Cancer develops as a consequence of genetic and epigenetic changes and much evidence indicates that tumorspecific gain or loss of genomic DNA methylation may play a prominent role in both. However a clear picture has not yet emerged to explain the role(s) of methylation in neoplasia since both global hypomethylation as well as regional hypermethylation changes are found regularly in the same tumor. It is the aim of this proposal to determine which of these mechanisms operates in neoplasia arising in four different tissues and whether the methylation changes which are regularly seen in cancer are causallyrelated or are merely a consequence of other cellular insults that occur during the transformation process. Our approach involves the precise alteration of genomic DNA methylation levels by either inactivation or overexpression of the major mammalian DNA methyltransferases (MTases) Dnmtl and Dnmt3 in specific tissues of tumorprone mice. We will test the following four hypotheses which link DNA methylation and cancer each of which may be of selective advantage to the incipient tumor cell hypermethylation may cause (i) silencing of tumor suppressor genes and/or (ii) induce point mutations; hypomethylation may (iii) increase expression of oncogenes and/or (iv) cause genomic instability. Because methylation changes of genes leading to altered expression are in contrast to mutations reversible DNA MTases have become attractive drug targets for cancer treatment or prevention. Indeed previous results established that inhibition of Dnmtl either by genetic or pharmacological means can act synergistically in vivo to prevent intestinal tumor formation. However DNA MTase inhibitors are not without potential risks as inhibition of Dnmtl resulted in significantly higher somatic recombination (LOH) in ES cells and an increased lymphoma incidence in otherwise normal mice. Therefore information as to the potential benefits and risks of therapies which target DNA MTases is vital and our aim is to assess the consequences of methylation changes on tumor incidence in different tissues. The role of methylation in transcriptional regulation has not yet been defined although it is known to be essential for normal vertebrate development. To investigate a possible causal relation between methylation and gene control we will compare gene expression in matched cell lines where due to inducible Dnmtl deletion the genome is either normal or hypomethylated.
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