Comparison of Short-Term Estrogenicity Tests for Identification of Hormone-Disrupting Chemicals

The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites, estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17β-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7 cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17β-Estradiol, 17α-ethynyl estradiol, and diethylstilbestrol induced a strong estrogenic response in all test systems. Colchicine caused cytotoxicity only. Bisphenol A induced an estrogenic response in all assays. The results obtained for the remaining test compounds—tamoxifen, ICI 182.780, testosterone, bisphenol A dimethacrylate, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol dodecylethoxylate, butylbenzylphthalate, dibutylphthalate, methoxychlor, o,p′-DDT, p,p′-DDE, endosulfan, chlomequat chloride, and ethanol—varied among the assays. The results demonstrate that careful standardization is necessary to obtain a reasonable degree of reproducibility. Also, similar methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods

ESUR prostate MR guidelines 2012

The aim was to develop clinical guidelines for multi-parametric MRI of the prostate by a group of prostate MRI experts from the European Society of Urogenital Radiology (ESUR), based on literature evidence and consensus expert opinion. True evidence-based guidelines could not be formulated, but a compromise, reflected by “minimal” and “optimal” requirements has been made. The scope of these ESUR guidelines is to promulgate high quality MRI in acquisition and evaluation with the correct indications for prostate cancer across the whole of Europe and eventually outside Europe. The guidelines for the optimal technique and three protocols for “detection”, “staging” and “node and bone” are presented. The use of endorectal coil vs. pelvic phased array coil and 1.5 vs. 3 T is discussed. Clinical indications and a PI-RADS classification for structured reporting are presented

Overdiagnosis and overtreatment of early detected prostate cancer

Early detection of prostate cancer is associated with the diagnosis of a considerable proportion of cancers that are indolent, and that will hardly ever become symptomatic during lifetime. Such overdiagnosis should be avoided in all forms of screening because of potential adverse psychological and somatic side effects. The main threat of overdiagnosis is overtreatment of indolent disease. Men with prostate cancer that is likely to be indolent may be offered active surveillance. Evaluation of active surveillance studies and validation of new biological parameters for risk assessment are expected

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK.

PURPOSE: Comparing gonadotrophin-releasing hormone (GnRH) antagonists and agonists as androgen deprivation therapy for advanced prostate cancer (PC). METHODS: This article stems from a round-table meeting in December 2014 to compare the properties of GnRH agonists and antagonists in the published literature in order to identify the patient groups most likely to benefit from GnRH antagonist therapy. A broad PubMed and congress abstract search was carried out in preparation for the meeting to ensure that the latest data and opinion were available for the discussions. RESULTS: In randomised, controlled trials, GnRH antagonist therapy provides more rapid suppression of luteinising hormone, follicle-stimulating hormone and testosterone than GnRH agonist treatment. Compared with the GnRH agonist, there is evidence of improved disease control by a GnRH antagonist, with longer interval to prostate-specific antigen progression and greater reduction of serum alkaline phosphatase. In a post hoc analysis of six randomised trials, the risk of cardiac events within 1 year of initiating therapy was significantly lower among men receiving GnRH antagonist than agonist. Pre-clinical laboratory data suggest a number of mechanisms whereby GnRH antagonist therapy may benefit men with pre-existing cardiovascular disease (CVD), the most plausible hypothesis being that, unlike GnRH agonists, GnRH antagonists do not activate T lymphocytes, which act to increase atherosclerotic plaque rupture. CONCLUSION: When making treatment decisions, clinicians should consider comorbidities, particularly CVD, in addition to effects on PC. GnRH antagonists may be appropriate in patients with significant CV risk, existing osteopenia, lower urinary tract symptoms and significant metastatic disease

Dopaminergic Activation of Estrogen Receptors Induces Fos Expression within Restricted Regions of the Neonatal Female Rat Brain

