WR Miller, AA Larionov, L Renshaw, TJ Anderson, S White, J Murray, E Murray, G Hampton, JR Walker, S Ho, A Krause, DB Evans, JM Dixon
OBJECTIVE: The aim of the study was to identify changes in tumour expression profiling associated with short-term therapy of breast cancer patients with letrozole. EXPERIMENTAL DESIGN: Microarray analysis was performed on RNA extracted from paired tumour core biopsies taken before and after 14 days of treatment with letrozole (2.5 mg/daily) in 58 patients. Changes in expression profile were identified by three different approaches on the basis of frequency of changes, magnitude of changes and significance analysis of microarray. RESULTS: No single gene was consistently changed by therapy in all cases. Fifty-two genes, however, were downregulated and 36 upregulated in at least 45 of the 58 cases. In terms of quantitative change, 46 genes showed at least a median 1.5-fold change in expression. Significance analysis of microarray identified 62 genes that were significantly changed by therapy (P<0.0001, 56 downregulated and six upregulated). All three approaches showed that greater numbers of genes were downregulated rather than upregulated. Merging data produced a total of 143 genes, which were subject to gene ontology and cluster analysis. The ontology of the 91 downregulated genes showed that they were functionally associated with cell cycle progression, particularly mitosis. In contrast, upregulated genes were associated with organ development, connective tissue extracellular matrix regulation and inflammatory response. Cluster analysis segregated the patients into four groups differing in patterns of gene expression. CONCLUSION: Genes have been identified which either change markedly or consistently in breast cancer after 14 days treatment with letrozole. These are new important data in understanding letrozole's molecular mechanism of action in breast cancers.