Estrogen Receptor Gene Research Articles

Association of ANXA1 and microRNA gene expression with cancer metastasis: A systematic review.

Metastasis is one of the major obstacles limiting the success treatment of cancer. Annexin A1 (ANXA1) is a key member of the subfamily and belongs to the multi-gene family of annexins, which is known to play an important role in cancer progression and metastasis. Although there were controversies surrounding the relationship between ANXA1 and metastasis, the role of ANXA1 in cancer metastasis has been increasingly recognized. Numerous ANXA1-related signaling pathways are involved in cancer metastasis. Recently through microarray experiments demonstrate that ANXA1 could regulate microRNAs (miRNAs) in cancer, such as miRNA-196a (miR-196a), microRNA-26 (miR-26) and microRNA-562 (miR-562), which promoted cell proliferation and angiogenesis. ANXA1 could regulate miRNAs to directly target NF-κB, estrogen receptor (ER) and angiogenesis gene transcripts. Thus, ANXA1 mediates cancer metastasis may via regulation of miRNA signaling. This review describes the mechanism by which ANXA1 contributes to cancer metastasis and summarizes new advances in research in ANXA1associated cancer metastasis.

A Simple Method to Assess Estrogen Receptor Gene (ESR1) Amplification in Paired Biopsies from Primary Tumor and Recurrence in Breast Cancer Patients Receiving Endocrine Therapy

Globally, Breast Cancer (BC) is the leading cause of cancer death among women. About 75% of patients are diagnosed with hormone-dependent tumors and are set to receive Endocrine Therapy (ET) targeting the estrogen receptor. Unfortunately, a significant proportion of these patients develops ET resistance. Still controversial, studies have proposed that Estrogen Receptor-Alpha Gene (ESR1) alterations may underlie ET resistance. Here, we describe the use of a Chromogenic in Situ Hybridization (CISH) assay for the assessment of ESR1 amplification in primary tumors and recurrences. This assay could be a useful clinical tool with therapeutic implications for estrogen receptor positive BC patients.

Estrogen receptor alpha gene variant, PvuII (rs2234693), as a potential pharmacogenetic biomarker for aneurysmal subarachnoid hemorrhage in postmenopausal women

Aneurysmal subarachnoid hemorrhage (aSAH) occurs more often in postmenopausal women than in men. Estrogen plays an important role in vascular homeostasis. Our aim was to elucidate whether a drop in circulating estradiol in conjunction with variants of estrogen receptor genes have a role in female gender susceptibility to aSAH. A total of 709 subjects were enrolled (349 aSAH patients, 360 controls) and genotyped for rs2234693 or PvuII (intron 1, T>C) in the ESR1 gene and rs4986938 or AluI (exon 8, 1730G>A) of ESR2 gene by PCR-RFLP. Serum estradiol was estimated by ELISA. Estrogen receptor gene expression was studied by qRT-PCR. Logistic regression analysis indicated a significant recessive effect of the T allele of PvuII on aSAH in females, and this association remained statistically significant even after adjusting for confounders(OR 1.702, CI 95% 1.062, 2.726, Pvalue = 0.027). ESR1 gene expression was significantly reduced (P value = 0.0089) in subjects carrying PvuII T allele. In postmenopausal women with TT genotype and low serum estradiol, the odds for developing aSAH were found to be 3.5-fold increase compared with premenopausal women (CI 95% 1.424-8.828, P value = 0.0074). However, this variant showed no significant association with aSAH in men. No significant difference was found in genotype and allelic distribution of AluI polymorphism in ESR2 gene, between patients and controls. We propose that the PvuII T allele could be a potential pharmacogenetic marker for strategizing personal medicine for preventing aSAH in postmenopausal women with low circulating estradiol. Further larger studies in other population are warranted.

Differential Allele-Specific Expression Uncovers Breast Cancer Genes Dysregulated by Cis Noncoding Mutations.

Identifying cancer-relevant mutations in noncoding regions is challenging due to the large numbers of such mutations, their low levels of recurrence, and difficulties in interpreting their functional impact. To uncover genes that are dysregulated due to somatic mutations in cis, we build upon the concept of differential allele-specific expression (ASE) and introduce methods to identify genes within an individual's cancer whose ASE differs from what is found in matched normal tissue. When applied to breast cancer tumor samples, our methods detect the known allele-specific effects of copy number variation and nonsense-mediated decay. Further, genes that are found to recurrently exhibit differential ASE across samples are cancer relevant. Genes with cis mutations are enriched for differential ASE, and we find 147 potentially functional noncoding mutations cis to genes that exhibit significant differential ASE. We conclude that differential ASE is a promising means for discovering gene dysregulation due to cis noncoding mutations.

