Synucleins are emerging as central player in the fundamental neural processes and in the formation of pathologically insoluble deposits characteristic of Alzheimer's disease and Parkinson's disease. However, gamma Synuclein (SNCG) is also highly associated with breast cancer and ovarian cancer progression. Whereas most studies of this group of proteins have been directed to the elucidation of their role in the formation of depositions in brain tissue, the normal cellular function of this highly conserved synuclein family remains largely unknown. A notable finding in this study is that SNCG, identified previously as a breast cancer-specific gene 1, strongly stimulated the ligand-dependent transcriptional activity of estrogen receptor-alpha (ER-alpha) in breast cancer cells. Augmentation of SNCG expression stimulated transcriptional activity of ER-alpha, whereas compromising endogenous SNCG expression suppressed ER-alpha signaling. The SNCG-stimulated ER-alpha signaling was demonstrated in three different cell systems including ER-alpha-positive and SNCG-negative MCF-7 cells, ER-alpha-positive and SNCG-positive T47D cells, and SNCG-negative and ER-alpha-negative MDA-MB-435 cells. The SNCG-mediated stimulation of ER-alpha transcriptional activity is consistent with its stimulation of the ligand-dependent cell growth. Whereas overexpression of SNCG stimulated the ligand-dependent cell proliferation, suppression of endogenous SNCG expression significantly inhibited cell growth in response to estrogen. The stimulatory effect of SNCG on ERalpha-regulated gene expression and cell growth can be effectively inhibited by antiestrogens. These data indicate that SNCG is required for efficient ER-alpha signaling and, thus, stimulated hormone-responsive mammary tumors.