy Number Alterations Related to mRNA and miRNA Expression in Endocrine Resistant Breast Cancers

Abstract

Background Endocrine resistance is a major clinical issue in breast cancer. Multiple studies provide data relating molecular features of primary tumours on their response to endocrine treatment. However, there is a paucity of data on molecular profiles of breast tumours at time when endocrine resistance has already manifested. Aim Provide multilayer molecular profiling of a series of breast tumours at time of relapse or progression on endocrine treatment. Results High density microarray-comparative genomic hybridisation (aCGH) analysis was performed in 39 endocrine treated breast tumours at time of progression or relapse. 25 of these tumours were also profiled using whole genome mRNA and miRNA arrays (HT-12 mRNA array and DASL Sentrix Array Matrix micro-RNA array, Illumina). Overall the aCGH profiles of resistant tumours were similar to aCGH profiles of un-selected luminal breast tumours and cell lines published earlier. The most common gene copy gain areas (>10M of length) were located in 1q23.1-44, 5p13.1-33, 8p11.23-q24.3, 16p12.1-13.3, 17q21.33-24.1 and 20q13.2-13.33, while the most common losses were in 1p33-36.32, 8p12-23.3, 11q22.3-24.1, 16q12.2-24.3 and 17p11.2-13.3. Unsupervised hierarchical clustering by gene copy number profiles split of the resistant tumours into 3 groups. As expected, on average mRNAs and microRNAs were higher expressed in tumours carrying gains of their genes and were decreased in tumours carrying the losses. Copy number gains in this series were associated with the upregulation of multiple RNAs, including C8orf76, TATDN1, CYC1, ZBTB10, C16orf63, THUMPD1, TFB2M, miR-454, miR-301a and miR-296-3p/5p. Losses were associated with the downregulation of RNAs including ACADVL, BNIP3L, UBE4A, REXO2, ATP5L, PPP2CB, NBL1 and PCM1. Of the above genes UBE4A and ATP5L are closely co-localised in 11q23.3; miR454-miR301a are located closely in 17q22. Such associations suggest that changes in expression of these genes in breast cancers may be driven by alterations in the gene copy number. Analysis of the recurrent amplification regions on this dataset is underway. Conclusions aCGH profiles of endocrine resistant tumours at time of relapse or progression are similar to those found in un-selected and non-treated luminal tumours. The study provides the first dataset integrating gene copy number with mRNA and microRNA gene expressions in clinical specimens of endocrine resistant breast cancers. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-03.