Potential Role Of Estrogen Research Articles

Vitamin D/Bone Mineral Density and Triglyceride Paradoxes Seen in African Americans: A Cross-Sectional Study and Review of the Literature.

Vitamin D is known to have a positive effect on bone health. Despite the greater frequency of vitamin D deficiency in African Americans (AA), they have a higher bone mineral density (BMD) compared to whites, demonstrating a disconnect between BMD and vitamin D levels in AA. Another intriguing relationship seen in AA is the triglyceride (TG) paradox, an unusual phenomenon in which a normal TG status is observed even when patients house conditions known to be characterized by high TG levels, such as Type II diabetes. To the best of our knowledge, no study has examined whether these two paradoxical relationships exist simultaneously in AA subjects with Type II diabetes. In this study, we compared levels of blood markers, including HbA1c, TG, and vitamin D, measured as serum 25-hydroxyvitamin D [25(OH)VD] µM/mL, [25(OH)VD]/TG, calcium, and BMD in AA (n = 56) and white (n = 26) subjects with Type II diabetes to see whether these relationships exist concurrently. We found that AA subjects had significantly lower TG and [25(OH)VD] levels and a significantly higher BMD status compared to white subjects, even when the ages, BMI, duration of diabetes, HbA1c, and calcium levels were similar between the two groups. This demonstrates that these two paradoxical relationships exist simultaneously in Type II diabetic AA subjects. In addition to these findings, we discuss the current hypotheses in the literature that attempt to explain why these two intriguing relationships exist. This review also discusses four novel hypotheses, such as altered circulating levels and the potential role of estrogen and hydrogen sulfide on BMD and HMG-CoA reductase as a possible contributor to the TG paradox in AA subjects. This manuscript demonstrates that there are still many unanswered questions regarding these two paradoxical relationships and further research is needed to determine why they exist and how they can be implemented to improve healthcare.

The ESTROGEN-MECHANISM OF NEUROPROTECTION

Estrogen is an important steroid hormone signal that regulates multiple tissues and functions in the body.The brain is an important target organ for estrogen. In addition to direct effects, estrogen influences brain function through effects on the vasculature and the immune system. Estrogen influences several neurotransmitter systems, including acetylcholine, serotonin, noradrenalin, and glutamate. There are complex mechanisms that underlie estrogen neuroprotective and neurotrophic actions (genomic, non-genomic kinase signalic pathways and membrane estrogen receptors pathways). Estradiol induces gene transcription and rapid membrane signaling mediated by estrogen receptor alpha (ERα), estrogen receptor-beta (ERβ), and a recently characterized G-protein coupled estrogen receptor, each with distinct distributions and ability to influence estradiol-dependent signaling.Vector-mediated expression of estrogen receptors in the hippocampus provides an innovative research approach and suggests that memory depends on the relative expression of ERα and ERβ interacting with estradiol levels.The potential role of estrogen as a neuroprotective factor and a multicellular mode of estrogen action in the regulation of neuronal survival and neurotrophism is discussed, as are potential future directions for the field. Key words: estrogen; estrogen  receptors; steroid hormone;  neuroprotection

Lipedema and the Potential Role of Estrogen in Excessive Adipose Tissue Accumulation.

Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema.

Prediagnostic use of estrogen-only therapy is associated with improved colorectal cancer survival in menopausal women: a Swedish population-based cohort study

Background Menopausal hormone therapy (MHT) reduces the risk of developing colorectal cancer (CRC), yet it is largely unclear whether it could also influence survival in women with CRC. Therefore, we aimed to investigate the influence of prediagnostic MHT use on CRC-specific and all-cause mortality in women with CRC. Methods This nationwide nested cohort study, within a large population-based matched cohort, included all women diagnosed with incident CRC between January 2006 and December 2012 (N = 7814). A total of 1529 women had received at least one dispensed prescription of systemic MHT before CRC diagnosis, and 6285 CRC women with CRC did not receive MHT during the study period, as ascertained from the Swedish Prescribed Drug Registry. Multivariable Cox regression models provided adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for CRC-specific mortality and all-cause mortality. Results Past use of prediagnostic estrogen-only therapy (E-MHT) was associated with lower CRC-specific (HR = 0.67, 95%CI 0.44–0.99) and all-cause mortality (HR = 0.68, 95%CI 0.59–0.93). However, all-cause mortality (HR = 1.23, 95%CI 1.02–1.48) was elevated among current prediagnostic E-MHT users who were 70+ years at diagnosis. Current estrogen combined progestin therapy (EP-MHT) was associated with higher CRC-specific mortality (HR = 1.61, 95%CI 1.06–2.44) in older women, but no association was shown for all-cause mortality. Conclusions Our findings suggest that E-MHT, but not EP-MHT use, might be associated with improved CRC survival, indicating a potential role of estrogens in sex hormone-related cancers. However, association of MHT use with grade of cancer remains unclear.