Association of genetic variants in Estrogen receptor (ESR)1 and ESR2 with susceptibility to recurrent pregnancy loss in Tunisian women: A case control study

Estrogen receptor (ER) signaling is key regulator for maintaining successful pregnancy. Several research suggested that genetic variation in ER genes (ESR)1 and ESR2 is associated with the susceptibility to unexplained recurrent pregnancy loss (RPL), often with inconclusive results. In this study, we investigate the relationship between ESR1 and ESR2 polymorphisms and idiopathic RPL. A total of 444 patients with RPL, defined as three or more consecutive pregnancy losses of unknown etiology, and 446 control women were recruited to the study and their genotypes for ESR1-rs2234693, ESR1-rs3020314, and ESR2-rs928554 variants were determined using allelic exclusion method on real-time polymerase chain reaction. Minor allele frequencies (MAF) of tagging SNPs ESR1 rs2234693 and rs3020314, and ESR2 rs928554 were not significantly different between RPL cases and control women. Considerable higher frequencies of homozygous (2/2) ESR1 rs2234693 genotype carriers were seen between patients vs. control women, which maintained after controlling for age, body mass index (BMI), and menarche. ESR1 haplotype analysis demonstrated two common haplotype (rs2234693-rs3020314) with no linkage disequilibrium between both polymorphisms, and no 2-locus haplotype linked with RPL risk was revealed.The present study confirmed a significant association of specific ESR1 variant (rs2234693) with an increased risk of RPL, further supporting a role for ESR1 as an important candidate locus inducing RPL.

Identification of California condor (Gymnogyps californianus) estrogen receptor variants and their activation by xenoestrogens

California condors released in costal sites are exposed to high levels of xenoestrogens, particularly p,p′-DDE, through scavenging of marine mammal carcasses. As a result, coastal condors carry a higher contaminant loads and experience eggshell thinning when compared to their inland counterparts. Given that condor estrogen receptors (Esrs) are activated by physiologically relevant levels of xenoestrogens, differences in vulnerability to endocrine disruption may exist depending on which Esr variant(s) an individual condor possesses. This work aims to characterize genetic polymorphisms in estrogen receptor genes (ESRs) in California condors; one identified for condor estrogen receptor 1 (ESR1) (N161S, E162D) and one in the ESR2 (T114M) gene. Each variant was confirmed in individual founder birds by direct PCR sequencing as well as in first generation offspring to understand the introduction of the alleles into the pedigree (6 birds for ESR1 and 5 birds for ESR2). Site-directed mutagenesis was performed on wild type receptors to produce each of the full-length ESR variants and activation of Esr1 and Esr2 variant and wild type receptors by xenoestrogens was compared. Maximal activation of the variant form of Esr1 was significantly higher (p < 0.05) in response to ethinyl estradiol (EE2), o,p′-DDE, p,p′-DDE, p,p′-DDT and p,p′-DDD compared to wild type Esr1. For Esr2 the wild type maximal activation was higher in response to o,p′-DDE, p,p′-DDE, o,p′-DDT, and p,p′-DDT. Although significant differences in activation of condor Esr variants by xenoestrogens occurred at high (micromolar) concentrations, they correspond to circulating concentrations previously reported in coastal birds. Release and relocation of California condors to the coast is a promising avenue for recovery, however, reproductive problems associated with xenoestrogen exposure pose a sub-lethal threat to long-term success. Based on above findings, future release decisions could be informed by ESR form(s) individual birds possess to reduce deleterious effects of xenoestrogen exposure and ultimately improve reproductive success in wild populations.

