RESUMEN
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)ß phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3ß increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3ß-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 GSK3ß phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.
Asunto(s)
Antineoplásicos Hormonales/efectos adversos , Glucógeno Sintasa Quinasa 3/metabolismo , Coactivador 1 de Receptor Nuclear/genética , Tamoxifeno/efectos adversos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Antineoplásicos Hormonales/uso terapéutico , Desmineralización Ósea Patológica/inducido químicamente , Desmineralización Ósea Patológica/genética , Densidad Ósea/efectos de los fármacos , Neoplasias de la Mama/prevención & control , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Femenino , Estudios de Asociación Genética , Glucógeno Sintasa Quinasa 3 beta , Humanos , Datos de Secuencia Molecular , Fosforilación , Polimorfismo de Nucleótido Simple , Procesamiento Proteico-Postraduccional , Estabilidad Proteica , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/metabolismo , Análisis de Secuencia de ADN , Tamoxifeno/uso terapéuticoRESUMEN
BACKGROUND: Premature thelarche is defined as breast development before 8 years of age. This is most often caused by central hormone disregulation and is accompanied by concurrent bone maturation. However, we present a case of premature thelarche with concurrent bone maturation without central hormone disregulation. Genes within the estrogen signaling pathway were examined for genetic changes which might be responsible for the clinical phenotype. PATIENT REPORT: A girl presented with breast development from 18 months of age with undetectable serum estrogens, prepubertal serum gonadotropins, advanced growth and skeletal maturation, but no increase of uterine size, thus presenting a premature thelarche variant. Serum estrogens remained below detectable limits until she entered into an unremarkable puberty at 12.1 years of age. No abnormalities or SNPs were found in the genes tested. CONCLUSION: We describe a case of premature thelarche which cannot be attributed to a central cause of abnormal hormone levels or to alterations in genes suspected for this phenotype. We conclude that other yet to be identified factors are involved in this unique case of premature thelarche.
