Estrogen receptor and aryl hydrocarbon receptor signaling pathways

Estrogen receptors (ERs) and the aryl hydrocarbon receptor (AhR) are ligand activated transcription factors and members of the nuclear receptor and bHLH-PAS superfamilies, respectively. AhR is involved in xenobiotic metabolism and in mediating the toxic effects of dioxin-like compounds. Crosstalk has been observed among AhR and nuclear receptors, but has been most well studied with respect to ER signaling. Activated AhR inhibits ER activity through a number of different mechanisms, whereas ERα has been reported to have a positive role in AhR signaling. Here we will discuss recent data revealing that dioxin bound AhR recruits ERα to AhR regulated genes. We will also consider the implications of ER recruitment to AhR target genes on ER and AhR signaling

The Environmental Estrogen Bisphenol A Inhibits Estradiol-Induced Hippocampal Synaptogenesis

Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers, as well as the BPA-containing plastics used in dental prostheses and sealants, considerable potential exists for human exposure to this compound. In this article we show that treatment of ovariectomized rats with BPA dose-dependently inhibits the estrogen-induced formation of dendritic spine synapses on pyramidal neurons in the CA1 area of the hippocampus. Significant inhibitory effects of BPA were observed at a dose of only 40 μg/kg, below the current U.S. Environmental Protection Agency reference daily limit for human exposure. Because synaptic remodeling has been postulated to contribute to the rapid effects of estrogen on hippocampus-dependent memory, these data suggest that environmental BPA exposure may interfere with the development and expression of normal sex differences in cognitive function, via inhibition of estrogen-dependent hippocampal synapse formation. It may also exacerbate the impairment of hippocampal function observed during normal aging, as endogenous estrogen production declines

Predictors of antiproliferative effect of lanreotide autogel in advanced gastroenteropancreatic neuroendocrine neoplasms

PURPOSE: The antiproliferative properties of lanreotide autogel (LAN) in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) were demonstrated in the CLARINET study. However, there is limited literature regarding factors that affect progression-free survival (PFS) in patients with GEP NENs treated with LAN. METHODS: We identified a total of 191 treatment-naive patients with advanced GEP NENs and positive SSTR uptake on imaging (Octreoscan or 68Gallium DOTATATE Positron Emission Tomography [68GaPET]) who received first-line LAN monotherapy, albeit at various starting doses (60, 90 or 120 mg/month). A group of 102 patients who initiated treatment at the standard dose of 120 mg/month were included in the study and further evaluated by univariate and multivariate analyses to identify predictors of PFS. RESULTS: The location of tumour primary was in the small bowel in 63 (62%), pancreas in 31 (30%) and colon/rectum in 8 patients (8%). The tumours were well-differentiated, and the majority were grade 1 (52%), or 2 (38%). About 60% of cases had progressive disease at the time of treatment initiation. Most patients with available pretreatment nuclear medicine imaging (Octreoscan or 68Ga PET) had a Krenning score of 3 (44%) or 4 (50%). The median PFS for the entire cohort was 19 months (95% CI 12, 26 months). The univariate analysis demonstrated that grade 2 tumours, progressive disease at baseline and metastatic liver disease were associated with a significantly shorter PFS, while other evaluated variables did not affect PFS at a statistically significant level. However, at multivariate analysis only the tumour grade remained statistically significant. CONCLUSIONS: The current study showed that, of many evaluated variables, only the tumour grade was predictive of PFS duration and this should be considered during patient selection for treatment

Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival

International audienc

Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts

Cells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β- catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML

Genes targeted by the estrogen and progesterone receptors in the human endometrial cell lines HEC1A and RL95-2

<p>Abstract</p> <p>Background</p> <p>When the steroid hormones estrogen and progesterone bind to nuclear receptors, they have transcriptional impact on target genes in the human endometrium. These transcriptional changes have a critical function in preparing the endometrium for embryo implantation.</p> <p>Methods</p> <p>382 genes were selected, differentially expressed in the receptive endometrium, to study their responsiveness of estrogen and progesterone. The endometrial cell lines HEC1A and RL95-2 were used as experimental models for the non-receptive and receptive endometrium, respectively. Putative targets for activated steroid hormone receptors were investigated by chromatin immunoprecipitation (ChIP) using receptor-specific antibodies. Promoter occupancy of the selected genes by steroid receptors was detected in ChIP-purified DNA by quantitative PCR (qPCR). Expression analysis by reverse transcriptase (RT)-PCR was used to further investigate hormone dependent mRNA expression regulation of a subset of genes.</p> <p>Results</p> <p>ChIP-qPCR analysis demonstrated that each steroid hormone receptor had distinct group of target genes in the endometrial cell lines. After estradiol treatment, expression of estrogen receptor target genes predominated in HEC1A cells (n = 137) compared to RL95-2 cells (n = 35). In contrast, expression of progesterone receptor target genes was higher in RL95-2 cells (n = 83) than in HEC1A cells (n = 7) after progesterone treatment. RT-PCR analysis of 20 genes demonstrated transcriptional changes after estradiol or progesterone treatment of the cell lines.</p> <p>Conclusions</p> <p>Combined results from ChIP-qPCR and RT-PCR analysis showed different patterns of steroid hormone receptor occupancy at target genes, corresponding to activation or suppression of gene expression after hormone treatment of HEC1A and RL95-2 cell lines.</p

