Gene Expression Responses to Oxidative Stress

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DESCRIPTION (provided by applicant): Many toxic agents induce oxidative stress along with other toxic effects, and it is often uncertain how these mechanisms interact to cause pathology. In this research, the toxicant doxorubicin (DOX) will be used as a model for dissecting pleiotropic toxic effects. DOX is a chemotherapeutic that both inhibits topoisomerase II and causes oxidative damage. Using DNA microarrays, the gene expression profile of generalized cellular stress will first be characterized in cell lines treated with diverse, well-characterized toxicants (i e protein synthesis and transcription inhibitors, etc ). Then, profiles associated with topo-II inhibition and oxidative stress will be identified using toxicants known to induce these effects specifically These profiles will be used to interpret the microarray profiles of DOX treated cells. Statistical analyses will identify changes specific to DOX treatment and oxidative stress. Basal and luminal breast epithelial cell lines with distinct characteristics (+/- p53) will be studied to assess the effect of genetic background of the cell on toxicity. The in vitro data for DOX response will be compared to an existing library of in vivo gene expression from a breast tumor cohort where samples were collected before and after DOX treatment. This will allow translation of the findings into substantial contributions to understanding of the role of oxidative stress in the cytotoxicity of DOX.