The Potential Role of Estrogen in Moderating Symptom Severity in Women with RYR1-Related Myopathy (P5.4-012)

The Potential Role of Estrogen in Moderating Symptom Severity in Women with RYR1-Related Myopathy (P5.4-012)

Effects of Estrogen in Gender-dependent Fetal Programming of Adult Cardiovascular Dysfunction.

Epidemiological studies and experimental studies have demonstrated that intrauterine adverse environment increases the risk of Cardiovascular Disease (CVD) in adulthood. However, whether an individual develops a cardiovascular dysfunctional phenotype may depend on genetic background, age, and sex. In this review, we summarize some of the recent experimental animal studies in the developmental programming of adult CVD with an emphasis on sex differences and the potential role of estrogen in mediating sexual dimorphism. Few epidemiological studies report the effect of sex on the developmental programming of CVD. However, numerous experimental animal studies have shown a sex difference in fetal programming of adult cardiovascular dysfunction. Most of the animal studies indicate that male offspring develop cardiovascular dysfunction and CVD in adulthood, whereas adult females appear to be protected. Estrogen is one of the key factors that contributes to the sex difference of adult CVD. Estrogen/its Receptor (ER) may interact with the RAS system by changes of DNA methylation patterns at the target gene promoter, serve as an antioxidant to counteract the prenatal insults-induced heightened ROS, and function as an eNOS activator to increase vasodilation, resulting in the protection of female offspring from the development of hypertension and other CVDs. These studies suggest that estrogen/ER may contribute to sex differences in cardiovascular response to an adverse intrauterine environment and play a significant role in modulating the cardiovascular response in adulthood.

Nonylphenol promotes the proliferation of colorectal cancer COLO205 cells by upregulating the expression of protein kinase C ζ.

Previous studies have indicated the potential role of estrogen in the development and prognosis of colorectal cancer (CRC). Nonylpheno (NP) is an endocrine-disrupting chemical, which may influence the development of estrogen-dependent types of cancer. However, the molecular mechanism of NP in the development of CRCs remains unclear. In the present study, various concentrations of NP were used to treat COLO205 CRC cells, and the expression of protein kinase C ζ (PKCζ) was knocked down using PKCζ small interfering RNA. The effects of NP in various concentrations on the cell cycle and apoptosis of COLO205 cells were examined, and the change in the expression level of PKCζ was analyzed. The results indicated that NP may significantly induce proliferation of COLO205 CRC cells, and significantly reduce cell apoptosis. However, suppression of PKCζ expression may inhibit proliferation, while NP could reduce this inhibition. The results of a western blot analysis indicated that the expression level of cyclin D1 and E were significantly increased following NP treatment, and the expression of p27 was significantly decreased. The phosphorylation of PKCζ and extracellular-signal-regulated kinase (ERK)1/2 was significantly increased following NP treatment in a dose-dependent manner. Overall, NP induced human CRC COLO205 cell proliferation and inhibited the apoptotic rate of COLO205 cells by increasing the activity of PKCζ and ERK1/2.

A potential role for estrogen in cigarette smoke-induced microRNA alterations and lung cancer.

Alteration in the expression of microRNAs (miRNAs) is associated with oncogenesis and cancer progression. In this review we aim to suggest that elevated levels of estrogens and their metabolites inside the lungs as a result of cigarette smoke exposure can cause widespread repression of miRNA and contribute to lung tumor development. Anti-estrogenic compounds, such as the components of cruciferous vegetables, can attenuate this effect and potentially reduce the risk of lung cancer (LC) among smokers.

