Estrogen receptor alpha (ERα) phospho-serine-118 is highly expressed in human uterine leiomyomas compared to matched myometrium

Abstract

It is thought that the growth of uterine leiomyomas may be mediated by the interaction of estrogen receptor alpha (ERα) and growth factor pathways and that phosphorylation of ERα at serine 118 (ERα-phospho-Ser118) is important in this interaction. In this study, immunoblotting and immunohistochemistry were used to investigate the expression of ERα-phospho-Ser118, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript phosphorylated p44/42 mitogen-activated protein kinase (phospho-p44/42 MAPK), and proliferating cell nuclear antigen (PCNA) in human leiomyoma and myometrial tissues during the proliferative and secretory phases of the menstrual cycle. We found that tumors taken from the proliferative phase expressed significantly higher levels of ERα-phospho-Ser118, phospho-p44/42 MAPK, and PCNA compared to patient-matched myometria and had significantly higher ERα-phospho-Ser118 and PCNA expression compared to secretory phase tumors. Also, enhanced colocalization and association of phospho-p44/42 MAPK and ERα-phospho-Ser118 were observed in proliferative phase tumors by confocal microscopy and immunoprecipitation, respectively. These data suggest that ERα-phospho-Ser118 may be important in leiomyoma growth and is possibly phosphorylated by phospho-p44/42 MAPK.

Estrogen receptors and human disease: an update

“…The expression of ER α -phospho-S118 by p44/42 MAPK from fibroids taken during the proliferative phase is increased, and these fibroids exhibit higher PCNA expression compared to patient-matched myometria and secretory-phase fibroids (Hermon et al 2008). Asada et al investigated the DNA methylation status of ER α promoter region (–1188 to +229 bp) and indicate hypomethylation of the CpG sites in leiomyomas coincides with increased ER α mRNA levels (Asada et al 2008).…”

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

“…ERα is phosphorylated at a higher rate on serine in leiomyoma compared with surrounding myometrium and colocalizes with phospho-p44/42 MAPK. Therefore, it is reasonable to assume that phosphorylated ERα, possibly regulated by p44/42 MAPK, may play a role in leiomyoma development (31).…”

The role of progesterone signaling in the pathogenesis of uterine leiomyoma

“…Another study demonstrated rapid increase of phosphorylated protein kinase C alpha (PKC alpha) and ERK1/2 by E2 in immortalized uterine smooth muscle which corresponded to increased proliferation [79]. The interaction between ERa and signaling pathways was suggested in a study that showed higher ER-alpha phosphorylation in leiomyoma tissues derived from patients in the proliferative phase of the menstrual cycle which correlated with an increased phosphorylation of p44/p42 MAPK proteins in leiomyoma [80]. Phosphorylated p44/42 colocalized with ER-alpha phosphorylated on serine 118 suggesting that MAPK may phosphorylate ER-alpha in leiomyoma.…”