Effects of Herceptin treatment on global gene expression patterns in HER2-amplified and nonamplified breast cancer cell lines.
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.