Altered expression of glial and synaptic markers in the anterior hippocampus of behaviorally depressed female monkeys

The anterior hippocampus is associated with emotional functioning and hippocampal volume is reduced in depression. We reported reduced neuropil volume and number of glia in the dentate gyrus (DG) and cornu ammonis (CA)1 of the anterior hippocampus in behaviorally depressed adult female cynomolgus macaques. To determine the biochemical correlates of morphometric and behavioral differences between behaviorally depressed and nondepressed adult female monkeys, glial and synaptic transcripts and protein levels were assessed in the DG, CA3 and CA1 of the anterior hippocampus. Glial fibrillary acidic protein (GFAP) was increased whereas spinophilin and postsynaptic density (PSD)-95 protein were decreased in the CA1 of depressed monkeys. GFAP was reciprocally related to spinophilin and PSD-95 protein in the CA1. Gene expression of GFAP paralleled the protein changes observed in the CA1 and was inversely related to serum estradiol levels in depressed monkeys. These results suggest that behavioral depression in female primates is accompanied by astrocytic and synaptic protein alterations in the CA1. Moreover, these findings indicate a potential role for estrogen in modulating astrocyte-mediated impairments in synaptic plasticity.

Abstract LB-152: Local estrogen formation and signaling through amphiregulin/EGFR may be implicated in human hepatocellular carcinoma: a unifying hypothesis.

Abstract Although there is evidence that hints at a potential role of estrogen in hepatocellular carcinoma (HCC), the use of antiestrogens has failed to improve survival of patients. We have investigated aromatase-driven estrogen formation in nontumoral and malignant human liver tissues and cells, also in relation to the expression of estrogen receptor (ER) α, ERβ and their splicing variants and of amphiregulin (AREG), an EGFR ligand, aiming to get insights in the potential role of estrogen and the underlying mechanism(s) in HCC. Chromatographic and exon-specific RT-PCR analyses were used to assess activity and expression of aromatase and the expression of wild-type (hERα66, hERβ1) and variant (hERα46, hERα36; hERβ2/Cx, hERβ5) ER, both in vivo and in vitro. Following incubation of tissue minces or cells with either testosterone or androstenedione used as precursor, human HCC tissues and HepG2 hepatoma cells showed elevated aromatase activity, with estrogen formation rates of 20% at 24h and >95% at 72h. By contrast, no aromatase activity could be detected in nontumoral hepatic tissues and HA22T liver cancer. Cirrhotic samples exhibited variable enzyme activity, with average estrogen formation rates of 4-8%, while Huh7 HCC cells gave rise to 34% estrogen formation. Markedly lower aromatase mRNA levels were observed in HA22T cells and nontumoral liver tissues, as compared to HepG2 cells and HCC samples. Cirrhotic specimens displayed variable transcript levels. Interestingly, no or low expression of wild type ERα and ERβ could be detected in liver cancer cells and malignant tissues. Conversely, equivalent amounts of the hERα46 variant were observed in both cells and tissues, while hERα36 expression was highest in HepG2 cells and HCC samples, intermediate in Huh7 cells and cirrhotic tissues, and very low in HA22T cells and nontumoral liver. Only occasional expression of the two ERβ variants was observed in liver cancer cells and tissues. It is noteworthy that the pattern of hERα36 expression was strictly related to that of aromatase, suggesting that this ERα variant may be primarily implicated as a mediator of estrogen action in the malignant liver. AREG expression was consistently associated with that of aromatase, with nearly 3-fold and 8-fold higher levels being seen in HepG2 cells than in Huh7 cells (P=0,002) and HA22T cells (P=0,0014), respectively. This evidence suggests that AREG expression may be upregulated by estrogens in human HCC by binding to the membrane-associated ERα36 variant. Based on present and previous experimental evidence, we propose here a unifying hypothetical model whereby locally elevated, aromatase-driven, estrogen formation, combined with a shift in ER wild type/variant expression and the activation of rapid AREG signaling, may be primarily implicated in development and/or progression of human HCC and other neoplastic or chronic human diseases. Citation Format: Giuseppe Carruba, Vitale Miceli, Letizia Cocciadiferro, Lucia M. Polito, Biagio Agostara, Orazia M. Granata. Local estrogen formation and signaling through amphiregulin/EGFR may be implicated in human hepatocellular carcinoma: a unifying hypothesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-152. doi:10.1158/1538-7445.AM2013-LB-152

