Synuclein gamma (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)-alpha36, a membrane-based variant of ER-alpha. SNCG bound to ER-alpha36 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-alpha36 expression and membrane-initiated estrogen signaling. However, expression of SNCG prevented ER-alpha36 degradation and completely recovered 17-AAG-mediated down-regulation of estrogen signaling. The function of SNCG in ER-alpha36-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-alpha36 expression and tamoxifen resistance. The present study indicates that ER-alpha36 is a new member of the ER-alpha family that mediates membrane-initiated estrogen signaling and that SNCG can replace the function of heat shock protein 90, chaperone ER-alpha36 activity, stimulate ligand-dependent cell growth, and render tamoxifen resistance.