Synuclein gamma stimulates membrane-initiated estrogen signaling by chaperoning estrogen receptor (ER)-alpha36, a variant of ER-alpha

Am J Pathol. 2010 Aug;177(2):964-73. doi: 10.2353/ajpath.2010.100061. Epub 2010 Jul 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Proliferation
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Mice
  • Mice, Nude
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Neoplasm Transplantation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • RNA Interference
  • Signal Transduction / physiology*
  • Tamoxifen / pharmacology
  • Tumor Cells, Cultured / drug effects
  • gamma-Synuclein / genetics
  • gamma-Synuclein / metabolism*


  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Estrogens
  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones
  • Protein Isoforms
  • gamma-Synuclein
  • Tamoxifen
  • Extracellular Signal-Regulated MAP Kinases