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

Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences (NIEHS), National Toxicology Program (NTP), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), NC 27709, USA.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin (Impact Factor: 2.65). 11/2008; 453(6):557-69. DOI: 10.1007/s00428-008-0679-5
Source: PubMed


It is thought that the growth of uterine leiomyomas may be mediated by the interaction of estrogen receptor alpha (ERalpha) and growth factor pathways and that phosphorylation of ERalpha at serine 118 (ERalpha-phospho-Ser118) is important in this interaction. In this study, immunoblotting and immunohistochemistry were used to investigate the expression of ERalpha-phospho-Ser118, 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 ERalpha-phospho-Ser118, phospho-p44/42 MAPK, and PCNA compared to patient-matched myometria and had significantly higher ERalpha-phospho-Ser118 and PCNA expression compared to secretory phase tumors. Also, enhanced colocalization and association of phospho-p44/42 MAPK and ERalpha-phospho-Ser118 were observed in proliferative phase tumors by confocal microscopy and immunoprecipitation, respectively. These data suggest that ERalpha-phospho-Ser118 may be important in leiomyoma growth and is possibly phosphorylated by phospho-p44/42 MAPK.

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    • "In addition to activation from estrogen binding, ERa is also activated through its phosphorylation by the mitogen-activated protein kinase (MAPK) pathway and possibly via other kinases (Hermon et al., 2008). Based on these findings, Hermon et al. (2008) hypothesized that estrogen-bound ERa induces growth factor expression, which can then stimulate the MAPK pathway and further activate ERa via phosphorylation in an autocrine fashion. "
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    ABSTRACT: BACKGROUND Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention.
    Human Reproduction Update 09/2014; 21(1). DOI:10.1093/humupd/dmu048 · 10.17 Impact Factor
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    • "Fibroids may also be targeted by environmental chemicals whose biological effects are mediated by hormone receptors (Di et al., 2008). Genomic events and nongenomic signaling in fibroids can result in 'cross talk' between hormone and growth factor receptors with activation of the downstream effectors such as MAPK and phosphorylation of estrogen receptor alpha (ERa) at serine 118 in fibroids (Swartz et al., 2005; Di et al., 2008; Hermon et al., 2008; Yu et al., 2010, 2012). Environmental estrogens derived from natural plant compounds (phytoestrogens ), synthetic and industrial by-products (industrial estrogens) have been found to increase the incidence of uterine leiomyomas in animal models (Newbold et al., 2002, 2007). "
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    ABSTRACT: BACKGROUNDUterine fibroids are the most common gynecologic tumors in women of reproductive age yet the etiology and pathogenesis of these lesions remain poorly understood. Age, African ancestry, nulliparity and obesity have been identified as predisposing factors for uterine fibroids. Symptomatic tumors can cause excessive uterine bleeding, bladder dysfunction and pelvic pain, as well as associated reproductive disorders such as infertility, miscarriage and other adverse pregnancy outcomes. Currently, there are limited noninvasive therapies for fibroids and no early intervention or prevention strategies are readily available. This review summarizes the advances in basic, applied and translational uterine fibroid research, in addition to current and proposed approaches to clinical management as presented at the 'Advances in Uterine Leiomyoma Research: 3rd NIH International Congress'. Congress recommendations and a review of the fibroid literature are also reported.METHODSThis review is a report of meeting proceedings, the resulting recommendations and a literature review of the subject.RESULTSThe research data presented highlights the complexity of uterine fibroids and the convergence of ethnicity, race, genetics, epigenetics and environmental factors, including lifestyle and possible socioeconomic parameters on disease manifestation. The data presented suggest it is likely that the majority of women with uterine fibroids will have normal pregnancy outcomes; however, additional research is warranted. As an alternative to surgery, an effective long-term medical treatment for uterine fibroids should reduce heavy uterine bleeding and fibroid/uterine volume without excessive side effects. This goal has not been achieved and current treatments reduce symptoms only temporarily; however, a multi-disciplined approach to understanding the molecular origins and pathogenesis of uterine fibroids, as presented in this report, makes our quest for identifying novel targets for noninvasive, possibly nonsystemic and effective long-term treatment very promising.CONCLUSIONSThe Congress facilitated the exchange of scientific information among members of the uterine leiomyoma research and health-care communities. While advances in research have deepened our knowledge of the pathobiology of fibroids, their etiology still remains incompletely understood. Further needs exist for determination of risk factors and initiation of preventive measures for fibroids, in addition to continued development of new medical and minimally invasive options for treatment.
    Human Reproduction Update 04/2014; 20(3). DOI:10.1093/humupd/dmt058 · 10.17 Impact Factor
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    • "Notably, differential (greater) expression of both ER-a and ER-b has been reported in leiomyomata compared with myometrium by several authors (Benassayag et al., 1999; Kovacs et al., 2001). In addition to its role in the activation of several signaling pathways such as mitogenactivated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and small body mothers against decapentaplegic (SMAD) for myometrial and leiomyoma cell proliferation, estradiol has also been shown to decrease expression of p53, a tumor suppressor, in leiomyoma cells in vitro (Hermon et al., 2008; Nierth-Simpson et al., 2009; Islam et al., 2013b). Investigations of the role of progesterone in the pathogenesis and progression of fibroids have not shown any evidence of a reduction of fibroid volume and uterine size, and have only demonstrated a reduction in heavy menstrual bleeding when progesterone is inhibited (Tristan et al., 2012; Shen et al., 2013). "
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    ABSTRACT: BACKGROUND Human leiomyomata (fibroids) are benign tumors of the uterus, represent the most common neoplasms of reproductive-aged women and have a prevalence of ∼70% in the general population. This disorder conveys a significant degree of morbidity and remains the leading indication for hysterectomy in the USA. Prior investigations of aberrant microRNA (miRNA) expression in various malignancies have provided invaluable insight into the role of this class of small non-coding RNAs in tumor growth. Evidence of irregular miRNA expression in uterine fibroids has garnered recent interest for diagnostic and therapeutic applications. Since miRNA gene targets modulate several processes implicated in the genesis of uterine fibroids, more focused investigation has the potential to elucidate the functional significance of miRNA in the genesis and pathology of the disease.
    Human Reproduction Update 04/2014; 20(5). DOI:10.1093/humupd/dmu017 · 10.17 Impact Factor
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