Overexpression of the tight junction protein Junctional Adhesion Molecule-A 
(JAM-A) has been linked to aggressive disease in breast and other cancers, but 
JAM-targeting drugs remain elusive. Screening of a natural compound library 
identified the antibiotic Tetrocarcin-A as a novel downregulator of JAM-A and 
human epidermal growth factor receptor-2 (HER2) protein expression in breast 
cancer cells. Lysosomal inhibition partially rescued the downregulation of JAM-A 
and HER2 caused by Tetrocarcin-A, and attenuated its cytotoxic activity. 
Tetrocarcin-A treatment or JAM-A silencing reduced AKT and ERK phosphorylation, 
inhibited c-FOS phosphorylation at Threonine-232 (its transcriptional regulation 
site), inhibited nuclear localization of c-FOS, and downregulated expression of 
the inhibitor of apoptosis proteins (IAP). This was accompanied by 
Tetrocarcin-A-induced caspase-dependent apoptosis. To begin evaluating the 
potential clinical relevance of our findings, we extended our studies to other 
models. Encouragingly, Tetrocarcin-A downregulated JAM-A expression and caused 
cytotoxicity in primary breast cells and lung cancer stem cells, and inhibited 
the growth of xenografts in a semi-in vivo model involving invasion across the 
chicken egg chorioallantoic membrane. Taken together, our data suggest that 
Tetrocarcin-A warrants future evaluation as a novel cancer therapeutic by virtue 
of its ability to downregulate JAM-A expression, reduce tumorigenic signaling 
and induce apoptosis.