The interaction between the type 1 receptor tyrosine kinases and the oestrogen receptor in human breast cancer: the role of the Ras/Raf-1/MAPK pathway

Tamoxifen and chemotherapy are key treatments for breast cancer patients. Tamoxifen, an oestrogen antagonist, is a non-steroidal that acts as a selective oestrogen receptor modulator (SERM). It competitively inhibits the interaction of oestrogen with the oestrogen receptor, blocking the effects of E2 and inhibiting receptor activity. Chemotherapy uses cytotoxic drugs to kill cancer cells, by preventing them from multiplying, invading and metastasing. Despite the extensive use of both treatments, failure to respond to them is a major clinical problem and this is the cause of significant morbidity and mortality. To overcome this and to improve patients' treatment options, we need to understand the mechanisms regulating the development of resistance. The Ras/Raf-l/MAPK pathway regulates multiple cellular processes such as proliferation, apoptosis, differentiation, senescence and migration. MAPK activation results in phosphorylation of more than 50 substrates within the cytosol and nucleus. One key substrate of MAPK is the oestrogen receptor (ERalpha). Activated MAPK directly and indirectly phosphorylates serine 118 and 167, respectively, in the AF-2 domain of the receptor. Stimulation of the Ras pathway results in the ligand-independent activation of the ERalpha. Consequently, this pathway has been identified as a key player in the development and progression of tumourigenesis. Research suggests that activation of this pathway mediates response to tamoxifen, by activating ERalpha in a ligand-independent manner, and to chemotherapy, by increasing cell proliferation. This current study investigated the hypothesis that expression and activation of Ras/Raf-l/MAPK influences patient outcome and treatment response, using breast tumours from three different patient cohorts and an immunohistochemical approach. It also examined the relationship between MAPK and oestrogen receptor, both can localise to the cytoplasm and/or nuclei of cells but it is unclear how and where they interact. Therefore, in vitro studies, including immunofluorescence, were performed to investigate the relationship between MAPK and ERalpha, and their role in driving tamoxifen resistance. The pilot study, comprised of ER positive and negative patients who received a range of treatments, revealed that increased expression of N-Ras in breast tumours was related to reduced disease-free and overall survival time. It also highlighted the unexpected finding that Ras localised to the nuclei of breast tumour cells. The presence of nuclear Ras was confirmed by in vitro studies. The expression of Ras, Raf-1 and MAPK proteins was investigated further, in tumours from ER positive patients, who were treated with tamoxifen (STB study), and in tumours from ER positive and negative patients who received chemotherapy treatment (NEAT/BR9601 study). These two studies highlighted that the Ras pathway mediated outcome in patients treated with Tamoxifen but not chemotherapy. This research highlights the impact of the Ras pathway on breast cancer patients' response to treatment. It also reveals some interesting findings regarding the interaction between MAPK and ER, and offers a possible mechanism for the development of Tamoxifen resistance. (Abstract shortened by ProQuest.)

Association between exposure to second-hand smoke and telomere length: cross-sectional study of 1303 non-smokers

Background: Both active smoking and second-hand smoke (SHS) are important risk factors for many age-related diseases. Active smoking is associated with shortened telomere length. However, whether SHS accelerates telomere attrition with age is uncertain. The aim of this study was to examine the association between SHS exposure and shortening by age of leukocyte telomere length among adult non-smokers. Methods: We undertook a cross-sectional study of the association between self-reported levels of SHS exposure and telomere length shortening per annum on a subgroup of participants from the Scottish Family Health Study. Inclusion was restricted to non-smokers aged ≥ 18 years, who had provided self-reported overall usual SHS exposure (total hours per week) and blood samples for telomere analysis. Linear regression models were used to compare the ratio of telomere repeat copy number to single copy gene number (T/S)by age according to SHS exposure. Results: Of the 1303 eligible participants, 779 (59.8%) reported no SHS exposure, 495 (38.0%) low exposure (1–19 h per week) and 29 (2.2%) high exposure (≥20 h per week). In the univariate linear regression analyses, relative T/S ratio declined with increasing age in all exposure groups. Telomere length decreased more rapidly with increasing age among those with high exposure to SHS [adjusted coefficient −0.019, 95% confidence interval (CI) −0.031- −0.007) when compared with both those with no exposure to SHS (adjusted coefficient −0.006, 95% CI −0.008- −0.004) (high vs no SHS: P = 0.010) and those with low exposure to SHS (adjusted coefficient −0.005, 95% CI −0.007- −0.003) (high vs low SHS: P = 0.005). Conclusions: Our findings suggest that high SHS exposure may accelerate normal biological ageing, and support efforts to protect the public from SHS exposure. Further studies on relevant mechanisms should be conducted

