Alea Mills utilizes a technique of “chromosome engineering” (reviewed in Mills and Bradley, 2001, Trends Genet 17: 331) to develop mouse models that can be used for cancer gene mapping and evaluation of cancer therapy regimens. Using a Cre/loxP-based recombination strategy, defined chromosome deletions and inversions can be generated in the mouse genome. Mouse strains generated from this approach can be analyzed to identify regions that, when copy number is reduced from two to one, display an increased risk for developing tumors, providing functional evidence for a tumor suppressor in the area. These regions are then further dissected to map the gene(s) contributing to the cancer phenotype.
Dr. Mills focused on mouse chromosome 4, a region syntenic with human chromosome 1p. Many human tumors are known to contain deletions at 1p, suggesting that genes underlying the tumorigenic process are located in this region of the genome. Using her chromosome engineering technique, Dr. Mills narrowed the candidate region on chromosome 4 to a single gene, CHD5. CHD5 is a novel tumor suppressor that appears to act as a master switch for (the p53?) tumor suppressive network. The existing evidence that deletions of this chromosomal region are found in many different types of cancer, coupled with the key role of CHD5 in regulating the (p53) pathway can explain a role for this gene in a large number of diverse forms of human cancers.
To determine whether CHD5 has a similar tumor suppressor function in human cells, Dr. Mills collaborated with Dr. Hannes Vogel and Dr. Markus Bredel at Stanford University. They found that glioma, a specific form of brain tumor, frequently had a deletion of CHD5, arguing for a role of CHD5 in human cancer.