Estrogen receptor transcription and transactivation: ErbB family of receptors in breast cancer

The ErbB2 receptor tyrosine kinase is overexpressed in many human breast tumors, a phenomenon correlating with more aggressive tumor characterisitcs and a worse patient prognosis. ErbB2 is considered, therefore, as a target for cancer therapy. In this respect, a growth inhibitory antibody (4D5) directed against the extracellular domain of ErbB2 has been raised. Furthermore, the humanized version (Hercepton™) is now being used in the clinic to treat metastatic breast cancer patients whose tumors overxpress ErbB2. In our work, 4D5 has been applied as a selective inhibitor of ErbB2 function. Treatment with 4D5 blocks G1/S phase progression in breast carcinoma cells that overexpress ErbB2. This block correlates with a rapid reduction in ErbB2 phosphotyrosine content, downregulation of signal transduction pathways, a reduction in the expression of proteins involved in the sequestration of the cyclin-dependent kinase inhibitor p27, and relocalization of p27 onto Cdk2 complexes. Strikingly, the 4D5-induced G1 block can be rescued by treatment with various ErbB ligands. The degree of rescue is ligand-related and is associated with activation of specific signaling pathways. Additionally, through comparison with an ErbB2-overexpressing gastric carcinoma cell line (MKN7) that proliferates normally in the presence of 4D5, we have demonstrated that decreased ErbB2 phosphotyrosine levels do not necessarily lead to growth inhibition in response to 4D5. These data imply that ErbB2 overexpression alone is insufficient to predict cellular response to ErbB2-directed therapies. The possible contribution of other ErbB receptors to the process of malignant transformation will be discussed in relation to the evolution of ErbB-directed treatment strategies.