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Stimulation of Estrogen Receptor Signaling by Synuclein¹

Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040 [Y. J., Y. E. L., I. D. G., Y. E. S.], and Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304 [A. L., A. G., J. L.]

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, 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- (ER-) in breast cancer cells. Augmentation of SNCG expression stimulated transcriptional activity of ER-, whereas compromising endogenous SNCG expression suppressed ER- signaling. The SNCG-stimulated ER- signaling was demonstrated in three different cell systems including ER--positive and SNCG-negative MCF-7 cells, ER--positive and SNCG-positive T47D cells, and SNCG-negative and ER--negative MDA-MB-435 cells. The SNCG-mediated stimulation of ER- 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 ER-regulated gene expression and cell growth can be effectively inhibited by antiestrogens. These data indicate that SNCG is required for efficient ER- signaling and, thus, stimulated hormone-responsive mammary tumors.

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