Immunodetection of nmt55/p54(nrb) isoforms in human breast cancer

BACKGROUND: We previously identified and characterized a novel 55 kDa nuclear protein, termed nmt55/p54(nrb), whose expression was decreased in a subset of human breast tumors. The objective of this study was to determine if this reduced expression in human breast tumors was attributed to the regulation of mRNA transcription or the presence of altered forms of this protein. RESULTS: Northern blot analysis and ribonuclease protection assay indicated that nmt55/p54(nrb) mRNA is expressed at varying levels in estrogen receptor positive (ER+) and estrogen receptor negative (ER-) human breast tumors suggesting that reduced expression of nmt55/p54(nrb) protein in ER- tumors was not due to transcriptional regulation. To determine if multiple protein isoforms are expressed in breast cancer, we utilized Western blot and immunohistochemical analyses, which revealed the expression of an nmt55/p54(nrb) protein isoform in a subset of ER+ tumors. This subset of ER+ human breast tumors expressed an altered form of nmt55/p54(nrb) that was undetectable with an amino-terminal specific antibody suggesting that this isoform contains alterations or modifications within the amino terminal domain. CONCLUSIONS: Our study indicates that nmt55/p54(nrb) protein is post-transcriptionally regulated in human breast tumors leading to reduced expression in ER- tumors and the expression of an amino terminal altered isoform in a subset of ER+ tumors. The potential involvement of nmt55/p54(nrb) in RNA binding and pre-mRNA splicing may be important for normal cell growth and function; thus, loss or alteration of protein structure may contribute to tumor growth and progression

Reflections on the labyrinth: Investigating Black and Minority Ethnic leaders’ career experiences

Black and Minority Ethnic (BME) employees appear to experience more difficulty reaching senior leadership positions than their white counterparts. Using Eagly and Carli’s (2007) metaphor of the labyrinth our aim was to give voice to black and minority ethnic managers who have successfully achieved senior management roles, and compare their leadership journeys with those of matched white managers. This paper used semi-structured interviews and attribution theory to examine how 20 black and minority ethnic and 20 white senior managers, from a UK government department made sense of significant career incidents in their leadership journeys. Template analysis was used to identify facilitators and barriers of career progression from causal explanations of these incidents. Although BME and white managers identified four common themes (visibility, networks, development, and line manager support), they differed in how they made sense of formal and informal organisational processes to achieve career progression. The findings are used to theorise about the individual and organisational factors that contribute to the leadership journeys of minority ethnic employees

Combined effects of time spent in physical activity, sedentary behaviors and sleep on obesity and cardio-metabolic health markers: a novel compositional data analysis approach

<div><p>The associations between time spent in sleep, sedentary behaviors (SB) and physical activity with health are usually studied without taking into account that time is finite during the day, so time spent in each of these behaviors are codependent. Therefore, little is known about the combined effect of time spent in sleep, SB and physical activity, that together constitute a composite whole, on obesity and cardio-metabolic health markers. Cross-sectional analysis of NHANES 2005–6 cycle on N = 1937 adults, was undertaken using a compositional analysis paradigm, which accounts for this intrinsic codependence. Time spent in SB, light intensity (LIPA) and moderate to vigorous activity (MVPA) was determined from accelerometry and combined with self-reported sleep time to obtain the 24 hour time budget composition. The distribution of time spent in sleep, SB, LIPA and MVPA is significantly associated with BMI, waist circumference, triglycerides, plasma glucose, plasma insulin (all p<0.001), and systolic (p<0.001) and diastolic blood pressure (p<0.003), but not HDL or LDL. Within the composition, the strongest positive effect is found for the proportion of time spent in MVPA. Strikingly, the effects of MVPA replacing another behavior and of MVPA being displaced by another behavior are asymmetric. For example, re-allocating 10 minutes of SB to MVPA was associated with a lower waist circumference by 0.001% but if 10 minutes of MVPA is displaced by SB this was associated with a 0.84% higher waist circumference. The proportion of time spent in LIPA and SB were detrimentally associated with obesity and cardiovascular disease markers, but the association with SB was stronger. For diabetes risk markers, replacing SB with LIPA was associated with more favorable outcomes. Time spent in MVPA is an important target for intervention and preventing transfer of time from LIPA to SB might lessen the negative effects of physical inactivity.</p></div

Absence of progesterone receptor associated with secondary breast cancer in postmenopausal women

