Tyrosine kinase signalling in breast cancer: ErbB family receptor tyrosine kinases

The close of the millenium is marked by unprecedented advances in our understanding of the mechanisms that underlie carcinogenesis. Each procarcinogenic pathway presents pharmacologists with an array of therapeutic targets. Most importantly, the first rational therapeutic agents targeted at oncogene products have now navigated the tortuous drug development pipeline. A monoclonal antibody, 'Herceptin', which binds to the receptor tyrosine kinase (RTK) Her-2/Neu/ErbB-2 is effecive for treatment of a subset of patients with advanced breast cancer [1**, 2**]. This antibody is at the vanguard of a host of therapeutic compounds that are under development to antagonize the acivities of ErbB family receptors.The development and application of clinical tools that intervene in ErbB-regulated processes will be most effective if close attention is paid to the biologic properties of these RTKs. Signaling through these receptors, even when they are overexpressed in tumors, is still subject to regulation. This means that there are potentially many points of vulnerability at which therapeutic interventions can be targeted. Furthermore, the ability of overexpressed ErbB family RTKs to alter responses to genotoxic drugs and to steroid hormones means that ErbB-targeted therapies will have complex interactions with existing breast cancer therapeutic agents.The ERBB family consists of four closely related genes: ERBB (HER), ERBB-2 (HER-2, NEU), ERBB-3 (HER-3), and ERBB-4 (HER-4). ERBB (HER) encodes the prototype EGF receptor, and the other genes encode structurally similar RTKs. ERBB-2 is amplified (extensively reduplicated) in 15-30% of breast cancers [3**]. Amplification is more common in tumors from patients with lymph node metastases than in those from node-negative patients (for review [4*]). Amplification and/or overexpression of ErbB-2 occurs most often (up to 60%) in in situ carcinomas [4*,5], so ErbB-2 overexpression may be an early change. ErbB-2 overexpression in conjunction