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Background: Chemicals that induce mammary tumors in rodents or activate estrogen or progesterone signaling are likely to increase breast cancer (BC) risk. Identifying chemicals with these activities can prompt steps to protect human health. Objectives: We compiled data on rodent tumors, endocrine activity, and genotoxicity to assess the key characteristics (KCs) of rodent mammary carcinogens (MCs), and to identify other chemicals that exhibit these effects and may therefore increase BC risk. Methods: Using authoritative databases, including International Agency for Research on Cancer (IARC) Monographs and the US Environmental Protection's (EPA) ToxCast, we selected chemicals that induce mammary tumors in rodents, stimulate estradiol or progesterone synthesis, or activate the estrogen receptor (ER) in vitro. We classified these chemicals by their genotoxicity and strength of endocrine activity and calculated the overrepresentation (enrichment) of these KCs among MCs. Finally, we evaluated whether these KCs predict whether a chemical is likely to induce mammary tumors. Results: We identified 279 MCs and an additional 642 chemicals that stimulate estrogen or progesterone signaling. MCs were significantly enriched for steroidogenicity, ER agonism, and genotoxicity, supporting the use of these KCs to predict whether a chemical is likely to induce rodent mammary tumors and, by inference, increase BC risk. More MCs were steroidogens than ER agonists, and many increased both estradiol and progesterone. Enrichment among MCs was greater for strong endocrine activity vs. weak or inactive, with a significant trend. Discussion: We identified hundreds of compounds that have biological activities that could increase BC risk and demonstrated that these activities are enriched among MCs. We argue that many of these should not be considered low hazard without investigating their ability to affect the breast, and chemicals with the strongest evidence can be targeted for exposure reduction. We describe ways to strengthen hazard identification, including improved assessments for mammary effects, developing assays for more KCs, and more comprehensive chemical testing. https://doi.org/10.1289/EHP13233, Introduction Breast cancer (BC) recently surpassed lung cancer to become both the most commonly diagnosed cancer type and leading cause of cancer death among women worldwide. (1) In the United [...]

Epidemiological studies focusing on the association between folate and breast cancer risk reported inconsistent findings. We conducted a systematic search of the literature using PubMed and EMBASE databases. A total of 23 prospective studies involving 41,516 cases and 1,171,048 individuals were included for meta-analysis. Folate intake may decrease the risk of oestrogen receptor (ER) negative (-) and ER-/progesterone receptor (PR)- breast cancer, with pooled risk ratios (RRs) of 0.88 [95% confidence interval (CI): 0.78-1.00] and 0.82 (95% CI: 0.68-0.97), respectively. An increment of folate intake of 100 [mu]g per day was associated with a deceased risk of ER- (RR = 0.94, 95% CI: 0.88-0.99) and ER-/PR- (RR = 0.90, 95% CI: 0.85-0.97) breast cancer. Moreover, high folate intake may have preventive effects against breast cancer in premenopausal women (RR = 0.94, 95% CI: 0.88-1.00) and individuals with moderate or high levels of alcohol consumption (RR = 0.82, 95% CI: 0.72-0.94)., Author(s): Jie Zeng [sup.1], Kun Wang [sup.2], Fayin Ye [sup.1], Lin Lei [sup.1], Yun Zhou [sup.1], Jia Chen [sup.1], Guohua Zhao [sup.1], Hui Chang [sup.1] [sup.2] Author Affiliations: (1) College [...]

Background: Established breast cancer risk factors, such as hormone replacement therapy and reproductive history, are thought to act by increasing estrogen and progesterone (P4) activity. Objective: We aimed to use in vitro screening data to identify chemicals that increase the synthesis of estradiol (E2) or P4 and evaluate potential risks. Method: Using data from a high-throughput (HT) in vitro steroidogenesis assay developed for the U.S. Environmental Protection Agency (EPA) ToxCast program, we identified chemicals that increased estradiol (E2-up) or progesterone (P4-up) in human H295R adrenocortical carcinoma cells. We prioritized chemicals by their activity. We compiled in vivo studies and assessments about carcinogenicity and reproductive/developmental (repro/dev) toxicity. We identified exposure sources and predicted intakes from the U.S. EPA's ExpoCast. Results: We found 296 chemicals increased E2 (182) or P4 (185), with 71 chemicals increasing both. In vivo data often showed effects consistent with this mechanism. Of the E2- and P4-up chemicals, about 30% were likely repro/dev toxicants or carcinogens, whereas only 5-13% were classified as unlikely. However, most of the chemicals had insufficient in vivo data to evaluate their effects. Of 45 chemicals associated with mammary gland effects, and also tested in the H294R assay, 29 increased E2 or P4, including the well-known mammary carcinogen 7,12- dimethylbenz(a)anthracene. E2- and P4-up chemicals include pesticides, consumer product ingredients, food additives, and drinking water contaminants. Discussion: The U.S. EPA's in vitro screening data identified several hundred chemicals that should be considered as potential risk factors for breast cancer because they increased E2 or P4 synthesis. In vitro data is a helpful addition to current toxicity assessments, which are not sensitive to mammary gland effects. Relevant effects on the mammary gland are often not noticed or are dismissed, including for 2,4- dichlorophenol and cyfluthrin. Fifty-three active E2-up and 59 active P4-up chemicals that are in consumer products, food, pesticides, or drugs have not been evaluated for carcinogenic potential and are priorities for study and exposure reduction. https://doi.org/10.1289/EHP8608, Introduction People are exposed to chemicals that affect hormonal regulation through diet (e.g., food and water), consumer products, pesticides, pharmaceuticals, and industrial processes. Although there is concern about adverse health [...]

