Novel Approaches to Breast Cancer Prevention and Inhibition of Metastases
Technical Report,30 Sep 2014,29 Sep 2015
IMBA-INSTITUTE OF MOLECULAR BIOTECHNOLOGY Vienna Austria
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Technologies such as transcriptional profiling, genome sequencing, SNP mapping, epigenetic, proteomic or metabolomic profiling have resulted in large sets of genome wide data. However, most of these datasets are of correlative. Functional and phenotypic annotation of the genome is thus a key challenge for a fundamental understanding of physiology and disease pathogenesis. We combine fly genetics with haploid ES cell mutagenesis and in vivo mouse genetics to functionally characterize candidate breast cancer genes. Using mouse genetics, we have now shown that inactivation of RANK markedly delays and in some cases even prevents the development of BRCA1-mutant breast cancer, providing a rationale for cancer prevention trials in BRCA1 carriers using RANKL blockade. We also performed a near-genome wide screen in Drosophila for genes that control tumor progression, allowing us to identify multiple novel tumor suppressor genes. Finally, we have now generated more than 100000 murine haploid ES cell clones targeting 16500 different genes. We also developed new methods to generate blood vessels from haploid ES cells which allows us to genetically explore novel factors for tumor angiogenesis. One of these factors, Apelin, indeed cooperates with VEGFR signaling and, in mutant mouse models, appears to be a key regulator of tumor neoangiogenesis and survival in breast cancer.