PDZK1 Upregulation in Estrogen-Related Hyperpigmentation in Melasma

The pathogenesis of melasma is unknown, although the potential role of estrogen has been considered. Microarray and real-time PCR analyses revealed that upregulation of PDZ domain protein kidney 1 (PDZK1) is clinically correlated with melasma. Although there has been no report that PDZK1 is involved in pigmentation and/or melanogenesis, PDZK1 expression can be induced by estrogen. In this study, the role of PDZK1 upregulation in melasma was examined, particularly in connection with estrogen, using biopsied skin specimens from 15 patients and monocultures and cocultures of melanocytes and keratinocytes with or without overexpression or knockdown of PDZK1. Estrogen upregulated PDZK1. Overexpression of PDZK1 increased tyrosinase expression and melanosome transfer to keratinocytes, whereas PDZK1 knockdown reduced estrogen-induced tyrosinase expression, through regulation of expression of estrogen receptors (ERs) ER-α and ER-β. The PDZK1-induced tyrosinase expression and melanosome transfer was regulated by ion transporters such as sodium-hydrogen exchanger (NHE), cystic fibrosis transmembrane conductance regulator (CFTR), and SLC26A3, which showed a specific association with each ER subtype. In the melanosome transfer, PDZK1 also increased phosphorylation of ezrin/radixin/moesin (ERM) and ras-related C3 botulinum toxin substrate 1, but not the expression of proteinase-activated receptor-2. Collectively, upregulation of PDZK1 could have an important role in the development of melasma in connection with estrogen through NHE, CFTR, and SLC26A3.

M270 DIFFERENTIAL EXPRESSION OF CAVEOLIN-1 IN UTERINE LEIOMYOMA AND MYOMETRIAL SMOOTH MUSCLE CELLS: THE POTENTIAL ROLE OF ESTROGEN

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S619-S619 Poster presentations M270 DIFFERENTIAL EXPRESSION OF CAVEOLIN-1 IN UTERINE LEIOMYOMA AND MYOMETRIAL SMOOTH MUSCLE CELLS: THE POTENTIAL ROLE OF ESTROGEN Y. Zhu, Y. ZhuSearch for more papers by this author Y. Zhu, Y. ZhuSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)61462-3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S619-S619 RelatedInformation

Abstract 5748: Elevated aromatase, estrogen receptor variants and human hepatocellular carcinoma: a unifying hypothetical model

Abstract Although there is evidence that hints at a potential role of estrogen in hepatocellular carcinoma (HCC), the use of antiestrogens has failed to improve disease-free and overall survival of HCC patients. In the present study we have investigated aromatase-driven estrogen formation in nontumoral and malignant human liver tissues and cells, also in relation to the expression of estrogen receptor (ER) β, ERα, and their splicing variants, aiming to get insights into the potential role of estrogens and the underlying mechanism(s) in human HCC. Chromatographic and exon-specific RT-PCR analyses were respectively used to assess activity and expression the aromatase enzyme and the expression of wild-type (hERα66, hERα1) and variant (hERα46, hERα36; hERα2/Cx, hERα5) ER, both in vivo and in vitro. Following incubation of tissue minces or liver cell lines, with either testosterone or androstenedione used as androgen labeled precursor, human HCC tissues and HepG2 hepatoma cells showed elevated aromatase activity, with estrogen formation rates of 20% at 24h and >95% at 72h. By contrast, no aromatase activity could be detected in nontumoral hepatic tissues and HA22T liver cancer. Cirrhotic samples exhibited variable enzyme activity, with average estrogen formation rates of 4-8%, while Huh7 HCC cells gave rise to 34% estrogen formation. Markedly lower aromatase mRNA levels were observed in HA22T cells and nontumoral liver tissues, as compared to HepG2 cells and HCC samples. Cirrhotic specimens displayed variable transcript levels, comparable in turn to those observed in nontumoral or HCC tissues. Interestingly, no or low expression of both wild type ERα and ERα could be detected in liver cancer cells and malignant tissues. Conversely, equivalent amounts of the hERα46 variant were observed in both cells and tissues, while hERα36 expression was highest in HepG2 cells and HCC samples, intermediate in Huh7 cells and cirrhotic tissues, and very low in HA22T cells and nontumoral liver. Only occasional expression of the two ERα variants was observed in liver cancer cells and tissues. It is noteworthy that the pattern of hERα36 expression was strictly related to that of the aromatase enzyme, suggesting that this ERα variant may be primarily implicated as a mediator of estrogen action in the malignant liver. Based on present and previous experimental evidence, we propose here a unifying hypothetical model whereby locally elevated, aromatase-driven, estrogen formation, combined with a shift in wild type/variant ER expression, may be primarily implicated in development and/or progression of human HCC and other neoplastic or chronic human diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5748. doi:1538-7445.AM2012-5748