Steroid receptor activation in the developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. Recent data suggests that dopamine can regulate expression of progestin receptors within restricted regions of the developing rat brain by activating estrogen receptors in a ligand-independent manner. It is unclear whether changes in neuronal activity induced by dopaminergic activation of estrogen receptors are also region specific. To investigate this question, we examined where the dopamine D1-like receptor agonist, SKF 38393, altered Fos expression via estrogen receptor activation. We report that dopamine D1-like receptor agonist treatment increased Fos protein expression within many regions of the developing female rat brain. More importantly, prior treatment with an estrogen receptor antagonist partially reduced D1-like receptor agonist-induced Fos expression only within the bed nucleus of the stria terminalis and the central amygdala. These data suggest that dopaminergic activation of estrogen receptors alters neuronal activity within restricted regions of the developing rat brain. This implies that ligand-independent activation of estrogen receptors by dopamine might organize a unique set of behaviors during brain development in contrast to the more wide spread ligand activation of estrogen receptors by estrogen

Genomics of Signaling Crosstalk of Estrogen Receptor α in Breast Cancer Cells

BACKGROUND: The estrogen receptor alpha (ERalpha) is a ligand-regulated transcription factor. However, a wide variety of other extracellular signals can activate ERalpha in the absence of estrogen. The impact of these alternate modes of activation on gene expression profiles has not been characterized. METHODOLOGY/PRINCIPAL FINDINGS: We show that estrogen, growth factors and cAMP elicit surprisingly distinct ERalpha-dependent transcriptional responses in human MCF7 breast cancer cells. In response to growth factors and cAMP, ERalpha primarily activates and represses genes, respectively. The combined treatments with the anti-estrogen tamoxifen and cAMP or growth factors regulate yet other sets of genes. In many cases, tamoxifen is perverted to an agonist, potentially mimicking what is happening in certain tamoxifen-resistant breast tumors and emphasizing the importance of the cellular signaling environment. Using a computational analysis, we predicted that a Hox protein might be involved in mediating such combinatorial effects, and then confirmed it experimentally. Although both tamoxifen and cAMP block the proliferation of MCF7 cells, their combined application stimulates it, and this can be blocked with a dominant-negative Hox mutant. CONCLUSIONS/SIGNIFICANCE: The activating signal dictates both target gene selection and regulation by ERalpha, and this has consequences on global gene expression patterns that may be relevant to understanding the progression of ERalpha-dependent carcinomas

Impact of age and comorbidities on health-related quality of life for patients with prostate cancer: evaluation before a curative treatment

<p>Abstract</p> <p>Background</p> <p>Interpretation of comparative health-related quality of life (HRQOL) studies following different prostate cancer treatments is often difficult due to differing patient ages. Furthermore, age-related changes can hardly be discriminated from therapy-related changes. The evaluation of age-and comorbidity-related changes was in focus of this study.</p> <p>Methods</p> <p>HRQOL of 528 prostate cancer patients was analysed using a validated questionnaire (Expanded Prostate Cancer Index Composite) before a curative treatment. Patients were divided into age groups ≤65, 6670, 7175 and >75 years. The impact of specific comorbidities and the Charlson Comorbidity Index (CCI) were evaluated. The questionnaire comprises 50 items concerning the urinary, bowel, sexual and hormonal domains for function and bother. For assessment of sexual and hormonal domains, only patients without prior hormonal treatment were included (n = 336).</p> <p>Results</p> <p>Urinary incontinence was observed increasingly with higher age (mean function scores of 92/88/85/87 for patients ≤65, 6670, 7175 and >75 years) complete urinary control in 78%/72%/64%/58% (p < 0.01). Sexual function scores decreased particularly (48/43/35/30), with erections sufficient for intercourse in 68%/50%/36%/32% (p < 0.01) a decrease of more than a third comparing patients ≤65 vs. 6670 (36%) and 6670 vs. 7175 years (39%). The percentage of patients with comorbidities was lowest in the youngest group (48% vs. 66%/68%/63% for ages 6670/7175/>75 years; p < 0.05). A multivariate analysis revealed an independent influence of both age and comorbidities on urinary incontinence, specifically diabetes on urinary bother, and both age and diabetes on sexual function/bother. Rectal domain scores were not significantly influenced by age or comorbidities. A CCI>5 particularly predisposed for lower urinary and sexual HRQOL scores.</p> <p>Conclusion</p> <p>Urinary continence and sexual function are the crucial HRQOL domains with age-related and independently comorbidity-related decreasing scores. The results need to be considered for the interpretation of comparative studies or longitudinal changes after a curative treatment.</p