Polymorphisms of Estrogen Receptor-α and Estrogen Receptor-β Genes and its Expression in Endometriosis

Objectives Endometriosis is a common gynecological disorder, characterized by the presence of endometrial-like tissue in the extrauterine location. The increasing estradiol concentration can influence endometriosis risk and estrogen receptor (ER) activity. Polymorphism in ER causes gene expression alteration and influences hormone-receptor interaction. This research aims to determine ER genetic polymorphisms in endometriosis pathogenesis. Materials and methods This study was performed on case-control polymorphisms, which compared 83 women with endometriosis and 76 women without endometriosis. However, the samples used for ER gene expression analysis and estrogen level measurement were obtained from 18 women with endometriosis and 18 women without endometriosis. Polymerase chain reaction-restriction fragment length polymorphism was used to determine ER genetic polymorphisms. Chi-square, Mann-Whitney test, Spearman's correlation (p), t-independent, and two-tailed tests were used to analyze the data. Results Association between the allele ERα rs9340799 A/G and endometriosis was significantly different (p=0.012), whereas rs2234693 T/C polymorphism showed no association with endometriosis. The correlation between the genotype frequencies of allele ERβ rs4986938 G/A and endometriosis was found significantly different (p=0.015; p=0.034). Conclusion Estradiol level and ERβ expression increases, polymorphism genotypes and alleles of ERβ rs4986938 G/A gene and allele frequency of ERα rs9340799 A/G gene have roles in endometriosis.

ROLE OF COL1A1 AND G2046T GENES IN UZBEKS WITH JUVENILE DYSMENORRHEA IN THE PRESENCE OF CRITERIA FOR UNDIFFERENTIATED CONNECTIVE TISSUE DYSPLASIA

Clinical and genetic examination of 118 girls was conducted, with signs of connective tissue dysplasia (СTD) - 64 and without it - 54, the control group consisted of 68 healthy girls with normal menstruation. The basis for the diagnosis of dysmenorrhea was a complaint of painful menstruation. An analysis of the distribution of allelic variants of the COL1A1 G2046T gene showed that in the group of patients with juvenile disease accompanied by СTD significantly higher compared with the control group of practically healthy individuals, only a tendency toward the reliability of alleles was observed, but they did not reach true significance. The study of the association of the COL1A1 G2046T genotype showed a significant increase in the mutant TT genotype in the group of girls with juvenile disease with СTD, compared with practically healthy individuals. Therefore, the single nucleotide variant of COL1A1 G2046T plays a role in the pathogenesis of the development of juvenile disease accompanied by СTD. This is indirectly confirmed by the indicators of oxyproline, an increase in which was significant both in comparison with practically healthy individuals and in comparison with a group of patients with juvenile disease without signs of СTD, suggests that this polymorphism is only one of the polymorphisms involved in the pathogenesis of the studied pathology. Based on the foregoing, we can conclude that the occurrence of the mutant allele of the estrogen receptor gene - alpha (single nucleotide replacement of guanine with adenine in rs2228480) is 1.9 times higher in the group of girls with juvenile dysfunction with СTD than in the group of juvenile dysfunction with СTD (χ2 = 4.515; p = 0.03). A significant difference was also found in the frequency of occurrence of type I collagen gene polymorphism (single nucleotide replacement of guanine with thymine in rs1800012) was found in girls with juvenile disease with СTD only in comparison with a group of healthy individuals (χ2 = 4.71; p = 0.03).

ASSESSMENT OF ESTROGEN RECEPTOR GENE POLYMORPHISM (T-397C VARIANT) IN PATIENTS WITH PREMENSTRUAL SYNDROME

The aim:of the study is to determine the frequency of polymorphism of estrogen receptor gene ESR1 (T-397C variant) in patients with premenstrual syndrome. Materials and methods: 50 women with diagnosis of premenstrual syndrome (the basic group) and 25 persons without it (the control group) were examined. Polymerase chain reaction was used to study T-397C polymorphism of estrogen receptor gene ESR1. Results:There was no significant difference in allele and genotype rates of ESR1 gene between persons with premenstrual syndrome and controls. TT genotype was determined in 24.0 % women in the control group and 24 % of patients in basic group (OR=1.00, 95 % CI=0.32-3.08, p=1.00), TC genotype - in 52.0 % and 46.0 % of individuals respectively (OR=0.79, 95 % CI=0.30-2.06, p=0.62), CC genotype - 24.0 % and 30.0 % of women respectively (OR=1.36, 95 % CI=0.45-4.07, p=0.59). Also, the frequency of T allele and C allele was similar in individuals with pathology and healthy women. There was no significant difference in allele and genotype rates of T-397C variant of ESR1 gene between patients with mild and severe forms of premenstrual syndrome and controls. Conclusions: There is no association of T-397C polymorphic variant of estrogen receptor gene ESR1 with the development of premenstrual syndrome.

