title: A SNP in steroid receptor coactivator-1 disrupts a GSK3β phosphorylation site and is associated with altered tamoxifen response in bone.
abstract: 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.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hartmaier
authors.forename: A S
authors.initials: AS
authors.lastname: Richter
authors.forename: R M
authors.initials: RM
authors.lastname: Gillihan
authors.forename: J Z
authors.initials: JZ
authors.lastname: Sallit
authors.forename: S E
authors.initials: SE
authors.lastname: McGuire
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: A V
authors.initials: AV
authors.lastname: Lee
authors.forename: C K
authors.initials: CK
authors.lastname: Osborne
authors.forename: B W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: P H
authors.initials: PH
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: T C
authors.initials: TC
authors.lastname: Skaar
authors.forename: S
authors.initials: S
authors.lastname: Philips
authors.forename: J M
authors.initials: JM
authors.lastname: Rae
authors.forename: F
authors.initials: F
authors.lastname: Azzouz
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Hayden
authors.forename: N L
authors.initials: NL
authors.lastname: Henry
authors.forename: A T
authors.initials: AT
authors.lastname: Nguyen
authors.forename: V
authors.initials: V
authors.lastname: Stearns
authors.forename: D F
authors.initials: DF
authors.lastname: Hayes
authors.forename: D A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: S
authors.initials: S
authors.lastname: Oesterreich
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects* / Q000627:therapeutic use; D018488:Bone Demineralization, Pathologic / Q000139:chemically induced / Q000235:genetics; D015519:Bone Density / Q000187:drug effects; D001943:Breast Neoplasms / Q000517:prevention & control; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D005260:Female; D056726:Genetic Association Studies; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013629:Tamoxifen / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D013629:Tamoxifen; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3