Highlights of my 25-plus year research career in studying the environmental and genetic basis of cancer include: 1) Discovered a causal role for p53 in tumor cell invasion and metastasis. 2) Discovered that p53 is a major barrier to ionizing radiation induced carcinogenesis. 3) Discovered synthetic lethality between DNA repair genes DNA-PK and Atm, the first such example in mammals and predating the current interest in synthetic lethality in cancer research by many years. 4) Co-discovered that p27 is a tumor suppressor gene. 5) Discovered the first example of a haploinsufficient tumor suppressor, thus modifying one of the central dogmas in cancer research (e.g. Knudson’s two hit hypothesis). The concept of tumor suppressor haploinsufficiency is now firmly integrated in the field of cancer genetics. 6) Discovered a novel p53 independent apoptotic pathway that is regulated by DNA-PK. 7) Most recently I have pioneered the application of proteomics to mouse models of cancer for early detection research. 8) A new direction for my laboratory is to apply functional genetics using RNA interference to identify mechanisms of toxicity of genotoxins and to pinpoint potential therapeutic targets.
Using primarily chemical or radiation-induced cancer models I have extensively analyzed the role of the p53 signaling pathway, including Hras, Atm, DNA-PK, and p19/Arf in tumor suppression, DNA damage response and apoptosis. I have experience with a number of cancer models, including skin, liver, colon, small intestine, lung, breast, and lymphoma. Collectively, this highlights my experience in the genetic and biologic analysis of carcinogenesis, the interplay between oncogene signaling and tumor suppressor genes, and my experience in multiple tumor models