Whole slide imaging (WSI) offers a convenient, tractable platform for measuring features of routine and special-stain histology or in immunohistochemistry staining by using digital image analysis (IA). We now routinely use IA for quantitative and qualitative analysis of theranostic markers such as human epidermal growth factor 2 (HER2/neu), estrogen and progesterone receptors, and Ki-67. Quantitative IA requires extensive validation, however, and may not always be the best approach, with pancreatic neuroendocrine tumors being one example in which a semiautomated approach may be preferable for patient care. We find that IA has great utility for objective assessment of gastrointestinal tract dysplasia, microvessel density in hepatocellular carcinoma, hepatic fibrosis and steatosis, renal fibrosis, and general quality analysis/quality control, although the applications of these to daily practice are still in development. Collaborations with bioinformatics specialists have explored novel applications to gliomas, including in silico approaches for mining histologic data and correlating with molecular and radiologic findings. We and many others are using WSI for rapid, remote-access slide reviews (telepathology), though technical factors currently limit its utility for routine, high-volume diagnostics. In our experience, the greatest current practical impact of WSI lies in facilitating long-term storage and retrieval of images while obviating the need to keep slides on site. Once the existing barriers of capital cost, validation, operator training, software design, and storage/back-up concerns are overcome, these technologies appear destined to be a cornerstone of precision medicine and personalized patient care, and to become a routine part of pathology practice. (doi: 10.5858/arpa.2016-0265-SA), Pathologists make crucial diagnoses and issue reports that directly affect patient care, primarily using microscopes and hematoxylin-eosin (H&E)-stained tissue with techniques that have not changed since the 19th century (1,2) [...]

Background Bayesian networks (BNs) are machine-learning-based computational models that visualize causal relationships and provide insight into the processes underlying disease progression, closely resembling clinical decision-making. Preoperative identification of patients at risk for lymph node metastasis (LNM) is challenging in endometrial cancer, and although several biomarkers are related to LNM, none of them are incorporated in clinical practice. The aim of this study was to develop and externally validate a preoperative BN to predict LNM and outcome in endometrial cancer patients. Methods and findings Within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), we performed a retrospective multicenter cohort study including 763 patients, median age 65 years (interquartile range [IQR] 58-71), surgically treated for endometrial cancer between February 1995 and August 2013 at one of the 10 participating European hospitals. A BN was developed using score-based machine learning in addition to expert knowledge. Our main outcome measures were LNM and 5-year disease-specific survival (DSS). Preoperative clinical, histopathological, and molecular biomarkers were included in the network. External validation was performed using 2 prospective study cohorts: the Molecular Markers in Treatment in Endometrial Cancer (MoMaTEC) study cohort, including 446 Norwegian patients, median age 64 years (IQR 59-74), treated between May 2001 and 2010; and the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study cohort, including 384 Dutch patients, median age 66 years (IQR 60-73), treated between September 2011 and December 2013. A BN called ENDORISK (preoperative risk stratification in endometrial cancer) was developed including the following predictors: preoperative tumor grade; immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), p53, and L1 cell adhesion molecule (L1CAM); cancer antigen 125 serum level; thrombocyte count; imaging results on lymphadenopathy; and cervical cytology. In the MoMaTEC cohort, the area under the curve (AUC) was 0.82 (95% confidence interval [CI] 0.76-0.88) for LNM and 0.82 (95% CI 0.77-0.87) for 5-year DSS. In the PIPENDO cohort, the AUC for 5-year DSS was 0.84 (95% CI 0.78-0.90). The network was well-calibrated. In the MoMaTEC cohort, 249 patients (55.8%) were classified with Conclusions In this study, we illustrated how BNs can be used for individualizing clinical decision-making in oncology by incorporating easily accessible and multimodal biomarkers. The network shows the complex interactions underlying the carcinogenetic process of endometrial cancer by its graphical representation. A prospective feasibility study will be needed prior to implementation in the clinic., Author(s): Casper Reijnen 1,2,*, Evangelia Gogou 3, Nicole C. M. Visser 4, Hilde Engerud 5,6, Jordache Ramjith 7, Louis J. M. van der Putten 1, Koen van de Vijver 8, [...]