Is telomere length a biomarker for aging: cross-sectional evidence from the west of Scotland?

Background <p> The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure. </p> Methodology/Principal Findings <p> Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites. </p> Conclusions <p> Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area.</p&gt

Pathfinder cells provide a novel therapeutic intervention for acute kidney injury

Pathfinder cells (PCs) are a novel class of adult-derived cells that facilitate functional repair of host tissue. We used rat PCs to demonstrate that they enable the functional mitigation of ischemia reperfusion (I/R) injury in a mouse model of renal damage. Female C57BL/6 mice were subjected to 30 min of renal ischemia and treated with intravenous (i.v.) injection of saline (control) or male rat pancreas-derived PCs in blinded experimentation. Kidney function was assessed 14 days after treatment by measuring serum creatinine (SC) levels. Kidney tissue was assessed by immunohistochemistry (IHC) for markers of cellular damage, proliferation, and senescence (TUNEL, Ki67, p16ink4a, p21). Fluorescence in situ hybridization (FISH) was performed to determine the presence of any rat (i.e., pathfinder) cells in the mouse tissue. PC-treated animals demonstrated superior renal function at day 14 post-I/R, in comparison to saline-treated controls, as measured by SC levels (0.13 mg/dL vs. 0.23 mg/dL, p<0.001). PC-treated kidney tissue expressed significantly lower levels of p16ink4a in comparison to the control group (p=0.009). FISH analysis demonstrated that the overwhelming majority of repaired kidney tissue was mouse in origin. Rat PCs were only detected at a frequency of 0.02%. These data confirm that PCs have the ability to mitigate functional damage to kidney tissue following I/R injury. Kidneys of PC-treated animals showed evidence of improved function and reduced expression of damage markers. The PCs appear to act in a paracrine fashion, stimulating the host tissue to recover functionally, rather than by differentiating into renal cells. This study demonstrates that pancreatic-derived PCs from the adult rat can enable functional repair of renal damage in mice. It validates the use of PCs to regenerate damaged tissues and also offers a novel therapeutic intervention for repair of solid organ damage in situ

Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria

CDKN2A is a proven and validated biomarker of ageing which acts as an off switch for cell proliferation. We have demonstrated previously that CDKN2A is the most robust and the strongest pre-transplant predictor of post- transplant serum creatinine when compared to “Gold Standard” clinical factors, such as cold ischaemic time and donor chronological age. This report shows that CDKN2A is better than telomere length, the most celebrated biomarker of ageing, as a predictor of post-transplant renal function. It also shows that CDKN2A is as strong a determinant of post-transplant organ function when compared to extended criteria (ECD) kidneys. A multivariate analysis model was able to predict up to 27.1% of eGFR at one year post-transplant (p = 0.008). Significantly, CDKN2A was also able to strongly predict delayed graft function. A pre-transplant donor risk classification system based on CDKN2A and ECD criteria is shown to be feasible and commendable for implementation in the near future

Is telomere length socially patterned? Evidence from the West of Scotland Twenty-07 study

Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages

Interval orders without odd crowns are defect optimal

SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman