Carcinogenesis

Cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes that control cell physiology and division. Mitotic recombination has been estimated to be the underlying cause of LOH 25-50% of the time (Gupta et al., 1997; Morley et al., 1990; Zhu et al., 1992). In collaboration with Prof. Bevin Engleward (BED, MIT), we will combine genetic engineering with mechanico-optical engineering to develop the technology to detect genetic instability in mammals. A transgenic mouse will be engineered to carry a fluorescent marker for identification of cells that have undergone a mitotic recombination event. A high-throughput two-photon microscope system will make it possible to quantify recombinant cells in situ in a variety of cells, to characterize the cell types most prone to mitotic recombination, and to discern the contribution of recombination events that occur in stem cells. Yet another important application will be in studying the effects of cancer chemotherapeutics on mitotic recombination and in determining how specific genetic traits effect cellular susceptibility to chemotherapy-induced mitotic recombination. It is hoped that this line of research will ultimately aid in pharmacogenomics. This new technology will be of fundamental importance in revealing genetic and environmental processes that drive cancer-promoting mitotic recombination events in mammals.