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Gene Expression Profiling Detects Gene Amplification and Differentiates Tumor Types in Breast Cancer

Clinical Pharmacogenetics Department, Novartis Pharmaceuticals Corporation, Gaithersburg, Maryland 20878 [M. A. D., A. B., R. M., L. B. A., I. K., M. H. P.], and Department of Biomedicine and Surgery, Division of Oncology, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden [T. M. Z.]

Global gene expression analysis using microarrays has been used to characterize the molecular profile of tumors. Gene expression variability at the mRNA level can be caused by a number of different events, including novel signaling, downstream activation of transcription enhancers or silencers, somatic mutation, and genetic amplification or deletion. Genomic amplifications are commonly observed in cancer and often include known oncogenes. The tyrosine kinase-type cell surface receptor, ERBB2, is an oncogene located on chromosome 17q21.1 that is amplified in 10–40% of breast tumors. We report for the first time that phenylethanolamine N-methyltransferase (PNMT), proteasome subunit, ß type 3 (PSMB3), ribosomal protein L19 (RPL19), and nuclear receptor subfamily 1, group D, member 1 (NR1D1) are coexpressed with ERBB2 in 34 breast cancer biopsies and also mapped within the same chromosomal location as the ERBB2 gene. Consistent with previous reports, we also observed that the steroidogenic acute regulatory protein-related gene, MLN64, and growth factor receptor bound protein 7 were coexpressed with ERBB2. Coexpression and colocalization of PNMT and MLN64 with ERBB2 suggested that the amplification of ERBB2 includes the chromosomal region harboring these genes. This hypothesis was validated in a subset of 12 biopsies. Gene amplification of ERBB2, PNMT, and MLN64 significantly correlated with increased mRNA gene expression (P < 0.05). These results suggest that gene expression profiling of breast biopsies may become a valuable method for adequately characterizing and choosing treatment modality for patients with breast cancer.

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