The relationship between expression of receptors for oestrogen and progesterone (ER and PR) and disease progression in breast cancer was investigated by comparing immunocytochemical determinations of ER and PR in fine needle aspirates from primary and secondary breast tumours. Rates of receptor expression were significantly higher in primary than in secondary lesions: for ER 63.3% (n = 689) compared with 45.3% (n = 223), and for PR 53.7% (n = 443) compared with 33.1% (n = 121). The effect of menopausal status was examined by subdividing the patient cohort into those over or under the age of 50 years. In both instances, ER expression in secondary tumours was relatively low; however, only postmenopausal patients had significantly lower rates of PR expression in secondary tumours. Consistent with this, an increase in the ER+PR– profile in secondary tumours compared with primary cases from postmenopausal patients was seen, and in a multivariate analysis, a specific absence of PR expression in secondary tumours was revealed. Comparison of ER and PR expression in simultaneously sampled primary tumours and lymph node metastases from the same patient showed that receptor expression was stable with progression to a metastatic site as results were concordant for ER in 92% (n = 88) and PR in 93.8% of cases (n = 65). These results suggest that absence of PR expression in primary breast cancer is associated with disease progression and may be a marker of an aggressive tumour phenotype. © 1999 Cancer Research Campaig

Estrogen receptor alpha gene polymorphism and endometrial cancer risk – a case-control study

Background: Estrogen is an established endometrial carcinogen. One of the most important mediators of estrogenic action is the estrogen receptor alpha. We have investigated whether polymorphic variation in the estrogen receptor alpha gene (ESR1) is associated with endometrial cancer risk. Methods: In 702 cases with invasive endometrial cancer and 1563 controls, we genotyped five markers in ESR1 and used logistic regression models to estimate odds ratios (OR) and 95 percent confidence intervals (CI). Results: We found an association between rs2234670, rs2234693, as well as rs9340799, markers in strong linkage disequilibrium (LD), and endometrial cancer risk. The association with rs9340799 was the strongest, OR 0.75 (CI 0.60–0.93) for heterozygous and OR 0.53 (CI 0.37–0.77) for homozygous rare compared to those homozygous for the most common allele. Haplotype models did not fit better to the data than single marker models. Conclusion: We found that intronic variation in ESR1 was associated with endometrial cancer risk

Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells

INTRODUCTION: Although the effects of progesterone on cell cycle progression are well known, its role in spreading and adhesion of breast cancer cells has not attracted much attention until recently. Indeed, by controlling cell adhesion proteins, progesterone may play a direct role in breast cancer invasion and metastasis. Progesterone has also been shown to modulate epidermal growth factor (EGF) effects in neoplasia, although EGF effects on progesterone pathways and targets are less well understood. In the present study we identify an effect of EGF on a progesterone target, namely desmoplakin. METHODS: Initially flow cytometry was used to establish the growing conditions and demonstrate that the T47D breast cancer cell line was responding to progesterone and EGF in a classical manner. Differential display RT-PCR was employed to identify differentially expressed genes affected by progesterone and EGF. Western and Northern blotting were used to verify interactions between EGF and progesterone in three breast cancer cell lines: T47D, MCF-7, and ZR-75. RESULTS: We found the cell adhesion protein desmoplakin to be upregulated by progesterone – a process that was suppressed by EGF. This appears to be a general but not universal effect in breast cancer cell lines. CONCLUSION: Our findings suggest that progesterone and EGF may play opposing roles in metastasis. They also suggest that desmoplakin may be a useful biomarker for mechanistic studies designed to analyze the crosstalk between EGF and progesterone dependent events. Our work may help to bridge the fields of metastasis and differentiation, and the mechanisms of steroid action

Intrinsic bias in breast cancer gene expression data sets

<p>Abstract</p> <p>Background</p> <p>While global breast cancer gene expression data sets have considerable commonality in terms of their data content, the populations that they represent and the data collection methods utilized can be quite disparate. We sought to assess the extent and consequence of these systematic differences with respect to identifying clinically significant prognostic groups.</p> <p>Methods</p> <p>We ascertained how effectively unsupervised clustering employing randomly generated sets of genes could segregate tumors into prognostic groups using four well-characterized breast cancer data sets.</p> <p>Results</p> <p>Using a common set of 5,000 randomly generated lists (70 genes/list), the percentages of clusters with significant differences in metastasis latencies (HR p-value < 0.01) was 62%, 15%, 21% and 0% in the NKI2 (Netherlands Cancer Institute), Wang, TRANSBIG and KJX64/KJ125 data sets, respectively. Among ER positive tumors, the percentages were 38%, 11%, 4% and 0%, respectively. Few random lists were predictive among ER negative tumors in any data set. Clustering was associated with ER status and, after globally adjusting for the effects of ER-α gene expression, the percentages were 25%, 33%, 1% and 0%, respectively. The impact of adjusting for ER status depended on the extent of confounding between ER-α gene expression and markers of proliferation.</p> <p>Conclusion</p> <p>It is highly probable to identify a statistically significant association between a given gene list and prognosis in the NKI2 dataset due to its large sample size and the interrelationship between ER-α expression and markers of proliferation. In most respects, the TRANSBIG data set generated similar outcomes as the NKI2 data set, although its smaller sample size led to fewer statistically significant results.</p