Principal Investigator Rudolf Jaenisch
The involvement of DNA methylation in cancer has been controversial: both hypomethylation as well as hypermethylation have been associated with malignant transformation. When the MTase mutation was introduced into mice with a genetic predisposition to colon cancer, a surprising result was seen: the MTase enzyme level directly correlated with the development of cancer. This argued that the MTase enzyme itself may act as an oncogenic determinant and may be a potentially attractive drug target for cancer prevention and treatment.
Genomic hypomethylation is a widely observed and early step in human tumorigenesis. Using different mutant alleles of the Dnmt1 gene we have shown that hypomethylation results in a substantial increase in the genomic mutation rates, the mutations being caused by enhanced mitotic recombination. These results are significant as they may explain the selective advantage of hypomethylation in early stages of transformation: hypomethylation leading to genomic instability may provide the incipient tumor cell with a mechanism to efficiently delete tumor suppressor genes by LOH. Indeed, the great majority of mice carrying a hypomorphic Dnmt1 allele develop aggressive thymic tumors. Our results indicate that therapeutic inhibition of Dnmt1 may prevent some forms of cancer such as intestinal tumors, but may promote cancer in other tissues. Therefore, to assess the consequences of Dnmt inhibitors as potential cancer drugs, it will be crucial to define the role of hypomethylation in diverse tumor models as Dnmt inhibitors may have opposite effects on cancer incidence when arising in different tissues. The MTases Dnmt3a and b are the best candidates to cause the silencing of tumor suppressor genes by de novo methylation. We have generated mice carrying conditional alleles of Dnmt3a and Dnmt3b that are being introduced into mice prone to develop intestinal and prostate cancer to directly test their role in carcinogenesis.