Stimulation of Estrogen Receptor Signaling in Breast Cancer by a Novel Chaperone Gamma Synuclein

摘要

The present study demonstrated SNCG can partially replace the chaperoning function of Hsp90 and protect HER2/Akt/mTOR stability and function in the stressful condition when the function of Hsp90 is blocked. Disruption of Hsp90 with 17-AAG resulted in a significant degradation of HER2. However, expression of SNCG completely recovered 17-AAG-mediated losses of HER2. This SNCG-mediated protection was demonstrated in breast cancer cells, tumor xenograft, and mammary glands from HER2/SNCG bitransgenic mouse. Consistent with its chaperoning activity, SNCG bound to HER2 in the presence and absence of Hsp90. While expression of SNCG renders resistance to 17-AAG-induced apoptosis both in vitro and in tumor xenograft, knockdown endogenous SNCG enhances the sensitivity to the Hsp90 disruption. Crossing SNCG transgenic mice with HER2 mice stimulated HER2-induced tumor growth and rendered resistance to 17-AAG-mediated antitumor effect on the transgenic mice. The present study indicates that SNCG functions as a tumor specific chaperone, which can replace the chaperoning function of Hsp90, protect its client protein HER2, and render a resistance to Hsp90 disruption.