Activation of multiple cancer-associated genes at the ERBB2 amplicon in breast cancer

During the past decade the role of the ERBB2 (neu/HER2) oncogene as an important predictor of patient outcome and response to various therapies in breast cancer has been clearly established. This association of ERBB2 aberrations with more aggressive disease and poor clinical outcome, together with the high prevalence of such alterations in breast cancer, has also made ERBB2 an attractive target for therapy. A specific antibody-based therapy, Herceptin, directed against the extracellular domain of the ERBB2 receptor tyrosine kinase, was recently developed and several clinical trials have shown the therapeutic efficacy of this drug against ERBB2-positive breast cancer. However, a relatively large fraction of patients does not benefit from Herceptin treatment, indicating that other factors beyond ERBB2 itself must influence therapy response in ERBB2-positive tumors. It is well known that amplification of the 17q12-q21 region is the most common mechanism for ERBB2 activation in breast cancer and that it leads to simultaneous activation of several other genes. These co-amplified and co-activated genes may have an impact on disease progression and the clinical behavior of ERBB2-positive tumors and thus represent important targets of research. In this paper we discuss the current knowledge on the structure of the ERBB2 amplicon, the genes involved, and their possible contribution to breast cancer pathogenesis.