Patients' and urologists' preferences for prostate cancer treatment: A discrete choice experiment

__Abstract__ Background: Patients' preferences are important for shared decision making. Therefore, we investigated patients' and urologists' preferences for treatment alternatives for early prostate cancer (PC). Methods: A discrete choice experiment was conducted among 150 patients who were waiting for their biopsy results, and 150 urologists. Regression analysis was used to determine patients' and urologists' stated preferences using scenarios based on PC treatment modality (radiotherapy, surgery, and active surveillance (AS)), and risks of urinary incontinence and erectile dysfunction.Results:The response rate was 110 out of 150 (73%) for patients and 50 out of 150 (33%) for urologists. Risk of urinary incontinence was an important determinant of both patients' and urologists' stated preferences for PC treatment (P<0.05). Treatment modality also influenced patients' stated preferences (P<0.05), whereas the risk of erectile dysfunction due to radiotherapy was mainly important to urologists (P<0.05). Both patients and urologists preferred AS to radical treatment, with the exception of patients with anxious/depressed feelings who preferred radical treatment to AS. Conclusion: Although patients and urologists generally may prefer similar treatments for PC, they showed different trade-offs between various specific treatment aspects. This implies that urologists need to be aware of potential differences compared with the patient's perspective on treatment decisions in shared decision making on PC treatment

Stromelysin-3 over-expression enhances tumourigenesis in MCF-7 and MDA-MB-231 breast cancer cell lines: involvement of the IGF-1 signalling pathway

BACKGROUND: Stromelysin-3 (ST-3) is over-expressed in the majority of human carcinomas including breast carcinoma. Due to its known effect in promoting tumour formation, but its impeding effect on metastasis, a dual role of ST-3 in tumour progression, depending on the cellular grade of dedifferentiation, was hypothesized. METHODS: The present study was designed to investigate the influence of ST-3 in vivo and in vitro on the oestrogen-dependent, non-invasive MCF-7 breast carcinoma cell line as well as on the oestrogen-independent, invasive MDA-MB-231 breast carcinoma cell line. Therefore an orthotopic human xenograft tumour model in nude mice, as well as a 3D matrigel cell culture system, were employed. RESULTS: Using both in vitro and in vivo techniques, we have demonstrated that over-expression of ST-3 in MCF-7 and MDA-MB-231 cells leads to both increased cell numbers and tumour volumes. This observation was dependent upon the presence of growth factors. In particular, the enhanced proliferative capacity was in MCF-7/ST-3 completely and in MDA-MB-231/ST-3 cells partially dependent on the IGF-1 signalling pathway. Microarray analysis of ST-3 over-expressing cells revealed that in addition to cell proliferation, further biological processes seemed to be affected, such as cell motility and stress response. The MAPK-pathway as well as the Wnt and PI3-kinase pathways, appear to also play a potential role. Furthermore, we have demonstrated that breast cancer cell lines of different differentiation status, as well as the non-tumourigenic cell line MCF-10A, have a comparable capability to induce endogenous ST-3 expression in fibroblasts. CONCLUSION: These data reveal that ST-3 is capable of enhancing tumourigenesis in highly differentiated "early stage" breast cancer cell lines as well as in further progressed breast cancer cell lines that have already undergone epithelial-mesenchymal transition. We propose that ST-3 induction in tumour fibroblasts leads to the stimulation of the IGF-1R pathway in carcinoma cells, thus enhancing their proliferative capacity. In addition, further different cellular processes seem to be activated by ST-3, possibly accounting for the dual role of ST-3 in tumour progression and metastasis