17β-estradiol modifies TRPV1 mRNA expression in DRG neurons

While it has been demonstrated that women experience greater cancer pain and pain severity than men, the potential role of estrogen in regulating nociception particularly as it relates to tumor pain remains unclear. Current data indicate that estrogens act directly on the nervous system to affect the severity of pain, but the mechanisms underlying this effect are unclear. A major nociceptive mechanism associated with the development of cancer pain is activation of the transient receptor potential vanilloid-1 (TRPV1) channel. TRPV1 is a Ca2+-permeable ionotropic receptor activated by multiple sensory stimuli including heat, acid, and protons. Antagonism of the TRPV1 channel attenuates nociception in a mouse bone cancer pain model. Both estrogen (ER) and TRPV1 receptors are known to be expressed on dorsal root ganglion (DRG) neurons, whose axons transmit pain from the periphery to the spinal cord. This raises the question of whether estrogen can alter TRPV1 receptor expression or function particularly in pain states like cancer pain. The present study was designed to evaluate the effects of estrogen on pain sensitivity and TRPV1 expression in the DRG of male and female C3H mice in a mouse model of bone cancer pain. One goal was to determine whether estrogen modulates nociceptive receptors in the DRG in a manner consistent with its effects on pain sensitivity. This study demonstrated that exposure to 17β-estradiol in gonadectomized males (ORCH+E), but the lack of this same hormone in gonadectomized females (OVX), significantly reduced the mRNA levels of TRPV1 in lumbosacral DRG neurons and this correlated with a reduction in tumor-induced nociception. Our results suggest that modulation of 17β-estradiol causes a down regulation in TRPV1 expression in DRG neurons, which may be associated with a reduction in fibrosarcoma-induced mechanical allodynia in both male female mice.

Estrogen signalling through amphiregulin may be implicated in human hepatocellular carcinoma

We investigated aromatase (Aro)-driven estrogen formation in non-tumoral and malignant liver tissues and cells, also in relation to expression of the estrogen receptors α and β (ERα and ERβ) and amphiregulin (AREG), aiming to gain insights into the potential role of estrogens in human hepatocellular carcinoma (HCC). Chromatographic and reverse transcriptase polymerase chain reaction (RT-PCR) analyses were used to assess activity and expression of the Aro enzyme and AREG as well as the expression of wild-type and variant ERs, both in vivo and in vitro. Following 24h and 72h incubation of liver tissues or cells with testosterone, human HCC tissues and HepG2 hepatoma cells showed elevated Aro activity (estrogen formation, respectively, of 20% and 52%-99%). By contrast, no Aro activity could be detected in non-tumoral tissues and HA22T liver cancer cells. Cirrhotic samples and Huh7 cells exhibited intermediate enzyme activity, with estrogen formation of 4% and 34%, respectively. Markedly lower or undetectable Aro mRNA levels were observed in HA22T cells and non-tumoral liver tissues compared with HepG2 cells and HCC samples. Cirrhotic specimens displayed variable transcript levels. Interestingly, no or low expression of wild-type ERα and ERβ could be observed in liver cancer cells and malignant tissues. However, ubiquitous expression of the hERα46 variant and occasional expression of the hERβ2/Cx variant were observed in cancer tissues and cells. It is noteworthy that the pattern of wild-type ERα was inversely related to Aro, whilst AREG expression was consistently associated with that of Aro. This combined evidence suggests that locally elevated Aro activity may increase malignant cell proliferation also through AREG signalling.

