Targeting Mre11 overcomes platinum resistance and induces synthetic lethality in XRCC1 deficient epithelial ovarian cancers

Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n = 331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p = 0.002). In the ovarian cancer genome atlas (TCGA) cohort (n = 498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p < 0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n = 1259), Mre11 overexpression was associated with poor PFS (p = 0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer

Impact of vitamin D metabolism on clinical epigenetics

The bioactive vitamin D (VD) metabolite, 1,25-dihydroxyvitamin D3 regulates essential pathways of cellular metabolism and differentiation via its nuclear receptor (VDR). Molecular mechanisms which are known to play key roles in aging and cancer are mediated by complex processes involving epigenetic mechanisms contributing to efficiency of VD-activating CYP27A1 and CYP27B1 or inactivating CYP24 enzymes as well as VDR which binds to specific genomic sequences (VD response elements or VDREs). Activity of VDR can be modulated epigenetically by histone acetylation. It co-operates with other nuclear receptors which are influenced by histone acetyl transferases (HATs) as well as several types of histone deacetylases (HDACs). HDAC inhibitors (HDACi) and/or demethylating drugs may contribute to normalization of VD metabolism. Studies link VD signaling through the VDR directly to distinct molecular mechanisms of both HAT activity and the sirtuin class of HDACs (SIRT1) as well as the forkhead transcription factors thus contributing to elucidate complex epigenetic mechanisms for cancer preventive actions of VD

Analysis of SNPs and Haplotypes in Vitamin D Pathway Genes and Renal Cancer Risk

In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR), most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC) etiology. RCC cases (N = 777) and controls (N = 1,035) were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P) tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP) sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02) and retinoid-X-receptor-alpha (RXRA) (p-value = 0.10) were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991) across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09–1.57) haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3′ of the coding sequence (rs748964, rs3118523), increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings

Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation

Background: Estrogen receptors alpha (ERa) and beta (ERb) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERb being able to modulate the effects of ERa on gene transcription and cell proliferation. ERb is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERb in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. Results: Expression of full-length ERb in hormone-responsive, ERa-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERb and 6024 ERa binding sites in estrogen-stimulated cells, comprising sites occupied by either ERb, ERa or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERb+ vs ERb- cells, 424 showed one or more ERb site within 10 kb. These putative primary ERb target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERb binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. Conclusions: Results indicate that the vast majority of the genomic targets of ERb can bind also ERa, suggesting that the overall action of ERb on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell

Modelling species responses to extreme weather provides new insights into constraints on range and likely climate change impacts for Australian mammals

Conservation of species under climate change relies on accurate predictions of species ranges under current and future climate conditions. To date, modelling studies have focused primarily on how changes in long‐term averaged climate conditions are likely to influence species distributions with much less attention paid to the potential effect of extreme events such as droughts and heatwaves which are expected to increase in frequency over coming decades. In this study we explore the benefits of tailoring predictor variables to the specific physiological constraints of species, or groups of species. We show how utilizing spatial predictors of extreme temperature and water availability (heat‐waves and droughts), derived from high‐temporal resolution, long‐term weather records, provides categorically different predictions about the future (2070) distribution of suitable environments for 188 mammal species across different biomes (from arid zones to tropical environments) covering the whole of continental Australia. Models based on long‐term averages‐only and extreme conditions‐only showed similarly high predictive performance tested by hold‐out cross‐validation on current data, and yet some predicted dramatically different future geographic ranges for the same species under 2070 climate scenarios. Our results highlight the importance of accounting for extreme conditions/events by identifying areas in the landscape where species may cope with average conditions, but cannot persist under extreme conditions known or predicted to occur there. Our approach provides an important step toward identifying the location of climate change refuges and danger zones that goes beyond the current standard of extrapolating long‐term climate averages

Evaluating 318 continental-scale species distribution models over a 60-year prediction horizon: what factors influence the reliability of predictions?

Aim Species distribution models (SDMs) are currently the most widely used tools in ecology for evaluating the suitability of environments for biodiversity in the face of future environmental change. In this study we seek to provide an assessment of the predictive performance of SDMs over time. How well do SDMs predict for future time periods and what factors influence predictive performance? Innovation We used a historical spatially explicit database of 1.8 million occurrence records for 318 tetrapod species from across continental Australia over the period 1950–2013. We fitted distribution models for each species to data from four multi‐decadal time slices and used these to predict the species distributions up to 60 years after the data collection period for the fitted models. We evaluated predictions against observed data from the relevant time period. Predictions were made assuming either complete knowledge of changes in climatic and environmental conditions or assuming the environment and climate remained unchanged between the fitting and evaluation time periods. We used generalized linear mixed models to model variation in the predictive performance of SDMs over time in relation to a variety of factors, including the length of time between fitting and evaluation, species traits, taxonomic group and attributes of the dataset used to fit models. Main conclusions We found that most models provided useful predictions even when the period between model fitting and evaluation was 60 years (area under the receiver operator characteristic curve > 0.7 in 80% of the species evaluated). Variation in predictive performance over time was strongly related to the species range breadth (models for species with broad geographical ranges tended to perform worse than models for locally restricted species) and to the environmental coverage of occupancy data. Conversely, taxonomic group, habitat preferences and body size were not highly influential in describing the variation in predictive performance over time

Temporal Changes in Socio-Ecological Systems and Their Impact on Ecosystem Services at Different Governance Scales: A Case Study of Heathlands

Heathlands are considered biodiversity hotspots of high conservation interest. However, they are at risk of degradation and disappearance in most parts of Europe mainly due to land abandonment, degradation, and conversion to other land uses. Heathlands are semi-natural systems: their maintenance and survival depends on specific practices such as extensive grazing or burning. Traditionally they provide a wide range of goods and services to societies. In this study we used the ecosystem services (ES) framework to analyze the changes in the demand for and delivery of ES for the heathland landscapes of the Cantabrian Mountains (NW Spain), since the 1950s. Particularly, we analyzed how the social changes since the 1950s have determined changes in stakeholders' demand for provisioning, cultural and regulating services and how these changes have influenced the vegetation dynamics and conservation status of these systems. We identified a general shift from the provisioning of grazing facilities and local products for the local-regional market to the provisioning of conservation services to satisfy national-international demand. For the present situation we found a clear mismatch between the conservation demand, management practices, and land-use forms. This mismatch threatens to lead to further landscape changes and loss of biodiversity. The results of our multi-scale and -services study can help to increase awareness of the value of currently obtainable benefits from heathlands among stakeholders and managers. The ES approach can improve understanding of the functioning of the socio-ecological heathland system, and inform the development of new management strategies for heathland protection