Synuclein γ Stimulates Membrane-Initiated Estrogen Signaling by Chaperoning Estrogen Receptor (ER)-α36, a Variant of ER-α

Synuclein γ (SNCG), previously identified as a breast cancer-specific gene, is highly expressed in malignant cancer cells but not in normal epithelium. The molecular targets of SNCG during breast cancer progression have not been fully identified. Here we analyzed the effect of SNCG on stimulation of membrane-initiated estrogen signaling. While SNCG expression enhanced estrogen-induced activation of ERK1/2 and mammalian target of rapamycin, knockdown of endogenous SNCG decreased membrane-initiated estrogen signaling. SNCG functions as a molecular chaperone protein for estrogen receptor (ER)-α36, a membrane-based variant of ER-α. SNCG bound to ER-α36 in the presence and absence of functional molecular chaperone heat shock protein 90. Disruption of heat shock protein 90 with 17-AAG significantly reduced ER-α36 expression and membrane-initiated estrogen signaling. However, expression of SNCG prevented ER-α36 degradation and completely recovered 17-AAG-mediated down-regulation of estrogen signaling. The function of SNCG in ER-α36-mediated estrogen signaling is consistent with its ability to stimulate cell growth in response to estrogen. Expression of SNCG also renders tamoxifen resistance, which is consistent with the clinical observation on the association of ER-α36 expression and tamoxifen resistance. The present study indicates that ER-α36 is a new member of the ER-α family that mediates membrane-initiated estrogen signaling and that SNCG can replace the function of heat shock protein 90, chaperone ER-α36 activity, stimulate ligand-dependent cell growth, and render tamoxifen resistance.