The effect of standard laboratory diets on estrogen signaling and spatial memory in male and female rats

Phytoestrogens are plant-derived compounds that can modulate estrogen activity in the brain and periphery. Laboratory rodent diets are typically high in soy-based phytoestrogens and therefore may influence neurophysiological and behavioural measures that are sensitive to estrogen signaling. Here we assessed such measures in rats (males and females) fed Australian made diets that varied in their soy levels. We found that a low-soy diet promoted greater weight, and lower levels of plasma estradiol, particularly in male rats. It also produced sex-specific effects on estrogen receptor gene expression in the brain, increasing ESR2 expression in the hippocampus and prefrontal cortex in female rats, and decreasing dopamine D1 receptor gene expression in the striatum of both male and female rats. We also found a dietary effect on short-term place recognition memory, but this was independent of soy levels in the diet. These results demonstrate that the choice of rodent laboratory diet can influence physiology, neurobiology and behavior, particularly on measures related to estrogen signaling.

Dose Dependence of Hypermethylation of Gene Promoters in Blood Leukocytes in Humans Occupationally Exposed to External γ-Radiation

Abstract—A study of promoter hypermethylation of cell cycle (RASSF1A, p16/INK4A, p14/ARF, p53, АТМ), xenobiotic detoxification (GSTP1), antioxidant defense (SOD3), and estrogen receptor (ESR1) genes in blood leukocytes of 88 nuclear industry workers from the Mayak facility (53–86 years old at sampling) exposed to prolonged external γ-radiation was carried out. Accumulated doses to red bone marrow (RBM) ranged from 0.2 to 2.95 Gy. The time between the end of work with radiation and blood sampling was on average 15.95 ± 1.22 years. Fifty unirradiated residents of Ozyorsk matched by age to the exposed group were enrolled as a control group. Promoter hypermethylation was analyzed using methylation-sensitive polymerase chain reaction (PCR) assay. The trend towards dependence of promoter hypermethylation of p14/ARF and RASSFA genes on age rather than radiation exposure (logistic regression: p = 0.072) confirms previous results. The frequency of individuals with promoter methylation of at least one of the following six genes: p16/INK4A, GSTP1, р53, АТМ,SOD3,ESR1, in irradiated group was significantly higher than in the control group (62.5 versus 34%, respectively, p = 0.001, OR = 3.24, 95% CI 1.56–6.69). A significantly elevated frequency of individuals with hypermethylated СpG islands in GSTP1 and SOD3 promoters was revealed among exposed subjects compared to the control group (p = 0.014 and p = 0.021, respectively). A statistically significant association between the cumulative dose and the number of methylated promoters was revealed (r = 0.304, р = 3.2 × 10–4). Therefore, the dose-dependent hypermethylation of CpG islands in gene promoters that is revealed in blood leukocytes long term after external exposure to γ-radiation was found.

The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy.

Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of ESR1 mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring ESR1 mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of ESR1 mutant breast cancer, and highlight the potential clinical developments in this field.

Glutathione peroxidase-1 regulates adhesion and metastasis of triple-negative breast cancer cells via FAK signaling

Triple-negative breast cancer (TNBC) cells, which do not express genes for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu, develop highly aggressive and metastatic tumors resistant to chemo- and hormonal therapies. We found that expression of glutathione peroxidase-1 (Gpx1) is silenced in the non-TNBC cells but significantly maintained in the TNBC cell lines. Such Gpx1 expression plays a vital role in the metastasis of TNBC cells by regulating cell adhesion. Transcriptomic and signaling pathway analyses demonstrate that depletion of Gpx1 essentially impairs cell adhesion/spreading by down-regulating FAK/c-Src activation. Mechanistically, Gpx1 interacts with FAK kinase and prevents the kinase inactivation by H2O2, not lipid hydroperoxide. As a result, depletion of Gpx1 suppresses lung metastasis of TNBC cells in vivo. Overall, our study identifies that Gpx1 is a redox safeguard of FAK kinase and its inhibition may provide an effective way to control the metastasis of deadly malignant TNBC.

Effects of vitamin D and estrogen receptor polymorphisms on bone mineral density in adolescents with anorexia nervosa.

