Dr. Fulton has previously demonstrated that breast tumor- associated macrophages induce mutations in bacteria, and both DNA strands breaks and drug resistance in mouse mammary tumor cells. These activities are mediated by reactive oxygen species. She has further demonstrated that 8-hydroxyguanine (8-OH-G), which is an indicator of oxidative DNA damage, is present in metastatic murine mammary tumors, and hypothesizes that macrophages present in situ stimulate tumor progression via oxidant stress. The following specific hypotheses are to be tested in this application. (1) Macrophage-induced tumor cell oxidant stress results in specific DNA damage. To test this hypothesis, normal mammary gland, preneoplastic lesions, mammary tumors with various metastatic potentials, and human breast cancers, will be examined for the presence of 8-OH-G, and a determination will be made if oxidant stress or macrophages induce 8-OH-G in cultured mammary tumor cells. (2) The second hypothesis to be tested is that cytokines that modulate macrophage function alter tumor target cell oxidative injury.
This aim will focus on the ability of IL-10 to alter tumor growth and metastatic potential, macrophage infiltration into mammary tumors and 8-OH-G levels in the tumors. (3) The final hypothesis to be tested is that sublethal oxidant stress leads to tumor progression through specific oxidant responsive genes. In this aim, Dr. Fulton will use differential hybridization to identify genes whose expression is modulated by oxidant stress, and determine if these genes can alter metastatic potential.
