γ Synuclein, a Novel Heat-Shock Protein-Associated Chaperone, Stimulates Ligand-Dependent Estrogen Receptor α Signaling and Mammary Tumorigenesis

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Abstract
Synucleins are emerging as central players in the formation of pathologically insoluble deposits characteristic of neurodegenerative diseases. γ synuclein (SNCG), previously identified as a breast cancer-specific gene (BCSG1), is also highly associated with breast or ovarian cancer progression. However, the molecular targets of SNCG aberrant expression in breast cancer have not been identified. Here, we demonstrated a chaperone activity of SNCG in the heat-shock protein (Hsp)-based multiprotein chaperone complex for stimulation of estrogen receptor (ER)-α signaling. As an ER-α-associated chaperone, SNCG participated in Hsp-ER-α complex, enhanced the high-affinity ligand-binding capacity of ER-α, and stimulated ligand-dependent activation of ER-α. The SNCG-mediated stimulation of ER-α transcriptional activity is consistent with its stimulation of mammary tumorigenesis in response to estrogen. These data indicate that SNCG is a new chaperone protein in the Hsp-based multiprotein chaperone complex for stimulation of ligand-dependent ER-α signaling and thus stimulates hormone-responsive mammary tumorigenesis.