Background Anorexia nervosa (AN) is a serious eating disorder that is associated with decreased bone mineral density (BMD) and greater lifetime risk for fractures. The aim of this study was to determine the correlation between BMD and genetic polymorphisms in AN. Methods This case-control study analyzed vitamin D receptor (VDR) (VDRBsml, VDRFokl) and estrogen receptor (ESR) (ESR1Xbal, ESR1Pvull) polymorphisms in 45 adolescents diagnosed with AN and 46 age-matched healthy controls. BMD values of the AN group were classified as low or normal, and polymorphisms were compared between cases and controls. The effects of body mass index (BMI), duration of disease and amenorrhea on BMD were also evaluated. Results In girls with AN, a positive effect of the bb genotype of VDRBsmI polymorphism on femur Z-scores (p = 0.103) and of the Ff genotype of VDRFokI polymorphism on vertebra Z-scores (p = 0.097) was observed. In boys with AN, a positive effect of the Ff genotype of VDRFokI polymorphism on vertebra BMD (g/cm2) was detected (p = 0.061). No association was detected between ESR polymorphisms. An inverse relationship was observed between BMD and duration of illness and amenorrhea. A direct relationship was detected between BMD and BMI. Conclusions Specific VDR gene polymorphism genotypes may have positive effects on BMD in patients with AN. Additionally, the lack of association between ESR gene polymorphisms on BMD could be attributed to the low estrogen status of the patient.

Primary hippocampal estrogenic dysfunction induces synaptic proteins alteration and neuronal cell death after single and repeated paraquat exposure

The extensively utilized herbicide Paraquat (PQ) was reported to generate cognitive disorders and hippocampal neuronal cell death after unique and extended exposure. Although, most of the mechanisms that mediate these actions remain unknown. We researched whether PQ induces synaptic protein disruption, Tau and amyloid beta protein formation, oxidative stress generation, and hippocampal neuronal cell loss through anti-estrogen action in primary hippocampal neurons, after day and two weeks PQ treatment, as a probable mechanism of such learning and memory impairment. Our results reveal that PQ did not alter estrogen receptors (ERα and ERβ) gene expression, yet it decreased ER activation, which led to synaptic proteins disruption and amyloid beta proteins generation and Tau proteins hyperphosphorylation. Estrogenic signaling disruption induced by PQ also downregulated the NRF2 pathway leading to oxidative stress generation. Finally, PQ exposure induced cell death mediated by ER dysfunction partially through oxidative stress and amyloid beta proteins generation and Tau proteins hyperphosphorylation. The results presented provide a therapeutic strategy to protect against PQ toxic effects, possibly giving an explanation for the learning and memory impairment generated following PQ exposure.

Evaluation of sanger sequencing method for ESR1 mutation detection in primary breast tumor

Objective: Exon 8 estrogen receptor 1 (ESR1) mutations in the ligand-binding domain play an important role in mechanisms of hormonal therapy resistance in breast cancer. Identification of ESR1 mutations is very important in determining the appropriate steps of therapy. In this study, we evaluate Sanger sequencing technique to detect the ESR1 mutation. Methods: This retrospective study was conducted using 49 advanced breast cancer patients with estrogen receptor positive. Deoxyribonucleic acid (DNA) material was extracted from primary breast tumor samples. Exon 8 ESR1 gene mutation was analyzed by Sanger sequencing method using BigDye Direct Sequencing Kit (Applied Biosystem) with gBlock synthesis gene fragment (Integrated DNA Technologies) D538G as a positive control. Results: The mean age of patients was 46.14 (±9.6) years, and 61.2% were in stage 4. There are no exon 8 ESR1 gene mutations detected in 49 primary tumor samples, whereas the gBlock-positive control showed base substitution in 1613A>G (D538G) indicating the success of sequencing reaction. Conclusion: Sanger sequencing has failed to detect ESR1 mutation in primary tumor breast samples. Other advanced molecular techniques should be performed for diagnosis of primary breast tumors.

DNA Methylation in Healthy Older Adults With a History of Childhood Adversity-Findings From the Women 40+ Healthy Aging Study.

