Hartmaier, R.J.Richter, A.S.Gillihan, R.M.Sallit, J.Z.McGuire, S.E.Wang, J.Lee, A.V.Osborne, C.K.O'Malley, B.W.Brown, P.H.Xu, J.Skaar, Todd C.Philips, S.Rae, J.M.Azzouz, F.Li, L.Hayden, J.Henry, N.L.Nguyen, A.T.Stearns, V.Hayes, D.F.Flockhart, D.A.Oesterreich, S.2022-10-102022-10-102012-02Hartmaier RJ, Richter AS, Gillihan RM, et al. A SNP in steroid receptor coactivator-1 disrupts a GSK3β phosphorylation site and is associated with altered tamoxifen response in bone. Mol Endocrinol. 2012;26(2):220-227. doi:10.1210/me.2011-1032https://hdl.handle.net/1805/30312The 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.en-USHormonal antineoplastic agentsPathologic bone demineralizationEstrogen receptorsTamoxifenArticle