Abstract 1726: Estrogen implication in human hepatocellular carcinoma is associated with changes in estrogen receptors and aromatase expression

Abstract There is evidence that hints at a potential role of sex steroids in development and progression of human hepatocellular carcinoma (HCC). Previous studies have revealed that estrogen receptors (ER) are expressed in primary HCC. However, the use of antiestrogens has failed to improve disease-free and overall survival of patients. In the present study we have investigated aromatase-driven estrogen formation in nontumoral and malignant human liver tissues and cells, also in relation to the expression of ERα, ERβ, and their splicing variants, aiming to get insights into the potential role of estrogens and the underlying mechanism(s) in human HCC. Chromatographic and exon-specific RT-PCR analyses were used to respectively assess activity and expression the aromatase enzyme and the expression of wild-type (hERα66, hERβ1) and variant (hERα46, hERα36; hERβ2/Cx, hERβ5) ER, both in vivo and in vitro. Following 24h and 72h incubation of tissue minces or hepatic cell lines, with either testosterone (T) or androstenedione (Ad) being used as tritiated androgen precursor, human HCC tissues and HepG2 hepatoma cells showed elevated aromatase activity, with estrogen formation rates respectively of 20% at 24h and >95% at 72h. By contrast, no aromatase activity could be detected in nontumoral hepatic tissues and HA22T liver cancer cells at any incubation time. Cirrhotic samples exhibited intermediate enzyme activity, with average estrogen formation rates of nearly 4%, while Huh7 HCC cells gave rise to 34% estrogen formation by 72h. Markedly lower aromatase mRNA levels were observed in HA22T cells and nontumoral liver tissues, as compared to HepG2 cells and HCC samples. Cirrhotic specimens displayed variable transcript levels, comparable in turn to those observed in nontumoral or HCC tissues. Interestingly, no or low expression of both wild type ERα and ERβ could be detected in liver cancer cells and malignant tissues. Conversely, equivalent amounts of the hERα46 variant were observed in both cells and tissues, while hERα36 expression was highest in HepG2 cells and HCC samples, intermediate in Huh7 cells and cirrhotic tissues, and very low in HA22T cells and nontumoral liver. On the other hand, only occasional expression of the two ERβ variants was observed in liver cancer cells and tissues. It is noteworthy that the pattern of hERα36 expression was strictly related to that of the aromatase enzyme, suggesting that this ERα variant may be primarily implicated as a mediator of estrogen action in the malignant liver. The above evidence may advance the current appraisal of the endocrine status of human liver tumors and represent an experimental basis to develop novel, personalized, endocrine therapeutic strategies for HCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1726.

Potential role of estrogen in regulation of the Insulin-like growth factor2–H19 locus in the rat testis

The selective estrogen receptor modulator, tamoxifen, has been shown to reduce DNA methylation at Insulin-like growth factor 2/H19 differentially methylated region ( Igf2/H19 DMR) in the spermatozoa of the Holtzman rats. Since imprint at this locus is acquired during spermatogenesis in the male germ-line, we hypothesized role for estrogen signaling in the methylation dynamics in the testis. The present study was designed to identify putative estrogen response elements (ERE) at Igf2/H19 DMR and their interaction with DNA methylation pathway. Here, we demonstrate presence of functional ERE at 2637/2655 base pair on Igf2/H19 DMR in testicular germ cells, which was found to bind to estrogen receptor β (ERβ) in the chromatin immunoprecipitation assay. Tamoxifen attenuated ERβ-ERE association thereby acting as an estrogen antagonist at this locus. Further mechanistic study involving colocalization and immunoprecipitation assay revealed interaction of ERβ and Dnmt1 in the testis. The study provides evidence for the role for estrogen in acquisition of imprint at Igf2/H19 DMR in testis and help in understanding molecular mechanism of environmental estrogens impacting male fertility.