Background: Adversity in early development seems to increase the risk of stress-related somatic disorders later in life. Physiologically, functioning of the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes is often discussed as long-term mediators of risk. In particular, DNA methylation in the glucocorticoid receptor gene promoter (NR3C1) has been associated with type and strength of early life adversity and subsequent effects on HPA axis signaling in humans. Animal studies, moreover, suggest changes in DNA methylation in the estrogen receptor gene (ERα) upon early life adversity. We investigated the association of type and severity of childhood adversity with methylation in NR3C1 and ERα and additionally considered associations between methylation and steroid hormone secretion. Methods: The percentage of methylation within the NR3C1 promoter and the ERα shore was investigated using dried blood spot samples of 103 healthy women aged 40–73 years. Childhood adversity was examined with the Childhood Trauma Questionnaire. Linear regression analyses were performed with methylation as dependent variable and the experience of emotional abuse and neglect, physical abuse and neglect, and sexual abuse (compared to non-experience) as independent variables. All analyses were controlled for age, BMI, annual household income, and smoking status and were adjusted for multiple testing. Results: Overall, over 70% of the sample reported having experienced any kind of abuse or neglect of at least low intensity. There were no significant associations between childhood adversity and methylation in the NR3C1 promoter (all p > .10). Participants reporting emotional abuse showed significantly higher methylation in the ERα shore than those who did not (p = .001). Additionally, higher levels of adversity were associated with higher levels of ERα shore methylation (p = .001). Conclusion: In healthy women, early life adversity does not seem to result in NR3C1 promoter hypermethylation in midlife and older age. This is the first study in humans to suggest that childhood adversity might, however, epigenetically modify the ERα shore. Further studies are needed to gain a better understanding of why some individuals remain healthy and others develop psychopathologies in the face of childhood adversity.

The correlation of sexual dysfunction and estrogen receptor gene polymorphism in Chinese Han women with epilepsy

Objective To investigate the correlation between sexual dysfunction(SD)and estrogen receptor (ER) gene polymorphism in Chinese Han women with epilepsy (WWE). Methods A total of 112 married Chinese Han women with epilepsy were collected from outpatients and inpatients of the Affiliated Hospital of Yangzhou University, and 120 matched healthy women were taken as the control group.WWE were treated with antiepileptic drugs (AEDs) for one year or more.The Chinese version of female sexual function index (FSFI) was used to investigate the sexual function of the subjects.The chemiluminescence method was used to detect the sex hormones levels such as prolactin(PRL), follicle-stimulating hormone(FSH), luteinizing hormone(LH), estradiol(E2), progesterone(P) and testosterone(T). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the ER gene polymorphism.Chi-square test, t-test and binary logistic regression were used for statistical analysis.The differences of the sexual function, sex hormone, ER genotype, and allele frequency were compared between the two groups.And the correlation between SD and ER gene polymorphism was analyzed. Results (1) The proportion of SD in Chinese Han WWE was 70.5%(79/112), while that was 24.2%(29/120) in the control group.The serum prolactin (PRL) level in the WWE group was significantly higher than that in the control group (t=2.072, P=0.039). (2) The allele frequencies of ER PvuII C and AluI A in the WWE group were significantly higher than those in the control group (P=0.001; P=0.001). (3) Binary logistic regression analysis showed that PvuII CC genotype and serum testosterone level were independently correlated with SD (OR=6.074, 95%CI: 1.257-29.352, P=0.025; OR=0.412, 95%CI: 0.201-0.842, P=0.015). Conclusion ERα PvuII polymorphism may be related to the susceptibility of SD in Chinese Han WWE, and PvuII CC genotype may be the risk genotype of SD in WWE. Key words: Epilepsy; Women; Sexual dysfunction; Sex hormone; Estrogen receptor

High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer

The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts. HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort. Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ2 = 12.07; P = 0.002) and advanced nuclear grade (χ2 = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes. Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.

Dysregulated expression of repetitive DNA in ER+/HER2- breast cancer

Limited studies on breast cancer indicated pathogenic changes in the expressions of some repeat elements. A global analysis was much needed within this context to distinguish the most significant repeats from more than a thousand repeat motifs. Utilising a previously presented RNA-seq dataset, we studied expression changes of all repeats in ER+/HER2- human breast tumour samples obtained from 22 patients in comparison to matched normal tissues. Fifty six (56) repeat subtypes including satellites and transposons were found to be differentially expressed and most of them were novel for breast cancer. HERVKC4-int and HERV1_LTRc, whose expressions correlated well with that of the estrogen receptor gene ESR1, were upregulated at the highest level. REP522 and D20S16 satellites were also significantly upregulated along with insignificant increases in the expressions of other satellites including HSATI and BSR/beta. Interestingly, expressions of REP522 and D20S16 correlated with many key breast cancer pathway (e.g. BRCA1, BRCA2, AKT1, MTOR, KRAS) and survival genes; possibly highlighting their importance in the carcinogenesis of breast. Additional differentially expressed elements such as L1P and various MER transposons also exhibited a similar pattern. Finally, our repeat enrichment analysis on the promoters of differentially expressed genes revealed further links between additional repeats and nearby genes.