A SNP in steroid receptor coactivator-1 disrupts a GSK3β phosphorylation site and is associated with altered tamoxifen response in bone

Mol Endocrinol. 2012 Feb;26(2):220-7. doi: 10.1210/me.2011-1032. Epub 2011 Dec 15.


The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)β phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3β increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3β-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3β phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Antineoplastic Agents, Hormonal / adverse effects*
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Bone Demineralization, Pathologic / chemically induced
  • Bone Demineralization, Pathologic / genetics
  • Bone Density / drug effects
  • Breast Neoplasms / prevention & control
  • Cell Line, Tumor
  • Clinical Trials as Topic
  • Female
  • Genetic Association Studies
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Molecular Sequence Data
  • Nuclear Receptor Coactivator 1 / genetics*
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Protein Processing, Post-Translational
  • Protein Stability
  • Receptors, Estrogen / agonists
  • Receptors, Estrogen / metabolism
  • Sequence Analysis, DNA
  • Tamoxifen / adverse effects*
  • Tamoxifen / therapeutic use


  • Antineoplastic Agents, Hormonal
  • Receptors, Estrogen
  • Tamoxifen
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3