The aim was to evaluate the effects of nutritional plane on in vitro progesterone (P4) secretion by granulosa (G) cells cultured in the presence or absence of effectors of the nitric oxide (NO) system. Ewes were randomly assigned into three nutritional groups: control (C), overfed (O; 2 x C), or underfed (U; 0.6 x C). Follicular development was induced by FSH injections. On day 15 of the estrous cycle, G cells were isolated and cultured with or without DETA-NONOate (NO donor), L-NAME (NO synthase [S] inhibitor), Arg and (or) LH for 8 h. DETA-NONOate decreased basal and LH-stimulated P4 secretion, and L-NAME increased basal P4 secretion in all groups. In U, Arg decreased LH-stimulated P4 secretion. These data demonstrate that (i) plane of nutrition affects basal P4 secretion by G cells, (ii) the NO donor decreases, NOS inhibitor increases but Arg does not affect basal P4 secretion, and (iii) effects of Arg on LH-stimulated P4 secretion are affected by plane of nutrition in FSH-treated sheep. Thus, plane of nutrition affects G cell function, and the NO system is involved in the regulation of basal and LH-stimulated P4 secretion. The mechanism of the NO system effects on secretory activity of G cells remains to be elucidated. Key words: nitric oxide, progesterone, granulosa cells, in vitro, sheep, nutrition. Cette etude avait pour objectif d'evaluer les effets du niveau de nutrition sur la secretion de progesterone (P4) par les cellules de la granulosa cultivees in vitro avec ou sans effecteurs du systeme de l'oxyde nitrique (NO). Des brebis ont ete reparties aleatoirement en trois groupes : un groupe temoin, un groupe suralimente (2 x le regime alimentaire des temoins) et un groupe sous-alimente (0,6 x le regime alimentaire des temoins). Le developpement folliculaire etait induit par des injections de FSH. Au 15e jour du cycle restral, les cellules de la granulosa etaient isolees et cultivees avec ou sans DETA-NONOate (donneur de NO), L-NAME (inhibiteur de la NO synthase), Arg et/ou LH pendant 8 h. Dans tous les groupes, la presence de DETA-NONOate a entrame une diminution de la secretion basale de P4 et de la secretion de P4 stimulee par la LH, alors que la presence de L-NAME a entrame une augmentation de la secretion basale de P4. Chez les brebis sous-alimentees, la presence d'Arg a entrame une diminution de la secretion de P4 stimulee par la LH. Ces donnees montrent 1) que le niveau de nutrition joue un role dans la secretion basale de P4 par les cellules de la granulosa, 2) que la presence de donneur de NO et d'inhibiteur de la NO synthase entrainent une augmentation et une diminution de la secretion basale de P4, respectivement, alors que la presence d'Arg ne la modifie pas et 3) que les effets de l'Arg sur la secretion de P4 stimulee par la LH dependent du niveau de nutrition chez les brebis soumises aux effets de la FSH. Par consequent, le niveau de nutrition joue un role dans l'activite des cellules de la granulosa, et le systeme du NO, dans la regulation de la secretion basale de P4 et de la secretion de P4 stimulee par la LH. Les mecanismes par lesquels le systeme du NO agit sur l'activite secretoire des cellules de la granulosa demeurent a elucider. [Traduit par la Redaction] Mots-cles: oxyde nitrique, progesterone, cellules de la granulosa, in vitro, mouton, nutrition., Introduction Ovarian function is regulated by numerous factors including plane of nutrition, body condition, endocrine, and other systems that can have a profound effect on fertility (Robinson et al. 1999; [...]

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered [CD8.sup.+] T cell response, as evidenced by a reduction of tolerogenic [CD8.sup.+][CD122.sup.+] T cells and an increase of cytotoxic [CD8.sup.+] T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of [CD8.sup.+] T cells revealed that progesterone suppresses [CD8.sup.+] T cell cytotoxicity, whereas the generation of [CD8.sup.+][CD122.sup.+] T cells is supported by Hmox1 and ameliorates fetal- growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies., Introduction Intrauterine growth restriction (IUGR) in humans is associated with poor fetal growth and impaired fetal development. In Western societies, the incidence of IUGR varies to between 3% and 10% [...]