Mechanisms of ErbB2-mediated paclitaxel resistance and trastuzumab-mediated paclitaxel sensitization in ErbB2-overexpressing breast cancers

The ErbB2 gene encodes a transmembrane growth factor receptor that belongs to the ErbB receptor tyrosine kinase subfamily. ErbB2 protein is overexpressed in approximately 30% of breast cancers. Although controversies exist, data from our laboratory and from clinical trials of trastuzumab indicate that ErbB2 overexpression confers chemoresistance to certain chemotherapeutic agents such as paclitaxel. One of the molecular mechanisms of ErbB2-mediated paclitaxel resistance is that overexpression of the ErbB2 receptor leads to deregulation of the G₂/M cell cycle check-point that inhibits paclitaxel-induced apoptosis. Several promising ErbB2-targeting strategies have now been developed to conquer the adverse consequences of ErbB2 overexpression such as paclitaxel resistance. Among these, trastuzumab has brought great promise. We have recently shown that trastuzumab can effectively sensitize ErbB2-overexpressing breast cancer cells to paclitaxel by reversing the antiapoptotic function of ErbB2. Our studies provide additional support for chemotherapy combined with trastuzumab for ErbB2-overexpressing breast cancers, and it may bring insights into designing more effective and specific therapies that could offer great benefits to patients.