Gender disparities in hepatocellular cancer survival

e15517 Background: Recent reports suggest that estrogen mediated inhibition of IL-6 protects against the development of HCC and may explain the decreased risk of liver cancer in women. We investigated the relation-hip between gender, age, and survival for patients with localized HCC. Methods: We identified 11,097 patients with localized, histologically defined HCC, from 1988- 2003, using the Surveillance, Epidemiology, and End Results (SEER) registry. Age at diagnosis, sex, ethnicity, and overall survival were evaluated using Cox proportional hazards model. The models were adjusted for treatment modality, tumor differentiation, tumor size, lymph node involvement, and number of lesions; they were stratified by year of diagnosis and SEER registry site. Results: 8,111 (73%) patients were men and 2,986 (27%) were women. In univariate and multivariate analyses, female gender, young age (< 55 yo), and Asian ethnicity were all associated with improved overall survival (p<0.001). In patients less than 55 yo, women had a superior OS and cancer specific survival (CSS) when compared to men (OS: 18 months vs. 9, CSS: 31 months vs. 14, p<0.001). Conversely, in patients older than 55, there were no gender differences (OS: 8 months vs. 8, CSS 13 months vs. 11, p = 0.08). Local therapies, including, ablation (HR = 0.47 [0.43–0.53]), hepatectomy (HR = 0.40 [0.36–0.44]), radiation (HR = 0.67 [0.57–0.78]) and transplantation (HR = 0.17 [0.15–0.20]) were also associated with improved survival. There were no interactions identified between gender and treatment use. Conclusions: To our knowledge, this is the first report to highlight the superior outcome of premenopausal women with HCC compared to men. We postulate a potential role for estrogen in influencing the biology of HCC and the response to treatment. These observations are consistent with ones made in other gastrointestinal cancers and with reported preclinical data suggesting a protective role for estrogen. Further studies that confirm these observations and elucidate the biology of estrogen's influence on HCC are needed. [Table: see text] No significant financial relationships to disclose.

Comparative contents of mRNAs of sex steroid receptors and enzymes of their metabolism in arterial walls of men

The potential role of estrogens in regulation of metabolism in arteries of men was studied. Contents of mRNAs of sex hormone receptors, of some enzymes of their metabolism, and of some potential markers of the hormone effects were determined by real-time polymerase chain reaction in fragments of 18-54-year-old men's large arteries with and without atherosclerotic lesions. Contents of estrogen receptor alpha (ERalpha) and transferrin receptor mRNAs were significantly different in undamaged fragments of the aorta and of the carotid and coronary arteries. Contents of some mRNAs in the carotid artery and aorta were found to correlate, which suggested a similarly directed regulation of their expressions. The levels of ERalpha and aromatase mRNAs negatively correlated with the blood plasma concentration of estradiol. Levels of steroid sulfatase and aromatase mRNAs were lower and the level of estrogen sulfotransferase mRNA was higher in blood vessel fragments with atherosclerotic lesions than in undamaged fragments. It is suggested that large arteries should be different in sensitivity to estrogens and that atherosclerotic lesions could lead to local suppression of the effect of estrogen on the cells of arteries.

Estrogen upregulates proinflammatory IFNγ via IL‐12, IL‐27, and STAT4β phosphorylation

Estrogen has been shown to be involved in many autoimmune diseases. Estrogen-modulated induction of IFNγ and IFNγ-inducible molecules are of key importance due to their potential role in autoimmunity. Therefore, we investigated IFNγ-inducing cytokines and related molecular pathways in splenocytes from estrogen-treated mice. A key IFNγ-inducing cytokine, IL-12p70, was increased in estrogen-treated mice compared to controls. Exposure of splenocytes from estrogen-treated mice to Con-A or rIL-12 induced selective phosphorylation of STAT4β with corresponding increase in expression of IFNγ, IFNγ-inducible nitric oxide, IL6, MCP1. This increase was followed by decreased expression of Th2 transcription factors (STAT6 and STAT5) in estrogen-treated mice. The modulation of IL-12-inducible molecules by estrogen could be due to a macrophage-derived Th1 early-inducing cytokine IL-27. Estrogen-treated mice had noticeably increased IL-27p28 in both from Con-A and LPS stimulated splenocytes and macrophages. rIL-27 also increased T-bet from estrogen samples. Splenocytes from estrogen-treated mice pretreated with IL-27 and then cultured with rIL-12 showed an increasing trend in IFNγ. These findings provide fresh insight into the potential role of estrogen in regulating IFNγ-inducing cytokines and may lead to novel therapeutic approaches in treating autoimmune diseases.