1. ¹Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33520 Tampere, Finland
2. ²Institute of Signal Processing, Tampere University of Technology, FIN-33101 Tampere, Finland
3. ³Biomedicum Biochip Center, University of Helsinki, Biomedicum Helsinki, FIN-00290 Helsinki, Finland
4. ⁴Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA

Correspondence: A Kallioniemi, E-mail: anne.kallioniemi@uta.fi

Received 26 May 2003; Revised 2 September 2003; Accepted 10 September 2003; Published online 1 December 2003.

Abstract

Herceptin is a humanized monoclonal antibody targeted against the extracellular domain of the HER2 oncogene, which is amplified and overexpressed in 10–34% of breast cancers. Herceptin therapy provides effective treatment in HER2-positive metastatic breast cancer, although a favorable treatment response is not achieved in all cases. Here, we show that Herceptin treatment induces a dose-dependent growth reduction in breast cancer cell lines with HER2 amplification, whereas nonamplified cell lines are practically resistant. Time-course analysis of global gene expression patterns in amplified and nonamplified cell lines indicated a major change in transcript levels between 24 and 48 h of Herceptin treatment. A step-wise gene selection algorithm revealed a set of 439 genes whose temporal expression profiles differed most between the amplified and nonamplified cell lines. The discriminatory power of these genes was confirmed by both hierarchical clustering and self-organizing map analyses. In the amplified cell lines, the Herceptin treatment induced the expression of several genes involved in RNA processing and DNA repair, while cell adhesion mediators and known oncogenes, such as c-FOS and c-KIT, were downregulated. These results provide additional clues to the downstream effects of blocking the HER2 pathway in breast cancer and may provide new targets for more effective treatment.