Lipocalin 2 expression is associated with aggressive features of endometrial cancer

Background: Increased expression of lipocalin 2 (LCN2) has been observed in several cancers. The aim of the present study was to investigate LCN2 in endometrial cancer in relation to clinico-pathologic phenotype, angiogenesis, markers of epithelial-mesenchymal transition (EMT), and patient survival. Methods: Immunohistochemical staining was performed using a human LCN2 antibody on a population-based series of endometrial cancer patients collected in Hordaland County (Norway) during 1981-1990 (n = 256). Patients were followed from the time of primary surgery until death or last follow-up in 2007. The median follow-up time for survivors was 17 years. Gene expression data from a prospectively collected endometrial cancer series (n = 76) and a publicly available endometrial cancer series (n = 111) was used for gene correlation studies. Results: Expression of LCN2 protein, found in 49% of the cases, was associated with non-endometrioid histologic type (p = 0.001), nuclear grade 3 (p = 0.001), >50% solid tumor growth (p = 0.001), ER and PR negativity (p = 0.028 and 0.006), and positive EZH2 expression (p < 0.001). LCN2 expression was significantly associated with expression of VEGF-A (p = 0.021), although not with other angiogenesis markers examined (vascular proliferation index, glomeruloid microvascular proliferation, VEGF-C, VEGF-D or bFGF2 expression). Further, LCN2 was not associated with several EMT-related markers (E-cadherin, N-cadherin, P-cadherin, β-catenin), nor with vascular invasion (tumor cells invading lymphatic or blood vessels). Notably, LCN2 was significantly associated with distant tumor recurrences, as well as with the S100A family of metastasis related genes. Patients with tumors showing no LCN2 expression had the best outcome with 81% 5-year survival, compared to 73% for intermediate and 38% for the small subgroup with strong LCN2 staining (p = 0.007). In multivariate analysis, LCN2 expression was an independent prognostic factor in addition to histologic grade and FIGO stage. Conclusion: Increased LCN2 expression is associated with aggressive features and poor prognosis in endometrial cancer

Integrated Genomic Analysis of the 8q24 Amplification in Endometrial Cancers Identifies ATAD2 as Essential to MYC-Dependent Cancers

Chromosome 8q24 is the most commonly amplified region across multiple cancer types, and the typical length of the amplification suggests that it may target additional genes to MYC. To explore the roles of the genes most frequently included in 8q24 amplifications, we analyzed the relation between copy number alterations and gene expression in three sets of endometrial cancers (N = 252); and in glioblastoma, ovarian, and breast cancers profiled by TCGA. Among the genes neighbouring MYC, expression of the bromodomain-containing gene ATAD2 was the most associated with amplification. Bromodomain-containing genes have been implicated as mediators of MYC transcriptional function, and indeed ATAD2 expression was more closely associated with expression of genes known to be upregulated by MYC than was MYC itself. Amplifications of 8q24, expression of genes downstream from MYC, and overexpression of ATAD2 predicted poor outcome and increased from primary to metastatic lesions. Knockdown of ATAD2 and MYC in seven endometrial and 21 breast cancer cell lines demonstrated that cell lines that were dependent on MYC also depended upon ATAD2. These same cell lines were also the most sensitive to the histone deacetylase (HDAC) inhibitor Trichostatin-A, consistent with prior studies identifying bromodomain-containing proteins as targets of inhibition by HDAC inhibitors. Our data indicate high ATAD2 expression is a marker of aggressive endometrial cancers, and suggest specific inhibitors of ATAD2 may have therapeutic utility in these and other MYC-dependent cancers

An 18-gene signature for vascular invasion is associated with aggressive features and reduced survival in breast cancer.

AIMS: Vascular invasion by tumor cells is known to be important for cancer progression. By microarray and qPCR analyses, we earlier identified an 18-gene signature associated with vascular involvement in endometrial cancer. Here, we explored the significance of this vascular invasion signature in multiple series of breast cancer patients. METHODS AND RESULTS: The study includes 11 open access gene expression data sets which collectively provide information on 2423 breast cancer patients. The 18-gene signature showed consistent associations with aggressive features of breast cancer, like high tumor grade, hormone receptor negativity, HER2 positivity, a basal-like phenotype, reduced patient survival, and response to neoadjuvant chemotherapy. Also, the vascular invasion signature was associated with several other gene expression profiles related to vascular biology and tumor progression, including the Oncotype DX breast cancer recurrence signature. CONCLUSIONS: The 18-gene vascular invasion signature showed strong and consistent associations with aggressive features of breast cancer and reduced survival

Association between the 18-gene signature score and response to treatment (mean signature score is given).

1<p>Near-complete pathologic response,</p>2<p>Pathologic complete response,</p>3<p>No response,</p>4<p>Partial respons,</p>5<p>Mann-Whitney U test,</p>6<p>Residual disease.</p

Multivariate survival analysis (Cox' proportional hazards regression model) of the vascular invasion signature score.

1<p>Adjusted Hazard ratio,</p>2<p>95% confidence interval,</p>3<p>Lratio test, Final model after inclusion of: ⁴Vascular invasion score, histologic grade and molecular subtype or ⁵Vascular invasion score and molecular subtype.</p><p>Data presented for disease specific survival, overall survival and recurrence free survival.</p

Associations between ER-status, PR-status, HER2-status and the 18-gene vascular invasion signature score (mean signature score is given).

1<p>Mann-Whitney U test, significance level 0.05.</p

High Vascular Invasion Signature score is associated with reduced recurrence free survival.

<p>High signature score is associated with reduced recurrence free survival in data sets GSE1456, GSE2506 and GSE20685. In data set GSE7849, there is a trend between high signature score and reduced recurrence free survival. Survival curves are estimated by the Kaplan-Meier method (log-rank significance test). For each category, the number of cases is given followed by the number of breast cancer deaths.</p

Transition Pathways for the Farmed Salmon Value Chain: Industry Perspectives and Sustainability Implications

Publisher´s version / Útgefin greinSalmon is the most consumed farmed seafood in the EU and there is no indication that demand will abate. Yet salmon aquaculture’s environmental impacts are significant, and its future is likely to be shaped by demands of increased but at the same time more sustainable production. This study developed an integrated theoretical framework based on the multi-level perspective (MLP) and a global value chain (GVC) governance framework and applied it to the global farmed salmon value chain. The objective was to provide insights on the most likely transition pathway towards sustainability based on industry and expert perspectives. The perceptions on challenges and drivers of change, were gathered through focus groups and in-depth interviews, and fitted to the integrated framework to facilitate the transition pathway analysis. Viewing the qualitative findings in the context of the MLP framework provided information about the current workings of the system, the drivers of change in the socio-technical landscape and niche-innovations and their potential to challenge or enhance the current system and thus indicated possible system transitions. To emphasize the role of industry actors in shaping the future of the salmon value chain, the analysis was strengthened using the GVC model which added information about power relations, signaling the ability of system actors to motivate or resist change. The findings indicate that, due to resistance in the regime and the fact that niche-innovations are not yet sufficiently developed, the farmed salmon value chain will continue to be predominated by traditional sea-based aquaculture but that there will be a gradual shift towards more diversity in terms of production methods in response to landscape pressures. The discussion addresses sustainability challenges and policy implications for the farmed salmon value chain and highlights the need for a food system perspective.Peer Reviewe