Differential Effects of Short Term Feeding of a Soy Protein Isolate Diet and Estrogen Treatment on Bone in the Pre-Pubertal Rat

BACKGROUND: Previous reports suggest that beneficial effects of soy on bone quality are due to the estrogenic actions of isoflavone phytochemicals associated with the protein. However, mechanistic studies comparing the effects of soy diet and estrogens on bone, particularly in rapidly growing animals are lacking. METHODOLOGY AND PRINCIPAL FINDINGS: We studied the effects of short term feeding of soy protein isolate (SPI) on bone in comparison to the effects of 17β-estradiol (E2) in pre-pubertal rats. Female rats were weaned to one of 4 treatments: 1) a control casein-based diet (CAS); 2) CAS with subcutaneous E2 (10 µg/kg/d) (CAS+E2); 3) a SPI-containing diet (SPI); or 4) SPI with subcutaneous E2 (SPI) or SPI with 10 µg/kg/d E2 (SPI+E2) for 14 days beginning on postnatal day 20. SPI increased while E2 decreased bone turnover compared to CAS. In contrast, both treatments decreased serum sclerostin levels. Microarray analysis of RNA isolated from bone revealed 652 genes regulated by SPI, 491 genes regulated by E2, and 266 genes regulated by both SPI diet and E2 compared to CAS. The expression of caveolin-1, a protein localized in the cell membrane, was down-regulated (p<0.05) in rats fed SPI, but not by E2 compared to rats fed casein. Down-regulation of caveolin-1 by SPI was associated with increased BMP2, Smad and Runx2 expression in bone and osteoblasts (p<0.05). CONCLUSIONS/SIGNIFICANCE: These results suggest SPI and E2 have different effects on bone turnover prior to puberty. Approximately half of the genes are regulated in the same direction by E2 or SPI, but in combination, SPI blocks the estrogen effects and returns the profile towards control levels. In addition, there are E2 specific and SPI-specific gene changes related to regulation of bone formation

DAX-1 expression in human breast cancer: comparison with estrogen receptors ER-α, ER-β and androgen receptor status

BACKGROUND: So far there have been no reports on the expression pattern of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) in human breast cells and its relationship to the estrogen receptors, ER-α and ER-β, and the androgen receptor (AR). METHODS: In this study we evaluated, by immunohistochemistry and Western blot analysis, the presence and distribution of DAX-1 in benign breast disease (BBD), in situ carcinoma (CIS), and ductal and lobular breast carcinomas. RESULTS: In BBD and breast carcinomas, DAX-1 was present in both the nuclei and the cytoplasm of epithelial cells, although in infiltrative carcinomas the percentage of nuclear immunoreaction was higher than in CIS. An important relation was observed between DAX-1 and AR expression and between this orphan receptor and nodal status. CONCLUSION: DAX-1 might modify the AR and ER-β intracellular location, and because a direct positive relation between the expression of these three receptors was found it could be assumed that the presence of DAX-1 in neoplastic cells might indicate a possible failure of endocrine therapies

Working Group on Biological Parameters (WGBIOP) 2021

The main objective of the Working Group on Biological Parameters (WGBIOP) is to review the status, issues, developments, and quality assurance of biological parameters used in assessment and management. WGBIOP (1) plans workshops, exchanges, and validation studies on a range of biological varia-bles to review the quality of information supplied for stock assessment and improve quality as-surance and training; (2) investigates data availability and develops documentation and methods to improve communication between data collectors and end-users; (3) delivers new and im-proved functionality for the SmartDots platform. Four otolith exchanges and two workshops were completed in 2020–2021 using SmartDots— eight further exchanges are ongoing. Proposed future exchanges and workshops were reviewed and approved. The development of the SmartDots platform proceeded with the inclusion of the maturity, eggs, atresia, fecundity, and larval identification modules into the software version. A live SmartDots tutorial for event coordinators was conducted. Work to further develop quality assurance guidelines—and review national applications of these—progressed. Age and maturity validation studies were reviewed and a new method for prioritizing future validation work was proposed. Progress with the Stock Identification Database (SID) was reviewed, and the potential for creating a WGBIOP library collection and active involvement of WGBIOP in updating FishBase.org data were evaluated. The importance of identifying and documenting links be-tween all relevant databases and document repositories was identified, and a task to address this was initiated. Work on improving the feedback loop between data collectors and stock assessors on the usage and quality of biological parameters in stock assessment continued. Moving forward, WGBIOP aims to continue collaboration with WGALES and WGSMART on the development of the SmartDots platform, encouraging cross-group sharing of skills and ex-perience to optimize results. WGBIOP aims to improve accessibility to its outputs through up-dates to SID and FishBase.org, and the potential creation of a WGBIOP library collection. WGBIOP hopes to improve two-way communication between data collectors and end-users around the quality and utility of biological parameters used in assessment. WGBIOP also aims to amalgamate all validation activities into one coherent workstream.ICE