Cover Caption

Abstract

Her2 positive breast cancer patients faced a poor survival prognosis until the introduction of the anti-Her2 antibody, trastuzumab. Unfortunately, many of these patients ultimately become resistant to the antibody. Overcoming resistance has been difficult, in part because the precise signaling mechanism of action of trastuzumab leading to an anti-tumor effect has been unclear. One potential mechanism is that trastuzumab enhances the endocytic downregulation of ErbB2 via lysosomal/proteasomal pathways. It has been postulated that the E3 ligase, Cbl, may mediate trastuzumab-mediated downregulation of ErbB2. In contrast, Hsp90 inhibitors induce ubiquitylation of ErbB2 by the E3 ligase, CHIP. Raja and colleagues hypothesized that treating breast cancer cells with both 17-AAG to inhibit Hsp90 and trastuzumab would increase the ubiquitylation and downregulation of ErbB2.

 

On the cover of this month’s Cancer Biology & Therapy, 21MT1 breast cancer cells were treated with 17-AAG and lactacystin, a proteasomal inhibitor. The image shows that proteasomal function is required for receptor endocytosis. ErbB2 (green) remains localized at the cell membrane when treated with 17-AAG in the presence of lactacystin. LAMP-1, a late endosomal/lysosomal marker is seen in red. To see the localization of ErbB2 to the lysosomal compartment after 17-AAG and to learn more about the effects of the 17-AAG/trastuzumab combination, see the article by Raja and colleagues.