Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580
D-69120 Heidelberg, Germany.
| Functional
Genome Analysis (B070) Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580 D-69120 Heidelberg, Germany. |
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| Pancreatic Cancer |
Breast Cancer | Ovarian Cancer | Other tumour entities |
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| - EU network MolDiagPaCa |
- DNA-methylation | - Lethality screens | - Epigenetic studies | |||
| - NGFNplus consortium PaCaNet |
- MicroRNA studies | - Epigenetic studies | ||||
| - Drug & compound effects | - Transcriptional profiling | |||||
| - SNPs & mutations |
- Protein expression | Archive | ||||
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Pancreatic
Cancer
...  Pancreatic
ductal
adenocarcinoma remains one of the most difficult cancers to treat. It is the
commonest cancer affecting the exocrine pancreas and is one of the
major causes
of cancer death. There are approximately 28,000 deaths per year in the
USA... Hence, intense efforts have been made to identify persons at risk for pancreatic cancer. In multiple studies only smoking has consistently been identified as relevant environmental risk factor for pancreatic cancer. Also, a number of hereditary syndromes such as familial pancreatic cancer, hereditary pancreatitis and the Peutz Jeghers syndrome are associated with an increased risk for pancreatic cancer. Another major focus of the recent years has been the identification of percursor lesions for pancreatic cancer. Recently, an international expert committee classified these precursor lesions on the basis of histological criteria, into three grades of Pancreatic Intraepithelial Neoplasia (PanIN; for detailed information on the PanIN classification see http://pathology.jhu.edu/pancreas_panin). ... It is expected that global differential genetic analyses on the genome, transcriptome and proteome level of precursor lesions, early and advanced tumours may help to identify molecular patterns associated with the individual progression stages. Combined with innovative diagnostic approaches such as molecular imaging technology or detection of minimal amounts of marker genes in secretions, these analyses will create the tools that are necessary to devise early diagnostic strategies for patients at risk. Equally important, the collection of aberrantly expressed genes and proteins generated by such analyses may prove instrumental to the identification of targets for innovative chemoprevention strategies, which may in the future replace the current only curative treatment option (surgery) by a pharmacological approach. ... We pursue a global analysis of pancreatic cancer at the local, national and international level. Locally, we have formed a strong collaboration with Nathalia Giese at the Surgery Department of Heidelberg University Clinics headed by Prof. Markus Büchler. At the national level, there are several bilateral collaborations and we participate in the NGFN Translational Genome Research Network Pancreatic Cancer (PaCaNet). Internationally, we are partner in the EU integrated project Molecular Tools for the Prevention and Diagnosis of Pancreatic Cancer (MolDiagPaCa). ... Transcriptional analyses yielded interesting information for the identification of malignancy factors or possible new routes of therapy. This kind of analysis is continued also beyond the two major network approaches presented below. In addition, we combine data from mRNA profiling with results of mutational and epigenetic analyses, microRNA profiling, protein expression and protein-protein interaction studies. |
NGFNplus
Translational Genome Research Network Pancreatic
Cancer
 ...
...  Virtually
every pancreatic cancer
patient will die within the first year after diagnosis, making
pancreatic
cancer the The genome project has generated knowledge and technology with great potential to contribute to the understanding of the molecular pathogenesis in the pancreas and to provide molecular targets. However, even though multiple genome scale screening approaches of pancreatic tumours and their preneoplastic lesions have been conducted, only few targets have reached the level of preclinical or clinical applications. The fact that the tumour is hard to study in humans due to its particular anatomical and histopathological characteristics, the lack of well characterised clinical resources, and in particular the limited availability of valid in vitro and mouse models of the disease have been rate limiting steps so far. The PaCaNet consortium is an Integrated Genome Research Network comprising groups who (i) set the standards of clinical care and histopathology of pancreatic cancer and its precursor lesions, (ii) have pioneered the use of high-throughput genome technology in pancreatic research, (iii) have generated in-vitro and in-vivo models of the disease and (iv) were among the first to transfer individual target genes or groups of target genes into preclinical and clinical applications. These German centers of excellence in pancreatic cancer research are now joined by genome research groups and partners from the pharmaceutical industry in an integrated approach for an efficient characterisation and exploitation of genome project candidate genes for pancreatic cancer. The prime objective is to foster the rapid development and transfer of novel genome-based, molecular targeted therapeutic and diagnostic approaches from basic research, over preclinical testing into clinical applications. The workplan will be conducted at several levels of research: ... - Level 1: Platforms: data, patients, resources, models - Level 2: Functional characterisation in human in vitro and mouse in vitro and in vivo models - Level 3: Preclinical testing in mouse models of pancreatic cancer - Level 4: Clinical testing ... For more details see the PaCaNet webpage. |
| RECENTLY FINISHED PROJECT: Developing novel molecular tools for the prevention and diagnosis of pancreatic cancer ...
