Abstract
HER2-positive breast cancers that have become resistant to HER2-targeting agents, such as trastuzumab (also known as Herceptin), have limited treatment options. In this issue of Science Signaling, Singh et al. have identified a characteristic increase in the endoplasmic reticulum (ER)-associated degradation (ERAD) system in HER2-positive tumors as a mechanism of relieving proteotoxic stress. Synthetic lethality arising from targeted disruption of ERAD signaling in conjunction with other HER2-dependent signaling may improve therapeutic management of this difficult class of breast tumors.