Identification of Functional Networks of Estrogen- and c-Myc-Responsive Genes and Their Relationship to Response to Tamoxifen Therapy in Breast Cancer

BACKGROUND: Estrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance. METHODOLOGY/PRINCIPAL FINDINGS: With the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis), cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes) in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The 'cell cycle', 'cell growth' and 'cell death' gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature was predictive independent of the cell cycle and cell growth signatures. CONCLUSIONS/SIGNIFICANCE: These functionally-based gene signatures can stratify patients treated with tamoxifen into groups with differing outcome, and potentially identify distinct mechanisms of tamoxifen resistance

Key signalling nodes in mammary gland development and cancer: Myc

Myc has been intensely studied since its discovery more than 25 years ago. Insight has been gained into Myc's function in normal physiology, where its role appears to be organ specific, and in cancer where many mechanisms contribute to aberrant Myc expression. Numerous signals and pathways converge on Myc, which in turn acts on a continuously growing number of identified targets, via transcriptional and nontranscriptional mechanisms. This review will concentrate on Myc as a signaling mediator in the mammary gland, discussing its regulation and function during normal development, as well as its activation and roles in breast cancer

Meta-Analysis and Gene Set Enrichment Relative to ER Status Reveal Elevated Activity of MYC and E2F in the “Basal” Breast Cancer Subgroup

10.1371/journal.pone.0004710PLoS ONE43

Comparison of Methods for Detection of Blastocystis Infection in Routinely Submitted Stool Samples, and also in IBS/IBD Patients in Ankara, Turkey

BACKGROUND: This study compared diagnostic methods for identifying Blastocystis in stool samples, and evaluated the frequency of detection of Blastocystis in patients with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). RESULTS AND DISCUSSION: From a set of 105 stool specimens submitted for routine parasitological analysis, 30 were identified as positive for Blastocystis by the culture method. From that group of 30 positives, Lugol's stain, trichrome staining, and an immunofluorescence assay identified 11, 15, and 26 samples as positive respectively. Using culture as a standard, the sensitivity of Lugol's stain was 36.7%, trichrome staining was 50%, and the IFA stain was 86.7%. The specificity of Lugol's stain was 91%, trichrome staining was 100%, and the IFA stain was 97.3%. In the group of 27 IBS and IBD patients, using all methods combined, we detected Blastocystis in 67% (18/27) of the patients. Blastocystis was detected in 33% (2/6) of IBD patients and 76% (16/21) of IBS patients. For comparison, trichrome staining alone, the method most frequently used in many countries, would have only identified Blastocystis infection in 29% (6/21) of the IBS patients. No parasitic co-infections were identified in the IBS/IBD patients. Most Blastocystis-positive IBS/IBD patients were over 36 with an average length of illness of 4.9 years. CONCLUSIONS: Most IBS patients in this study were infected with Blastocystis. IFA staining may be a useful alternative to stool culture, especially if stool specimens have been chemically preserved

Pacing and Decision Making in Sport and Exercise: The Roles of Perception and Action in the Regulation of Exercise Intensity

In pursuit of optimal performance, athletes and physical exercisers alike have to make decisions about how and when to invest their energy. The process of pacing has been associated with the goal-directed regulation of exercise intensity across an exercise bout. The current review explores divergent views on understanding underlying mechanisms of decision making in pacing. Current pacing literature provides a wide range of aspects that might be involved in the determination of an athlete's pacing strategy, but lacks in explaining how perception and action are coupled in establishing behaviour. In contrast, decision-making literature rooted in the understanding that perception and action are coupled provides refreshing perspectives on explaining the mechanisms that underlie natural interactive behaviour. Contrary to the assumption of behaviour that is managed by a higher-order governor that passively constructs internal representations of the world, an ecological approach is considered. According to this approach, knowledge is rooted in the direct experience of meaningful environmental objects and events in individual environmental processes. To assist a neuropsychological explanation of decision making in exercise regulation, the relevance of the affordance competition hypothesis is explored. By considering pacing as a behavioural expression of continuous decision making, new insights on underlying mechanisms in pacing and optimal performance can be developed. © 2014 Springer International Publishing Switzerland