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Epigenetically
de-regulated miR-375 is involved in a positive feedback loop with
Estrogen Receptor alpha in breast cancer cells
 Breast cancer is the leading cause of cancer death in women worldwide. Although it is a heterogeneous disease, two-thirds of breast cancers share the common feature of being dependent on the presence and interaction of estrogen with the nuclear Estrogen Receptor α (ERα) protein. Approximately 70% of invasive breast cancers express ERα in actively proliferating cells. It has become evident that ERα is up-regulated in luminal mammary epithelial cells during early stages of tumorigenesis and its overexpression is an important stimulatory factor for proliferation of mammary cells, leading to cell division and eventually to tumor development. The obvious role of ERα signalling in orchestrating the expression of genes involved in growth-related pathways, has established ERα as an important therapeutic target in breast cancer treatment. However, our understanding of the molecular mechanisms underlying deregulation of this signaling pathway is scarce. ... We identified a high expression of microRNA 375 (miR-375) in ERα-positive cell lines. miR-375 overexpression is mainly caused by the loss of epigenetic marks, such as H3K9me2 and local DNA hypomethylation, which, in turn, triggers the dissociation of the transcriptional repressor CTCF from the promoter and enables interactions of ERα with regulatory regions of miR-375. Inhibition of miR-375 in ERα positive MCF-7 cells results in reduced ERα activation and cell proliferation. A combination of expression profiling from tumour samples and miRNA target prediction identified RASD1 as a potential miR-375 target. Our findings show that miR-375 regulates RASD1 through targeting its 3' UTR. In addition, we demonstrated that RASD1 negatively regulates ERα expression. Our data indicate the existence of a positive regulation between ERα and miR-375 and suggest new strategies for the treatment of ER-positive invasive breast tumours. de Soza Rocha Simonini et al. (2010) Cancer Res. 11, 162-167. |
 Focussing
on hormone-independent breast cancer: chemical and genetic-synthetic
lethality screens About two-thirds of breast cancer patients do not respond to endocrine therapy either because they do not express the drug target gene product, the Estrogen Receptor (ER) α protein, or develop drug-resistance during treatment. These patients are therefore being treated, for the most part, by untargeted chemotherapeutics. These patients tend to develop metastases, and therefore face an aggressive disease with high mortality. In collaboration with the group of Dani Canaani, we decided to take advantage of the recent generation of several human breast carcinoma cell lines belonging to Triple-Negative subclass among the ERα-deficient breast cancer patient groups. Using these cell lines for expression of genetic elements that specifically inhibit expression of the host cell endogenous genes, we are trying to identify lead compounds and human genes whose ablation lead to synergistic cell death of breast carcinoma cells deficient in ERα expression. The strength of these screenings stems from their relatively unbiased manner as well as the fact that they select for the desired phenotype cell death, which can be further tested in vivo by using the same cell systems in mouse models for human tumour growth and metastasis formation. Therefore, this work may broaden the range of both breast cancer therapeutic drugs and targets. RNAi screens via pooled short hairpin RNAs (shRNAs) have recently become a powerful tool for the identification of cell essential genes. Using commercially available lentiviral vector shRNA libraries and a novel method to decode pooled RNAi screens, namely barcode tiling array analysis, we could precisely quantify the abundance of individual shRNAs, clearly outperforming the commonly used analysis via the shRNAs’ half hairpin sequences. We used the technique to predict anti-proliferative effects of individual shRNAs from pooled negative selection screens. Out of a pool of 305 shRNAs, we identified 28 shRNAs to impair fully or partially the viability of the breast carcinoma cell line MDA-MB-231, for example. Böttcher et al. (2010) BMC Genomics 11, 7.  Böttcher& Hoheisel (2010) Curr. Genom., in press. |
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